Responsive Polymeric Nanotherapeutics

CHAPTER

RESPONSIVE POLYMERIC NANOTHERAPEUTICS

2 Daniela Pamfil and Cornelia Vasile

Physical Chemistry of Polymers Department, Romanian Academy, “Petru Poni” Institute of Macromolecular Chemistry, Iasi, Romania

2.1 INTRODUCTION The stimuli-responsive nanobiomaterials constitute a highly active area of current research located at the interface between materials science, biotechnology, and medicine. The presence of different characteristics between unhealthy and normal cells has inspired researchers to synthesize nanomaterials with actions at a specific site which show great potential in the pharmaceutical and biomedical fields (Prasad et al., 2018). Although the applicability of stimuli-responsive polymeric nanosystems in the biomedical field is no longer a novelty, it is essential, and new research seeks to utilize the design and problem to address the challenges in biomedical practice, such as carriers for targeted drugs and gene delivery, cell culture, tissue engineering, bioseparation, biosensing, regenerative medicine, diagnostics, and therapy (e.g., neurological and cancer diseases) (Lale and Koul, 2018). Because of the controllable interactions with the surroundings, nanoparticles (NPs) are able to achieve the responsiveness of the systems, which usually is not possible at a macroscopic scale (Liu et al., 2017). When used in drug delivery, stimuli-responsive nanosystems can achieve better control over drug release, leading to not only better therapeutic effects but also reduced or no adverse effects (Torchilin, 2014). Intelligent polymers have emerged as strong candidates in biomedical applications and are not just limited to natural polymers but also a wide range of synthetic polymers (Hosseini et al., 2016). Stimuli-responsive polymeric nanosystems capable of altering physical or chemical properties (volume, color, and shape) can be actuated by an appropriate stimulus, whether endogenous or exogenous stimuli (Fig. 2.1). The exogenous stimuli, also called external or artificial stimuli, are represented by the electric and magnetic fields, light [ultraviolet (UV), visible, and near-infrared (NIR)], heat, and ultrasound (US). The physiological stimuli include temperature, pH, redox potential, or biological stimuli, such as enzymes, adenosine triphosphate (ATP), reactive oxygen species (ROS), glutathione (GTH), and glucose. Stimuli-responsive polymeric systems can be obtained in most types of known nanostructures, as NPs, nanogels (NGs), micelles, nanocapsules, and nanovesicles, nanoliposomes modified with polymers (Blanco-Fernandez et al., 2014), etc. Smart materials can also be precursors for the fabrication of “smart nanofibers,” a type of fiber that can respond to stimuli and one that can be fabricated by conventional methods such as electrospinning (Bou et al., 2016). High surface-to-volume ratio and the capability to recapitulate the native ECM architecture make electro-conductive Polymeric Nanomaterials in Nanotherapeutics. DOI: https://doi.org/10.1016/B978-0-12-813932-5.00002-9 © 2019 Elsevier Inc. All rights reserved.

67

68

CHAPTER 2 RESPONSIVE POLYMERIC NANOTHERAPEUTICS

FIGURE 2.1 Types of stimuli for responsive polymeric nanosystems. Adapted from Jiang, T., Jin, K., Liu, X., Pang, Z., 2017b. Chapter 8: Nanoparticles for tumor targeting. In: Sougata, J., Sabyasach, I. M., Subrata, J. (Eds.), Biopolymer-Based Composites, Drug Delivery and Biomedical Applications. Elesevier, pp. 221
267; Cheng, R., Meng, F., Deng, C., Zhong, Z., 2015. Bioresponsive polymeric nanotherapeutics for targeted cancer chemotherapy. Nano Today 10 (5), 656
670.

nanofibers an ideal platform for cell culture, tissue engineering, drug delivery, and biosensor applications (Jalili-Firoozinezhad et al., 2017). Different types of stimuli (i.e., pH, temperature, light, or redox reactions) can be used to stimulate these structures and induce permeability changes, disintegration, aggregation, swelling, and/or adsorption in a reversible or irreversible manner (Stuart et al., 2010).

2.2 EXTERNAL STIMULI-SENSITIVE NANOSYSTEMS

69

2.2 EXTERNAL STIMULI-SENSITIVE NANOSYSTEMS The exogenous stimuli are completely dissociated from the patient’s physiology and can be precisely controlled externally in magnitude, in space, and in time (Li et al., 2017c). The advantages of the external stimuli-responsive nanosystems include: • • •

Used for applications in areas that can be inaccessible to conventional drug delivery systems (e.g., in the brain) or where it is impractical to use endogenous stimuli; Minimal invasiveness, fewer side effects, and rapid recovery; Flexible equipment that allows precise control and accurate remote control.

Stimulation is a critical technique in treating diseases and investigating tissue functions. Traditional electrical stimulation uses electrodes to directly create intervening electric fields in the immediate vicinity of the tissues. Second generation stimulation techniques directly use light, magnetic fields, or US in a non-contact manner (Wang and Guo, 2016).

2.2.1 ELECTRICAL-RESPONSIVE POLYMERIC NANOSYSTEMS One stimulus which has long attracted attention is the application of an electric potential, and most electro-responsive systems reported to date have been based on intrinsically conducting polymers (CPs; Zhao et al., 2016). Among the advantages of using this stimulus are: low cost, simplicity, and portability of the control equipment. Electrically responsive nanosystems can be obtained from organic and/or inorganic materials. The organic material can be divided in two categories, respectively: (1) ionic (in which the electro-responsiveness is a result of an electric field-driven mobility of free ions to create a change in the local concentration of the ions in solution or within the material) and (2) dielectric electro-active polymers [the deformation is induced by electrostatic (Coulombic) forces developed between two electrodes], which comprises dielectric elastomers and electrostrictive polymers (Manouras and Vamvakaki, 2017). Ionic polymers require low actuation voltages but suffer low deformations and response rates, while they also normally operate in wet conditions, whereas dielectric polymers exhibit a fast response and high deformations and operate in dry conditions, but require high activation fields (Romasanta et al., 2015). The ionic electro-active polymers include: CPs, ionic polymers, and polymer gels. CPs are organic polymers which show a semiconducting nature with the electrical conductivity of conductors (Kondawar and Agrawal, 2013). Examples of such polymers are: polyacetylene, poly(pyrrole) (PPy), polyaniline, polythiophene, poly(phenylene vinylene), polyparaphenylene, polyparaphenylenevinylene, poly(3,4-ethylenedioxy-thiophene), and polyphenylacetylene. Polyelectrolytes include synthetic and natural polymers which contain a relatively high concentration of ionizable groups along the backbone —which are similar to the pH-responsive polymers: hyaluronic acid (HA), chondroitin sulfate, agarose, carbomer, xanthan gum, and calcium alginate, acrylate and methacrylate derivatives, and poly(sodium 4-vinylbenzene sulfonate) (PSS). Stimuli-responsive nanocapsules (100
400 nm) have been obtained by self-assembly of the noncovalent interactions of cyclodextrin (CD)-grafted dextran (Dex) polymers (host) and complementary ferrocene or azobenzene carriers (guest) (Wajs et al., 2016). The encapsulation and release

70

CHAPTER 2 RESPONSIVE POLYMERIC NANOTHERAPEUTICS

FIGURE 2.2 Drug loading into and release from the GO/PPy nanocomposite. Reprinted from Weaver, C., LaRosa, J., Luo, X., Cui, X., 2014. Electrically controlled drug delivery from graphene oxide nanocomposite films. ACS Nano 8 (2), 1834
1843, with permission from American Chemical Society; all rights reserved.

properties of the nanocapsules by applying electrochemical or light stimulus were reversible and could be repeated several times, indicating that the prepared nano-assemblies are very stable. These nano-sized carriers have great potential in stimuli-responsive drug-delivery carriers, cosmetics, or other biomedical applications. Electro-responsive drug release can be performed with various platforms including electroresponsive nanostructures, electro-responsive compound-loaded nanostructures, and the combination of electro-responsive materials with other stimuli-responsive vehicles, such as temperature or magnetic (Karimi et al., 2016a). In addition, nano-sized reservoirs can act as depots for increasing drug loading, without compromising responsiveness. Weaver et al. (2014) described an electrically controlled drug-delivery nanocomposite based on graphene oxide (GO) nanosheets incorporated into a CP (PPy) film. The nanocomposite is loaded with an anti-inflammatory molecule, dexamethasone, and exhibits favorable electrical properties. In response to voltage stimulation, the nanocomposite releases drug with a linear release profile and a dosage that can be adjusted by altering the magnitude of stimulation (Fig. 2.2). Ying et al. (2014) developed electro-responsive hydrogel NPs for targeted delivery of an antiseizure drug (phenytoin sodium). An increased degree of ionization in the structure was achieved under the influence of an electric field due to the presence of the polyelectrolyte PSS. The swelling ratio and the particle size could be tuned via the external electric field. In this study in vitro triggering and increased drug release with potential application in epilepsy treatment was shown. Two years later, they verified the electro-responsive characteristics directly in epileptic mice (Wang et al., 2016c). The antiepileptic drug-delivery nanocarriers (electro-responsive NPs) can penetrate the blood
brain barrier and subsequently release drugs and rapidly suppress neuronal discharges in a timely manner. Yuan’s group prepared redox-responsive polymer micelles based on host
guest interactions between β-CD functionalized PEG and ferrocene functionalized polylactide (PLA) or PCL. The application of an electric field led to the oxidation of ferrocene to ferrocenium and the dethreatening of the two polymers causing the micelle disassembly. The process is fully reversible upon the application of an opposite reductive voltage which leads to the reassembly of the micelles enabling the redox-controlled release of a model anticancer drug, paclitaxel (Feng et al., 2014; Peng et al., 2014).

2.2 EXTERNAL STIMULI-SENSITIVE NANOSYSTEMS

71

The electrical stimulation is widely used in drug-delivery systems but not so often in the gene transfection field. Therefore, remote-controlled gene delivery using electrical stimuli remain one of the most promising applications in biomedical and pharmaceutical applications.

2.2.2 MAGNETIC-RESPONSIVE POLYMERIC NANOSYSTEMS Magnetic nanoparticles (MNPs) have been intensively investigated for biomedical applications, such as drug/gene delivery, MRI for diagnosis, and magnetic fluid hyperthermia upon exposure to an alternating magnetic field (AMF) (Lee et al., 2011) (see Chapter 10). The use of MNPs incorporated into/on the surface of a nanosystem/nanomaterial is the way by which it can induce a change in the polymeric material morphology within an AMF. Moreover, MNP stability during storage and operation is improved and a proper surface coating of MNPs minimizes the nonspecific binding between MNPs and nontargets. The most common compounds, including organic cationic polymers and inorganic metals, which can be grafted onto the surface of MNPs to coat them through either ligand addition or ligand exchange, are 2,3-dimercaptosuccinic acids, catechol derivatives, polysaccharides (CS and N-acylated CS, cellulose, polyarabic acid), PEG, PNIPAm, PEI, poly(vinylpyrrolidinone), poly(L-Lys), cationic dendrimers, polymethacrylate derivatives, cationic liposomes, gold, silica, and carbon (Han et al., 2017; Li et al., 2017c). For biomedical applications, the surface modification of MNPs is applied to obtain magnetic nanomaterials with a sufficient degree of solubility and stability in the water phase. An external magnetic field is applied to guide the photosensitizer-loaded magnetic nanocarriers to the tumor site for improved treatment efficiency and reduced side effects (Ling and Hyeon, 2017). In particular, PNIPAm was used due to its tunable low critical solution temperature (LCST) temperature response. The hydroxyl-methylacrylamide component was used to crosslink and tune the LCST of the poly(NIPAm-co-HMAAm) to an appropriate working range for hyperthermia treatment (Kim et al., 2013). The combination of cancer drugs and the obtained smart hyperthermia nanofiber systems were shown to have a greater impact on cell apoptosis, with the advantage of controlled release using the AMF effect. Kurzhals et al. (2015) designed thermally and magnetically actuated core
shell NPs. NPs of 10 nm have been obtained by the encapsulation of superparamagnetic iron oxide (SPIO) cores in thermo-responsive PNIPAm polymer shells. It was demonstrated that local heating by magnetic fields can be used to efficiently and reversibly aggregate, magnetically extract NPs from solution, and spontaneously redisperse them. Temperature, US, and light external stimuli-responsive polymeric nanosystems are summarized in Table 2.1.

2.2.3 TEMPERATURE-RESPONSIVE POLYMERIC NANOSYSTEMS An externally applied temperature is effective due to the differences between the external environment and internal human body. Also, this stimulus is useful for producing local hyperthermia or hypothermia through physical means. The thermo-responsive nanosystems can be divided into two groups depending upon their critical temperature: positively [shrinkage occurs under upper critical solution temperature (UCST)] or negatively (shrinkage occurs above LCST) temperature responsive.

72

CHAPTER 2 RESPONSIVE POLYMERIC NANOTHERAPEUTICS

Table 2.1 Some Examples of External Stimuli-Responsive Polymeric Nanosystems Stimulus

Composition

Effects

References

Temperature

Micelle/PNIPAm-co-N,N dimethylacrylamide)-b-PDLLA

Intracellular uptake promoted by heating target area above micellar LCST of 39.4 C. Uptake above micellar LCST caused by enhanced interactions between micelles and cell membranes through dehydration of P(NIPAm-DMAAm) chains Irreversible sol-nanogel transition at body temperature (above LCST), deformation of micelle structure and drug release. DOX-loaded micelles effectively inhibited growth of tumor cells in vitro Possible shrinkage of the micellar aggregates with increasing temperature generated contraction stress for squeezing out dye molecules from the hydrophobic compartment. Decreasing micelle diameter with an increase in temperature, significantly enhanced release of Nile Red from micelles at 37 C vs that at 25 C under different pH conditions Temperature-dependent sol
gel transition which is a freeflowing solution at low temperatures and nonflowing; indometacin-loaded micelles exhibited controlled release in vitro, and significantly improved the anti-inflammatory effect of indometacin in rat arthritis models Polymeric micelles gradually dissolve due to hydrolysis of the lactic acid side groups. PTX-loaded micelles released B70% in 20 h at 37 C and at pH 7.4

Akimoto et al. (2010)

PEG, 1,3-bis(carboxyphenoxy) propane and sebacic acid

Y-shaped amphiphilic copolymers with two hydrophobic poly(solketal acrylate) branches and one mPEG2000 block

β-CD modified PCL-PEG-PCL copolymer

Copolymer of poly(N-(2hydroxypropyl) methacrylamide lactate) (PHPMA) and PEG

Zhao et al. (2010)

Yang et al. (2010)

Wei et al. (2013)

Rijcken et al. (2007a) and Soga et al. (2005)

2.2 EXTERNAL STIMULI-SENSITIVE NANOSYSTEMS

73

Table 2.1 Some Examples of External Stimuli-Responsive Polymeric Nanosystems Continued Stimulus

Composition PEG-b-poly(HPMA) diblock copolymers

Core-crosslinked HEMAm block copolymers derivatized with various monodispersed oligolactates and DOX derivative; actively targeted via conjugation of an antiepidermal growth factor receptor nanobody on the micellar surface Chitosan-g-PNIPAM NGs

Elastin-b-collagen-like peptide bioconjugate nanovesicles (average diameter of 100
200 nm)

Ultrasound Low frequency, 70 kHz

Pluronic 105

High frequency, 4 MHz

Methoxy PEG-b-PLDA

Effects Tunable biodegradability due to hydrolysis of the lactic acid side chains under physiological conditions. Crosslinking enables controlled release of the entrapped drug Excellent physical stability and a superior circulation profile compared to noncrosslinked micelles Increased tumor accumulation; increased cellular binding and uptake

NGs showed controlled delivery of curcumin into tested cells and dose-dependent cytotoxicity against cancer cells Targeted drug-delivery applications A thermo-responsive burst release was observed by dissociating the vesicles above the unfolding temperature of the collagen-like peptide domain, indicating the potential of using hyperthermia treatment for triggering the release of encapsulated drug Release of DOX from folatetargeted micelles increased as power intensity of ultrasound increased, maximum drug release (14%) at 5.4 W/cm2, drug release triggered by cavitation Twofold increase in intracellular PTX, decreased drug efflux, and greater cytotoxicity for ultrasoundtreated drug-sensitive as well as drug-resistant cell lines compared with no ultrasound treatment

References Talelli et al. (2010a) and Rijcken et al. (2005)

Rijcken et al. (2007b) and Talelli et al. (2010b, 2011)

Luckanagul et al. (2018)

Luo et al. (2017)

Husseini et al. (2013)

Sawant et al. (2011)

(Continued)

74

CHAPTER 2 RESPONSIVE POLYMERIC NANOTHERAPEUTICS

Table 2.1 Some Examples of External Stimuli-Responsive Polymeric Nanosystems Continued Stimulus

Composition

Effects

References

Low frequency, 20 kHz

Pluronic105-PEG2000-DSPE

Ugarenko et al. (2009)

30 s ultrasonic irradiation with 1 or 3 MHz ultrasound 1.1 MHz

mPEG2000-DSPE combined in a 1:1 ratio with Pluronic P105

High-power ultrasound release (7
10%) of DOX from mixed micelles, potential to form cytotoxic DNA adducts at tumor sites with coadministered formaldehyde-releasing drugs. Significant decrease in tumor volumes Enhanced accumulation; high frequency ultrasound (1 MHz)—better focusing on the tumor site and less damage to healthy tissues THPMA groups hydrolyzed, and caused the conversion of hydrophobic THPMA comonomer units into hydrophilic methacrylic acid

Enhanced gene transfer efficacy; increased the transfection rates up to 30% at concentrations 0.005%
0.1% Significant tumor regression related to enhancement of drug uptake by tumor cells; strong and long-lasting contrast under the effect of ultrasound for imaging Significant concentrationdependent US imaging contrast

Chen et al. (2006)

Azobenzene moieties inserted in the main chain. Micelle core formed by azobenzene undergoes reversible cis
trans isomerism due to polarity change UV irradiation converts linear trans-stilbene to bent cis form and this change of polarity reduces the hydrophobicity of the polymer causing micellar disruption to release encapsulated curcumin

Boissiere et al. (2011)

20 s at a power density of 1 W/cm2 Ultrasounds

Light

Water-soluble PEO block and a block of poly(2-(2methoxyethoxy)ethyl methacrylate) with incorporated labile 2-tetra hydropyranyl methacrylate (THPMA) comonomer units Pluronics F127, L61, and P85

DOX-loaded polymeric micelles (PEG-PLLA) and nanoemulsion droplets formed by perfluoropentane

SPIO NPs self-assembled with an amphiphilic CS derivative, carboxymethyl hexanoyl chitosan (CHC), to form CHC/ SPIO micelles, loaded with camptothecin, conjugated with albumin-based microbubbles PNIPAm-azobenzene-based micelles

Dialkoxycyanostilbene polymethacrylate-b-PEO

Gao et al. (2004) and Rapoport et al. (2004)

Xuan et al. (2012)

Rapoport et al. (2007)

Liu et al. (2013a)

Menon et al. (2011)

2.2 EXTERNAL STIMULI-SENSITIVE NANOSYSTEMS

75

Table 2.1 Some Examples of External Stimuli-Responsive Polymeric Nanosystems Continued Stimulus

NIR light

Composition

Effects

PEO-b-poly(4,5-dimethoxy-2nitrobenzyl methacrylate) with NaYF4. TmYb upconverting NPs (UCNPs) encapsulated in micelles. Nitrobenzyl groups on the micelle-core forming block undergo photocleavage Poly(2-ethyl-2-oxazoline)-bpoly(D,L-lactide) (PEOz-bPDLLA); photosensitizer: metatetra (hydroxyphenyl) chlorin (m-THPC)

Exposure to 980 nm (NIR) light caused UCNPs to emit photons in the UV region, which are absorbed by onitrobenzyl groups, activating photocleavage and dissociation of micelles to release coloaded Nile Red In vitro light exposure: 60 s (0.96 J/cm2), in vivo: single dose of 10 J/cm2 (652 nm light source), light spot diameter: 1 cm. m-THPC released under acidic conditions due to pHsensitivity of PEOz-b-PDLLA micelles. Phototoxicity in vitro and in vivo, with significantly reduced skin photosensitivity due to micelle encapsulation of photosensitizer UV light, photosolvolysis of the pyrenyl methyl esters caused cleavage of the ester bond 2-Nitrobenzyl esters lead to photo-controlled release from micelles

Amphiphilic diblock copolymer with PEO as hydrophilic block, linked to a hydrophobic polymethacrylate block bearing a pyrene moiety in the side group (PPy) via an ester linkage. Nile Red was incorporated into the PEO-bPPy micelles Dex-graft-DNQ amphiphilic copolymers

Poly(amido amine) dendron (D3) was used to form D3PCL-DNQ, and the propargyl was conjugated with sugartargeting groups (glucose and Lac) using click chemistry. Glucose/Lac-D3-PCL-DNQ amphiphiles formed micelles PEO and poly(L-glutamic acid) bearing a number of 6-bromo-7hydroxycoumarin-4-ylmethyl groups

References Yan et al. (2011)

Shieh et al. (2010)

Jiang et al. (2006) and Babin et al. (2009)

Azobenzenes can undergo trans
cis photoisomerization of (N 5 N) bond; intracellular delivery of DOX. Wolff inhibition of HepG2 cancer cells DOX occurred in a controlled manner; trigger release of rifampicin and paclitaxel from biocompatible

Boissiere et al. (2011), Liu et al. (2012), Jochum and Theato (2010)

NIR-induced removal of coumarin groups

Kumar et al. (2012)

Sun et al. (2010)

(Continued)

76

CHAPTER 2 RESPONSIVE POLYMERIC NANOTHERAPEUTICS

Table 2.1 Some Examples of External Stimuli-Responsive Polymeric Nanosystems Continued Stimulus

Composition

Effects

References

UV light (254 nm)

Block copolymers PEO-b-poly (n-butylmethacrylate-co-4methyl-[7-(methacryloyl) oxyethyloxy] coumarin); micelle-drug (5-FU) conjugates by covalent bonding

Biocompatible, photoresponsive, controlled release of 5-FU

Jin et al. (2011a,b)

Polymers showing an UCST in water are rare. Hence, it is hard to find any nanostructures made-up of polymers that exhibit UCST-type thermoresponsiveness in aqueous solution, however the most popular polymers are poly(N-acryloyl glycinamide), poly(acrylamide-co-acrylonitrile), poly(acrylic acid), and polymers with ureido groups (Biswas et al., 2017). The temperature-responsive polymers exhibiting LCSTs in the physiological range (30
40 C) attract a great deal of attention due to their potential biomedical applications, such as drug-delivery systems. The temperature in which the nanosystem is triggered should be kept at a maximum of 42 C, because at higher temperatures protein denaturation or function disruption occurs. Thermo-responsive nanofibers were prepared by electrospinning poly(hydroxylethylacrylate-cocoumaryl acrylate-co-ethylmethacrylate) (P(HEA
CA
EMA)) dissolved in methanol (Guo et al., 2016). The nanofibers were subjected to UV irradiation to crosslink the constituent copolymer chains. The release of a hydrophilic dye from UV-treated P(HEA
CA
EMA) nanofibers was suppressed below LCST (when the copolymer chains are hydrophilic and hydrated) and promoted above LCST due to the high thermodynamic activity of hydrophilic dye in nanofibers (when the copolymer chains are hydrophobic and dehydrated). The LCST varied from 20 C to 40 C, depending on the HEA/CA/EMA molar ratio. The electrospun thermo-sensitive nanofiber could be used as a drug carrier which can control the release of their hydrophilic payload in a temperaturedependent manner. There are different forms of thermo-sensitive nanotherapeutics like micelles, NGs, or NPs, dendrimers which possess specific characteristics of thermo-sensitive behavior. These forms will be further discussed and exemplified.

2.2.3.1 Thermo-sensitive micelles There are many types of block copolymers which are capable of micellization in response to stimuli. During these conformational changes, the therapeutic agents which could be entrapped in these structures would be released in response to stimuli (Mohamed et al., 2014). Due to the different triggered parts of amphiphilic block copolymers, thermo-sensitive polymeric micelles can be classified into two types: polymeric micelles with a thermo-sensitive outer shell and polymeric micelles with a thermo-sensitive inner core (Shao et al., 2011). For the first class, when the temperature is above the phase transition temperature, the structure of polymeric micelles becomes unstable caused by the shrinkage and hydrophobicity of the thermo-sensitive outer shell. The second class of micelles consists of hydrophobic blocks as the

2.2 EXTERNAL STIMULI-SENSITIVE NANOSYSTEMS

77

core played thermo-sensitivity. Once the temperature is above the LCST, the thermo-sensitive polymeric micelles are gradually destabilized due to hydrolysis of hydrophobic blocks. Thermo-sensitive micelles are prepared using blocks of thermo-sensitive polymers such as poly (N-isopropylacrylamide) (PNIPAm) and Pluronics. PNIPAm has a reversible and sharp phase transition at around 32 C below body temperature and the micelles with PNIPAm as a shell are expected to rapidly aggregate upon injection. Thus, it is not suitable for in vivo applications. The PNIPAm block copolymers also are not degradable and local hypothermia or hyperthermia is necessary for micellar destabilization and subsequent release of the encapsulated drug. To overcome these drawbacks the NIPAm was copolymerized with hydrophilic/biodegradable monomers to yield copolymers with an LCST above 37 C and/or that were biodegradable. P(NIPAm-co-acrylamide)b-(D,L-lactide) with an LCST of 41 C was used for the design of thermo-sensitive polymeric micelles for the triggered release of docetaxel by hyperthermia resulting in enhanced in vitro and in vivo effects (Yang et al., 2007). Another approach to develop thermo-sensitive polymeric micelles consists of polymerization of temperature-responsive hydrogels inside micelle cores forming NGs (Soga et al., 2005). As an example, the poly(propylene oxide) blocks of Pluronic P-105 and poly(N-alkylacrylamide) in Pluronic micelle cores were prepared. They exhibit a sharp reversible transition with a volume decrease (Husseini et al., 2002). In another approach, thermo-responsive Pluronic micelles were produced by crosslinking shells with gold NPs; the micelles exhibited reversible swelling/shrinking behavior during temperature cycling between 15 C and 37 C (Bae et al., 2006).

2.2.3.2 Thermo-sensitive nanogels Generally, stimuli-responsive NGs can be obtained by incorporating stimuli-responsive polymers or stimuli-sensitive units into their composition/structures (Pamfil and Vasile, 2018). The most important NG systems, from a biomedical point of view, are those sensitive to temperature and/or pH (Neamtu et al., 2017). Temperature can induce changes in a polymeric NG size by conversion from the swollen form (polymeric solution) to the collapsed form or vice versa. The swelling and collapse capacity of NGs is distinctive and provides multiple benefits for designing optimal drug loading and release of drugs. Thus, the NG networks allow the stimuli-controlled release of encapsulated biologically active compounds including drugs and other biopolymers. Temperature-responsive NGs can be prepared via different methods (Pamfil and Vasile, 2018; Karimi et al., 2016b). The techniques of reverse microemulsion combined with thermally induced gelation were used to prepare crosslinked κ-carrageenan hydrogel NPs (i.e., NGs). They were prepared via water-in-oil microemulsions with average diameters smaller than 100 nm. In a temperature range that was tolerable for living cells (37
45 C) the NGs were found to be thermo-sensitive with temperature-responsive reversible volume transitions (Daniel-da-Silva et al., 2011). Thermo-responsive CS-grafted-PNIPAm NGs were prepared by a sonication method, in which curcumin was encapsulated (Luckanagul et al., 2017). The
OH and
NH functionalities in chitosan (CS) NGs are prone to hydrogen bonding with curcumin as they have
OH as their terminal groups. NGs can deliver curcumin into tested cells and showed dose-dependent cytotoxicity against cancer cell lines. Recombinant silk-elastin-like protein polymers were used by Isaacson et al. (2017) for the first time in the synthesis of thermo-responsive NGs. The NGs respond to temperature stimuli via size changes and aggregation. The ratio and sequence of silk to elastin in the polymer backbone were

78

CHAPTER 2 RESPONSIVE POLYMERIC NANOTHERAPEUTICS

modified in order to obtain alterations in critical gel formation concentration, stability, aggregation, size contraction temperature, and thermal reversibility. The NGs sequester hydrophobic compounds and show promise in the delivery of bioactive agents. Positive thermo-sensitive NGs expand at elevated temperatures and collapse at reduced temperatures. A new class of polyelectrolytes, the so-called polymeric ionic liquids (ILs) or poly(ionic liquids) (PILs), was used for thermo-responsive NGs preparation. The thermo-responsive phase behavior of ILs/PILs was inherently derived from the noncovalent (hydrogen bonding) interactions between IL and solvents. In a recent study, IL-based monomers with hydroxyl- and carboxyl-groups, namely 1-vinyl-3-hydroxyethylimidazolium bromide and 1-vinyl-3-carboxyl methylimidazolium chloride, were prepared and copolymerized with crosslinkers (ethylene glycol dimethacrylate and azobisisobutyronitrile) in methanol to obtain NGs with sizes of less than 200 nm (Zuo et al., 2016). Owing to the H-bonding interaction between hydroxyl (carboxyl) groups, the as-prepared NGs are capable of reversible thermo-responsive performance. Their UCSTs could be tuned from 21 C to 40 C via the feed ratio of IL-based monomers and crosslinker. In addition, thermo-responsive NGs have been utilized in multi stimuli-responsive delivery systems, where thermo-responsive polymers were combined with other types of stimuli-responsive polymers or units, like pH-, glucose-, photo-responsive components (see Section 2.5).

2.2.3.3 Thermo-sensitive nanoparticles Thermo-sensitive polymeric NPs—nanospheres or nanocapsules (core
shell type)—have drawn attention as smart materials for biomedical applications due to their phase transition behavior in response to changes in temperature (Crucho, 2015). Novel thermo-sensitive folic acid-targeted succinylated poly(ethylene-co-vinyl alcohol) NPs were synthesized for the specific delivery of epirubicin to MCF-7 breast cancer cell line (Hassanzadeh et al., 2016). The optimized NPs had a particle size of 214 6 8.5 nm and a high encapsulation efficiency that released the drug efficiently within 450 h at a temperature of 40 C compared to 37 C. Thermo-responsive Pluronic/PEI nanocapsules were successfully synthesized by Park’s research group and exhibited a swelling/deswelling behavior over a temperature range of 24
33 C (Choi et al., 2006). The size of the nanocapsules decreased from 330 to 100 nm due to a temperature increase from 20 C to 37 C, and the volume transition was fully reversible. By applying a short cold-shock treatment, the Pluronic/PEI nanocapsules were able to break the endosome compartments within HeLa (human epithelial carcinoma) cells, delivering the siRNA cargo into the cytosol effectively (Lee et al., 2008). In a different manner, to release drugs in a site-specifically manner upon local heating (within a physiologically safe interval of 37 C and 42 C), Li et al. (2009) prepared novel thermo-sensitive polymeric NPs that were tailored to have an LCST suitable for localized hyperthermia. Polymeric NPs were self-assembled from poly(N,N-diethyl acrylamide-co-acrylamide)-block-poly(g-benzyl l-glutamate) as a carrier for PTX. PNIPAm grafting onto another polymer, such as a polysaccharide, is of greater interest than the copolymerization of NIPAm with other synthetic polymers, since the continuous stream of the PNIPAm chain can be broken, reducing the interaction between isopropyl groups above the LCST (Fundueanu et al., 2008, 2010). In this respect, thermo-responsive NPs of cashew gum grafted with

2.2 EXTERNAL STIMULI-SENSITIVE NANOSYSTEMS

79

NIPAm, with sizes ranged from 12 to 21 nm, have been synthetized (Abreu et al., 2016). In another study, a thermo-responsive graft copolymer was prepared by conjugation of amine-terminated PNIPAm with O-carboxymethyl chitosan through the grafting-onto method (Antoniraj et al., 2015). DOX-loaded polymeric NPs were fabricated using this copolymer.

2.2.3.4 Thermo-sensitive polymer-modified nanoliposomes To obtain excellent drug release kinetics and various thermo-sensitive functionalities, a strategy for preparing thermo-sensitive liposomes is conjugating thermo-sensitive polymers, as triggered parts of thermo-sensitive liposomes, in liposomal membranes (Hayashi et al., 1999). Thermo-sensitive polymers are fixed on liposomal membranes by anchors, which have hydrophobic side groups or amino groups at the end of the chain. The anchors can be connected randomly to the polymer backbone or specifically to the end of the polymer chain. Chountoulesi et al. (2015) focused on chimeric advanced drug-delivery systems based on thermo-sensitive liposomes, combining lipids and thermo-responsive polymers. In this investigation, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine chimeric liposomal systems were prepared, incorporating the homopolymer C12H25-PNIPAm-COOH and the block copolymer poly(n-butylacrylate-b-NIPAm), at six different molar ratios. A mucoadhesive-thermo-sensitive PEGylated-liposome was developed and proved to be able to protect the drug (opiorphin) and significantly enhance the extent and duration of its analgesic effect after intravenous administration to rats (Mennini et al., 2015). The mucoadhesive thermo-sensitive polymeric systems are fluid-like before nasal administration, and can be administered as drops, allowing high accuracy of drug dosage and ease of administration; however, they undergo a fast sol
gel transition at the temperature of the deposition site, so that the increased viscosity of the resulting gel system gives rise to an extended in situ residence time. A series of combinations of different mucoadhesive polymers (CS, hydroxypropylmethylcellulose, Poloxamer, Carbopol) in forming solutions able to rapidly form gel at the temperature of the nasal cavity were investigated (Mura et al., 2017). The optimized hydrogel formulation was based on a P407 (26.5%)
Carbopol (1%) combination, which presented the best compromise in terms of properly short gelation time at 34 C, i.e., the nasal cavity temperature (10 s), suitable gelation temperature (33.7 C), right gel strength, good mucoadhesive properties, and long mucoadhesion duration.

2.2.4 ULTRASOUND-SENSITIVE SYSTEMS The application of US offers the following advantages: noninvasiveness, deep penetration into tissues, ability to control and focus ultrasonic waves at tissues or tumor sites, enhanced drug absorption, and membrane permeability of drugs or genes (Husseini and Pitt, 2009). US-sensitive drug-delivery based on applying the local ultrasonic field is expected to be a more reliable method compared with the magnetic-sensitive drug delivery that is uncontrollable in drug release when triggered by magnetic fields. A noninvasive and external stimulus-driven local drug-delivery system based on titania nanotube (NT) arrays loaded with drug-encapsulated polymeric micelles as drug carriers and US generator was described by Aw and Losic (2013). The biological effects developed consist of the generation of thermal energy (hyperthermia), perturbation of cell membranes due to formation of oscillating or cavitating bubbles, and enhanced

80

CHAPTER 2 RESPONSIVE POLYMERIC NANOTHERAPEUTICS

permeability of blood capillaries. Responsive US micelles are obtained firstly based on Pluronic (Rapoport, 1999), which enhanced DOX release and lowered its IC50 by 12 times (Munshi et al., 1997). Non-Pluronic micelles such as PEG-co-poly(β-benzyl-laspartate) (Gao et al., 2005) and PLA-bPEG copolymer micelles (Zhang et al., 2009) have also been obtained for US-mediated drug release. The factors affecting US-triggered release of drugs from polymeric micelles are: time of application, frequency of the US, application of pulsed- versus continuous-wave US, power density, drug lipophilicity, and the concentration of drug and polymer (Marin et al., 2001; Husseini et al., 2000). Low-frequency US is more effective at drug release from micelles than high-frequency US (Marin et al., 2002). Low-frequency (20
100 kHz) US can penetrate deeper into tissue than high-frequency US (1
3 MHz), and is more appropriate for larger and deep-seated tumors, although it may damage healthy tissues owing to a strong cavitation effect, which may limit its use in the clinic. Highfrequency US is useful for small, superficial tumors (Marin et al., 2002; Rapoport, 2012). At high dilutions, the micelles disintegrated. To stabilize them highly hydrophobic cores or solid-like cores are created by crosslinking. Pluronic P105 micelles (PEG-diacyl phoshospholipids as mPEG2000-DSPE) have been crosslinked with N,N-diethylacrylamide (NNDEA) forming Plurogels (Gao et al., 2005). Polymer NNDEA is a thermo-responsive one with an LCST of 28 C. Below the LCST, in an expanded hydrophilic state, drug is loaded, while above the LCST, the interpenetrating network collapses into a tight hydrophobic core where the drug is entrapped (Pruitt et al., 2000). These stabilized Pluronic micelles released DOX in response to 70 kHz. The combination of polymeric micelles, ultrasonic tumor imaging, and chemotherapy has been studied (Liu et al., 2013a,b).

2.2.5 LIGHT-RESPONSIVE POLYMERIC NANOSYSTEMS As a highly orthogonal external stimulus, light enjoys wide usage in materials science, chemistry, biology, and drug-delivery systems because it possesses the unique ability to manipulate cellsignaling systems precisely. UV, visible, or NIR (Saneja et al., 2018) light can be used as external stimuli to spatially and temporally control and trigger drug release by disruption or local destabilization of micelles in the body. While the UV light is absorbed by the skin and does not penetrate deeply into the body, the NIR light penetrates more deeply through tissues (up to 10 cm) and water, has less harmful effects on healthy cells, and is therefore more suitable for tumor targeting (Alatorre-Meda et al., 2013). Some light-responsive drug-loaded nanosystems are single use, where light triggers an irreversible structural change with the aim of releasing the entire payload dose. Others are able to undergo reversible structural changes by applying light/dark cycles, behaving as multiswitchable carriers (the drug is released in a pulsatile manner) (Alvarez-Lorenzo et al., 2009). Light-responsive nanosystems are usually prepared by using inorganic NPs or by incorporating photochromic groups such as o-nitrobenzyl, SP, spirooxazine, azobenzene, pyrenylmethyl, DNQ, and coumarin into polymer backbone or side chain. Some light-responsive nanosystems are exemplified in Table 2.1.

2.2 EXTERNAL STIMULI-SENSITIVE NANOSYSTEMS

81

2.2.5.1 Light-sensitive micelles Light-responsive micelles designs suppose different chromophore or photo-responsive groups within the micelles as micellar core, shell, or at the core
shell interface (Gohy and Zhao, 2013). Micelle dissociation occurs due to the change in hydrophilic/hydrophobic balance as a result of photoreaction of the chromophore by reversibly changing the polarity of the hydrophobic polymer or the photoreaction leads to a structural change by irreversible cleavage of the chromophore from the hydrophobic block causing micelle destabilization. Micellar disruption occurs upon: (1) photoinduced cleavage at the junction of the hydrophilic and hydrophobic blocks; (2) photo-cleavable units by photoinduced degradation of the micelles; and (3) reversible photo-crosslinking reaction (Zhao, 2012). Polymeric micelles using spiropyran, dithienylethene, stilbene, and cinnamoyl derivatives dialkoxyanthracene (DN) have also been reported (Sawant and Jhaveri, 2014). Photodynamic therapy (PDT) combines the action of a photosensitizer (porphyrins, chlorins, and phthalocyanines) and a specific light source for the treatment of cancer. When a photosensitizer in excited state returns to the ground state, it releases energy, generating ROS-like singlet oxygen and free radicals that cause cellular toxicity. The mechanisms by which PDT can destroy tumors include (1) direct tumor cell killing; (2) ROS-induced damage to the vascular system and deprivation of nutrients and oxygen to tumors; and (3) immunosuppressive effects on the tumor.

2.2.5.2 Light-sensitive nanogels Hang et al. (2017) designed and developed NIR- and UV-responsive degradable HA NGs from HA-(7-N,N-diethylamino-4-hydroxymethyl coumarin) (HA-CM) conjugates for targeted and triggered intracellular DOX delivery. Both NIR and UV irradiation significantly enhanced DOX release by NG swelling and light-triggered cleavage of urethane bonds that connect CM to HA. These small-sized, negatively charged, and stable NGs, which have an average size of 40
80 nm in dry state and 147.2
165.4 nm in aqueous solution, have great potential for cancer chemotherapy. Self-assembled NGs in aqueous solution were designed as light-sensitive cholesteryl pullulan (Ls-CHP) substituted with photo-labile ortho-nitrobenzyl units (Nishimura et al., 2016) (Fig. 2.3). The NG-based film was obtained by evaporation of Ls-CHP solution. After light exposure, the light-sensitive units are cleaved, leading to decreasing of the physical crosslinking of the NG by decomposition with the formation of patterned film that can encapsulate insulin.

2.2.5.3 Light-sensitive nanoparticles Cui et al. (2011) reported the synthesis of polymeric NPs consisting of chitosan hydrochloride and photosensitive 4-oxo-4-(pyren-4-ylmethoxy)butanoic acid through ionic self-assembly. Due to the introduction of a photolabile chromophore group, these PNPs can disassemble under UV light or NIR and release guest molecules such as Nile Red. In recent work by Lv et al. (2012), a family of photodegradable polyurethanes was synthesized and self-assembled into NPs using an oil/water emulsion technique. The marine drug candidate

82

CHAPTER 2 RESPONSIVE POLYMERIC NANOTHERAPEUTICS

FIGURE 2.3 Chemical structure and illustration of a light-sensitive cholesteryl pullulan nanogel. Reproduced from Nishimura, T., Takara, M., Mukai, S., Sawada, S., Sasaki, Y., Akiyoshi, K., 2016. A light sensitive self-assembled nanogel as a tecton for protein patterning materials. Chem. Commun. 52 (6), 1222
1225, with permission of The Royal Society of Chemistry.

tagalsin G was successfully encapsulated, and photo-activation triggered the burst release of the bioactive compound to RAW 264.7 cells. Usually, polymeric NPs with diameter above 30 nm are easily prepared using several approaches. However, the preparation of smaller NPs is more challenging. A star-shaped azo-polymer has been obtained using olefin metathesis-based step-growth polymerization, called acyclic diene metathesis polymerization, that took place between acrylates and terminal olefins in the presence of multifunctional acrylates as the selective chain transfer agent. The obtained reactive star azo-polymers bearing terminal acrylate groups were converted into polymeric NPs with very small dimensions ranging between 17 and 32 nm and with interesting photoinduced reversible behavior transformations due to the presence of azo chromophore which underwent trans
cis
trans or cis
trans
cis isomerization cycles (Ding et al., 2016).

2.3 INTERNAL STIMULI-SENSITIVE NANOSYSTEMS

83

2.2.5.4 Near-infrared responsiveness In contrast to visible light, the NIR range (B70021000 nm) has less tissue scattering and blood absorption and less photo-damage for living organisms, and most importantly, it has much deeper tissue penetration than visible light (Zhang et al., 2016c). This can be accomplished using optical NPs exhibiting NIR absorbance. PPy, polyaniline, and poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate), which absorb NIR light, have acquired wide attention in recent times for their lower toxicity and better biocompatibility. A biocompatible zwitterionic block polymer—poly(2-methacryloyloxyethyl phosphorylcholine)b-poly(lipoic methacrylate)—has been involved in the preparation of gold NRs through a ligand exchange process in order to obtain a new nanomaterial for advanced biomedical applications which have low toxicity and high photothermal efficacy both in vitro and in vivo (Jiang et al., 2017a). The use of polymeric components in the synthesis of gold NR-based nanomaterials is very important when they are used as drug-delivery systems. To achieve sufficient drug-loading efficiency, gold NRs are chemically modified with drug carriers, including porous polymers and liposomes to deliver the cargo drugs (Kim et al., 2015). Data regarding the combining of NIR light stimuli with other stimuli such as pH in order to obtain dual stimuli-responsive nanosystems have been reported. PEG was involved in the nanomedicine design with pH- and NIR-light dual-stimuli responsiveness (Zhang et al., 2016b).

2.2.6 RADIATION NPs containing atoms of high atomic number (Z) are very sensitive to radiation and such nanosystems are useful for diagnostic purposes.

2.3 INTERNAL STIMULI-SENSITIVE NANOSYSTEMS: BIORESPONSIVE NANOTHERAPEUTICS Bioresponsive polymeric nanotherapeutics are mainly developed for targeted cancer chemotherapy. They do not require any external device, therefore their use will reduce the treatment cost and also improve patient compliance. Because the biosignals are unique to tumor or cancer cells, bioresponsive polymeric nanotherapeutics offer precision control over site, rate, and time of response. The bioresponsive polymeric nanotherapeutics offers superior therapeutic efficacy with decreased side effects. Some drawbacks include: (1) their development based on novel polymers, therefore the potential safety issues should be carefully tested; (2) bioresponsive polymeric nanotherapeutics show a slow response to the biosignals in the target site, leading to gradual and incomplete drug release and thereby reduced treatment efficacy. Nanostructures significantly impede the accessibility of biosignals including acid, enzyme, and GTH, showing lower bioresponsivity than expected; (3) some of the bioresponsive polymeric nanotherapeutics exhibit low stability and premature drug release in the circulation, which causes not only decreased therapeutic efficacy but also increased side effects in vivo; (4) if delivered to the wrong spot (e.g., healthy organs and cells) they might cause more significant detrimental effect than their nonresponsive counterparts. It is of critical importance that bioresponsive polymeric nanotherapeutics are selectively delivered to the target

84

CHAPTER 2 RESPONSIVE POLYMERIC NANOTHERAPEUTICS

FIGURE 2.4 Illustration of biosignals existing in the tumor extracellular microenvironments and cancerous cells. Reprinted from Cheng, R., Meng, F., Deng, C., Zhong, Z., 2015. Bioresponsive polymeric nanotherapeutics for targeted cancer chemotherapy. Nano Today 10 (5), 656
670, with permission from Elsevier.

tumor cells. In order to be applied in clinics, bioresponsive polymeric nanotherapeutics must be obtained from simple and well-established biocompatible and nonimmunogenic materials, such as natural polysaccharides, polyesters, polycarbonates, polypeptides, PEG, albumin, and small natural compounds (e.g., amino acids, lactic acid, cholesterol, vitamin C, etc.) with as little modification as possible. pH-responsive polymeric nanotherapeutics represent a valuable platform to realize triggered intracellular drug release (Meng et al., 2014b; Liu et al., 2014). Effective delivery of nanomedicines to tumor tissues depends on both the tumor microenvironment and nanomedicine properties. Tumor microenvironment modification or advanced design of nanomedicine should be taken into consideration to improve nanomedicine delivery to tumors (Zhang et al., 2016a). Bioresponsive polymeric nanotherapeutics facilitates tumor cell uptake and triggers drug release at the target site, which is safe and efficient in cancer therapy. In this case, the naturally occurring environment is characterized by tumor acidity (pH 6.5
7.2), tumor extracellular enzymes like MMP, endo (pH 5.5
6.8)/lysosomal pH lysosome (pH 4.5
5.5), elevated GTH levels in the cytoplasm and cell nucleus, lysosomal enzymes, as well as ROS in the mitochondria (Fig. 2.4). These act as potential internal stimuli to achieve active drug and protein release in the tumor tissue or cancer cells. The bioresponsive nanosystems do not need an external device, precision control over site of response led to the accumulation in the tumor via both passive and active targeting, and

2.3 INTERNAL STIMULI-SENSITIVE NANOSYSTEMS

85

spontaneous activation in the tumor site or inside the tumor cells (Cheng et al., 2015). For cancer therapy, nanotherapeutics confer prolonged circulation time, enhanced accumulation in the tumor sites via the enhanced permeability and retention effect, reduced drug side effects, improved drug tolerance, and better drug bioavailability. Although acidic endo/lysosomes elevated intracellular reducing potential, lysosomal enzymes and ROS are also present in healthy cells, the bioresponsive nanotherapeutics are able to specifically deliver drugs to the tumor cells, being superior to their non-responsive counterparts and could reverse multidrug resistance (Edinger and Wagner, 2010; Aili and Stevens, 2010).

2.3.1 TUMOR PH-RESPONSIVE POLYMERIC NANOTHERAPEUTICS pH is often used as the stimulus to invoke expansion because it can alter the protonation state of basic/acidic functionalities such as tertiary amino or carboxyl groups. Polymeric micelles, polymersomes, nanohydrogels, or other scaffolds loaded with these moieties can act as pH sensors whose hydrophobicity, conformation, or electrostatics are altered based on their protonation state (Blum et al., 2015). pH-sensitive micelles are obtained by using either pH-sensitive polymers bearing “titratable” groups such as amines or methacrylic acid, which display reversible protonation
deprotonation or pH-sensitive linkage cleavable bonds (hydrazine linkage) between the chemotherapeutic agents and the micelle-forming copolymers. The acid-sensitive bonds investigated inserted into the main chain, side chain, or at the terminal of the core-forming blocks or for the synthesis of the polymer
drug conjugates, are Schiff’s base, hydrazone, acetal, ortho ester, and oxime (Sawant and Jhaveri, 2014). Poly(L-His) with a pKa of around 6.5 is the most commonly used. Its imidazole ring provides pH-dependent amphoteric properties. It is ionized at the lower pH of the tumors or acidic intracellular vesicles such as endosomes and lysosomes. Poly(L-His) is able to induce an endosomal membrane disruption and interact with negatively charged membrane phospholipids. In order to achieve prolonged circulation time and enhanced tumor accumulation, nanotherapeutics are usually decorated by a nonfouling polymer like PEG or Dex. The pH-sensitive shielding/deshielding nanotherapeutics, which lose or change their charge at tumor pH, have been developed in order to enhance tumor cell uptake and cell internalization was achieved by using various polymer systems (Table 2.2). Tumor pH-activable fluorescent NPs are able to light up a broad range of tumors. pH-sensitive NGs based on poly(aspartic acid-g-imidazole)-poly(ethylene glycol) were obtained using linear PEG with different molecular weights (2000 and 4000 Da) as crosslinkers. The pHsensitive NGs showed reversible size changes during continuously alternating pH changes. The anticancer treatment potential of pH-sensitive NGs was studied using a model drug, irinotecan (IRI) (Sim et al., 2018). pH degradable polymeric NGs have been synthesized by self-assembly of amphiphilic block copolymers composed of a hydrophilic, PEG-like polymer block based on methoxy triethylene glycol methacrylate and a hydrophobic polymer block based on pentafluorophenyl methacrylate (PFPMA) (Nuhn et al., 2016). The PFPMA block allows for self-assembly into NPs in polar aprotic solvents followed by 1-(4-(aminomethyl) benzyl)-2-butyl-1H-imidazo [4,5-c] quinolin-4-amine (IMDQ) ligation and crosslinking of the PFP esters with bisamines. TLR7/8 agonists (agonists of toll-like receptors), used as activators of the innate immune system for anticancer immunotherapy,

86

CHAPTER 2 RESPONSIVE POLYMERIC NANOTHERAPEUTICS

Table 2.2 Examples of the pH-Sensitive Polymeric Nanotherapeutics pH-Sensitive Polymeric Nanotherapeutics Poly(L-His)-b-PEI and mPEG-bpolysulfadimethoxine Core
shell
corona polyion complex NPs ("NP/Pt@PPC-DA) from positively charged Pt(IV)-conjugated NPs ("NP/Pt) and tumor acidity-responsive negatively charged PPC-DA copolymer (PPC: PEG-bpoly(allyl ethylene phosphate) modified with cysteamine; DA: 2,3-dimethylmaleic anhydride)) Decorated PEG-b-PCL micelles with a tumor-pH activable TAT (transactivator of transcription) peptide by succinyl amidization of the primary amines Negatively charged poly(L-leucine)-poly(LLys)(DMA)-TAT(SA) micelles (DMA: 2,3dimethylmaleic anhydride; SA: succinyl chloride) PTX-loaded H7K(R2)2-PEG-PLGA micelles Poly(carboxybetaine) shell and sulfo groups near a DOX-loaded core mPEG-poly(Lys-3-diethylaminopropyl)2 miktoarm block copolymer loaded with chlorine6-tumor short-worm like PEG-b-poly(2-(diisopropylamino)ethyl methacrylate) copolymer

Methyl ether PEG-PAE block copolymer

PEG-poly(aspartate hydrazide) block copolymer. Hydrazide groups on side chains used as pH-sensitive binding linkers for drugs with ketone groups Micelles of asymmetric diblock and triblock copolymers of (methoxy)poly(ethylene oxide) and poly(acrylic acid)

Effects

References Hu et al. (2013) Yang et al. (2013)

Inhibited nonspecific interactions in the circulation; superior antitumor activity; very high tumoral DOX concentration and low cardiotoxicity comparatively with pHinsensitive TAT-PEG-PCL micelles Switched to positively charged NPs via hydrolysis of DMA amide in a narrow pH range increasing cellular uptake

Jin et al. (2013) and Han et al. (2015b)

Significant antitumor and antiangiogenic activity NPs for DOX delivery

Zhao et al. (2012) Wang et al. (2015b) Lee et al. (2014)

Super pH-responsive polymeric nanotherapeutics; improved phototoxicity

Han et al. (2015b)

Ultra pH-sensitive fluorescent NPs; showed a quenched fluorescence in the circulation; strongly activated in the tumor site due to fast dissolution and dissociation of NPs in response to tumor extracellular pH Sharp pH-dependent micellization/ demicellization at acidic tumor pH 6.4. Efficient release of drug/dye in acidic pH, 11-fold higher therapeutic efficacy in mice with pH-sensitive micelles compared to free drug or drug-loaded, non-pH-sensitive micelles Successful combination chemotherapy with DOX and 17-hydroxyethylamino-17demethoxygeldanamycin

Wang et al. (2013c)

The micelle formation/destruction in the copolymer solutions at pH alternation (micellar structures arising at pH , 5) is an important task in terms of their use as nanocarriers for drugs (α-tocopheryl acetate)

Permyakova et al. (2018)

Min et al. (2010)

Bae et al. (2010)

2.3 INTERNAL STIMULI-SENSITIVE NANOSYSTEMS

87

Table 2.2 Examples of the pH-Sensitive Polymeric Nanotherapeutics Continued pH-Sensitive Polymeric Nanotherapeutics

Effects

References

Mixed PLLA/PEG block copolymer with poly(L-His)-b-PEG and next they used folate or biotin specific ligands

Triggered release of adriamycin; pHdependent DOX release at tumor sites, inhibiting cancer cells growth and even metastasis Accelerated DOX release at acidic pH of 5.0, efficient internalization and high anticancer efficacy of micelles Cellular uptake of micelles enhanced under acidic conditions due to cleavage of PEG, greater accumulation and antitumor activity Increased cytotoxicity and efficacy of pHsensitive DOX micelles in HeLa cells

Lee et al. (2005) and Gao et al. (2011b)

Anticancer DOX was conjugated to glycopolymers by a pH-sensitive hydrazone linkage. The slow drug release at neutral pH and increased drug release in acidic environments demonstrated AuNP
DOX bioconjugates as promising drug carriers to improve intracellular drug release in the acidic environment of tumors

Yilmaz et al. (2018)

PEG-oxime tethered PCL-PEG oxime bonds imparted pH-sensitivity Stearic acid-g-CS modified with PEG via cis-aconityl linkage PEO-hyperbranched polyglycerol
DOX. DOX conjugated to PEO-hb-PG via an acidlabile hydrazone linkage Glycopolymer-coated gold nanoparticles

Jin et al. (2011a,b)

Hu et al. (2012)

Lee et al. (2012)

Sawant, R., Jhaveri, A., 2014. Chapter 3: Micellar nanopreparations for medicine. In: Torchilin, V. (Ed.), Handbook of Nanobiomedical Research: Fundamentals, Applications and Recent Developments. Northeastern University, Boston, MA, pp. 87
139.

were covalently ligated to the core of the NPs through amide bond formation between the primary amine of IMDQ and the activated PFP esters in the NP core. Conversion of residual pentafluorophenyl ester with 2-ethanolamine yielded fully hydrated NGs after transfer to the aqueous phase.

2.3.2 TUMOR EXTRACELLULAR ENZYME-RESPONSIVE NANOTHERAPEUTICS Specific enzymes, e.g., proteases [metalloproteinases (MMP)], glycosidases, and phospholipases are often involved in cancer invasion, progression, and metastasis, being present in high concentrations in the tumor tissue while they are absent or at very low concentrations in healthy tissues. These enzymes also influence the activity of nanocarriers. MMP-2-responsive nanocarriers such as micelles based on PEG-peptide-PEI-1,2-dioleoyl-sn-glycero-3-phosphoethanolamine copolymers were found to be effective in tumor targeting, cellular penetration, and enhanced cellinternalization (Zhu et al., 2013, 2014a). siRNA and paclitaxel (PTX) when dual drug-loaded were 2.4-fold higher for cell internalization than for an MMP-2 insensitive counterpart, showing enhanced in vitro and in vivo anticancer activity. The MMP-2/9 activatable low-molecular-weight protamine (ALMWP, E10-PLGLAG-VSRRRRRRGGRRRR) for enhanced glioblastoma therapy was used to modify biodegradable PEG-b-PCL NPs (Gu et al., 2013a). This modification reduced

88

CHAPTER 2 RESPONSIVE POLYMERIC NANOTHERAPEUTICS

by three to four times the half-maximal IC50 of PTX-loaded ALMWP NPs. By reversible addition fragmentation chain transfer (RAFT) copolymerization was obtained MMP-responsive N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-CXCR4 antagonist (BKT140) conjugate (P-BKT140) (Peng and Kopeˇcek, 2014) tested with good results for human prostate carcinoma cells. The hyaluronidase-responsive nanocarriers have been reported as PTX-loaded degradable cationic NGs (DpNG-PTX) based on acetylated pullulan and low-molecular-weight PEI (1.8 kDa) coated with HA, which exhibit deep tumor penetration and high antitumor effect (Yim et al., 2013). A self-assembled complex based on DOX, DNA, cationic gelatin, and human serum albumin, which removes its shell in response to the action of the gelatinase and Dnase I in the tumor microenvironment, was prepared (Zhu et al., 2014b). This complex assures an increased DOX accumulation in the tumor. G4 PAMAM dendrimer molecules were modified via covalently conjugating RGDC (Fmoc-arggly-asp-cys-SH), RAADyC (Ac-arg-ala-ala-asp-D-tyr-cys-NH2), and PEG chains on the periphery (Mac-1), by which an NG (with uniform size of 50 nm) drug carrier with enzyme sensitivity (NG-1) was constructed through an oxidation reaction by using NaIO4 to initiate the chemical crosslink of the functional groups on the periphery of dendrimers (Wang et al., 2016e). It was found that the obtained nanocarrier showed increased drug-loading capacity, sustained drug (e.g., DOX) release triggered by enzymes, and cytotoxicity to C6 cells.

2.3.3 ENDO/LYSOSOMAL PH-RESPONSIVE NANOTHERAPEUTICS Some pH-responsive polymeric nanotherapeutics can be internalized by tumor cells through endocytosis occurring at a low pH of 4.5
6.8. Because this pH is common for both tumor cells and normal cells, high selectivity is necessary to avoid the potential side effects. This can be achieved by using three strategies as presented in Table 2.3. The pH-sensitive polyelectrolytes can rapidly change their ionization under endo/lysosomal pH accompanied by modification in the molecular state and hydrodynamic diameter of the polymer chains. As a result, the nanotherapeutics is destabilized or dissociated and a fast intracellular drug release will occur. Such pH-responsive nanotherapeutics are prepared based on polyanions containing carboxylic acid or sulfonamide groups, as well as polycations containing imidazole pendant groups and PAE with tertiary amine groups (Gao et al., 2013). The second strategy consists of incorporation of acid-labile linkages such as hydrazone, acetal, ketal, cis-acotinyl, oxime, and orthoester in the main chains or side chains. Orthoester linkages are more sensitive towards acid-catalyzed hydrolysis than acetal and ketal linkages. The third strategy involves chemically conjugating drugs to polymer backbone via an acidlabile linkage. The acid-activatable prodrugs have the advantages of high stability and minimal drug leakage.

2.3.4 GLUTATHIONE-RESPONSIVE NANOTHERAPEUTICS Inside the cancer cells the reducing potential is about 100
1000 times higher than that in the extracellular spaces, which results in a reducing environment within the cell and an oxidizing environment in the extracellular space. This change in redox potential is attributed to the difference in

2.3 INTERNAL STIMULI-SENSITIVE NANOSYSTEMS

89

Table 2.3 Examples of the Endo/Lysosomal pH-Sensitive Polymeric Nanotherapeutic Endo/Lysosomal pH-Sensitive Polymeric Nanotherapeutic Micelles of PAE-based poly[(1,4butanediol)-diacrylate-b-5-PEI]-block-poly [(1,4-butanediol)-diacrylate-b-5-hydroxy amylamine] (PDP-PDHA) copolymer loaded with DOX Micelles of poly(2-ethyl-2-oxazoline)-poly (D,L-lactide) (PEOz-PDLLA) and cRGDyK-PEOz-PDLLA DOX-loaded cisplatin crosslinked Dexsuccinic acid conjugate PEG-poly(γ-propargyl L-glutamate) copolymers with pendant tertiary amine groups (PEG-PPLG-diisopropylamine/ diethylamine) Herceptin-conjugated pH-sensitive NPs from poly(D,L-lactide-co-glycolide)-poly(LHis)-PEG triblock copolymer Micelles obtained from PEG-b-poly(mono2,4,6-trimethoxybenzylidenepentaerythritol carbonate-co-acryloyl carbonate) (PEG-b-P(TMBPEC-co-AC)) and Gal-PEG-b-PCL copolymers and loaded with PTX

Acetalated α-CD PEG-poly(acetal urethane)-PEG triblock copolymer with multiple acetal bonds in the main chain Micelles-based ketal-containing poly (ketaladipate)-PEG block copolymer Acid degradable NGs based on poly (vinylcaprolactam), HPMA, and ketalcontaining 2,2-dimethacroyloxy-1ethoxypropane as a crosslinker DOX-loaded pH-sensitive amphiphilic sugar poly(orthoesters)-b-PEG NPs DOX-loaded pH-responsive micelles selfassembled from amphiphilic PEG-bpolymethacrylate diblock copolymer bearing acid-labile ortho ester side chains

Effects

References

Tumor inhibiting rate of 95.9%

Tang et al. (2014)

Enhanced cytotoxicity to prostate cancer cells

Gao et al. (2015)

Li et al. (2014d) Stable at pH 7.4; spontaneous destruction at pH 5, effectively suppressed tumor growth

Quadir et al. (2014)

80% and 60% of DOX were released in 8 h at pH 5.2 and 6.4, respectively; better in vitro cytotoxicity pH-sensitive degradable micelles; active targeting chemotherapy of hepatocellular carcinoma PTX release was inhibited at physiological pH and accelerated at pH 5.0 due to the hydrolysis of acetals in the core; significantly enhanced drug accumulation in the tumors; little damage to normal liver and kidney Decreased PTX resistance 96%, 73%, and 30% of drug were released within 48 h at pH 4.0, 5.0, and 7.4, respectively Rapidly dissociated at pH 5.4 leading to triggered release of CPT effective endosomal disruption Rapid and nearly complete DOX release at pH 5.0 while only about 13% of DOX was released at pH 7.4

Zhou et al. (2015b)

72% of DOX was released in 1 h and nearly 100% in 4 h, cytotoxicity is pHdependent High rate of DOX released

Li et al. (2015)

Zou et al. (2014)

He et al. (2013) Huang et al. (2015)

Lee et al. (2013a)

Wang et al. (2015a)

Tang et al. (2011)

(Continued)

90

CHAPTER 2 RESPONSIVE POLYMERIC NANOTHERAPEUTICS

Table 2.3 Examples of the Endo/Lysosomal pH-Sensitive Polymeric Nanotherapeutic Continued Endo/Lysosomal pH-Sensitive Polymeric Nanotherapeutic Acid-activatable prodrugs poly(styrene-comaleic anhydride)-hydrazone-DOX conjugates

pH-sensitive polymeric micelles based on PEG-b-poly(hydrazinyl-aspartamideMG132) conjugates containing hydrazone linkage between polyaspartate backbone and MG132 Dendronized heparine-Hyd-DOX conjugate NPs Folic acid
functionalized PEG-PCL-DOX micelles

Conjugation of PTX onto water-soluble PEG-b-poly(acrylic acid) (PEG-PAA) block copolymers via an acetal bond to the PAA block-micellar NPs PEO-block-polyphosphoester-graft-PTX (PEO-b-PPE-g-PTX), in which PTX was conjugated to PPE via the thiopropionate linkage Thin layer (10.3 6 1.4 nm) of PCL bioresponsive polymer coating was deposited on the surface of CPT anticancer-coated drug NRs

Effects

References

pH-responsive disulfiram and DOX prodrug-loaded micelles; DOX was released in a sustained and pH-dependent manner; effective combination therapy of DOX and disulfiram for drug-resistant MCF-7/ADR breast tumor xenografts Reduced side effects; increased therapeutic window by delivery of proteasome inhibitor MG132 into cancer cells

Duan et al. (2013)

80% of DOX released at pH 5.0; high antitumor activity in 4T1 breast tumor model Good stability at pH 7.4 and quick drug release at pH 5.0; prolonged the blood circulation time of DOX and enriched DOX into the tumors The release of PTX was found to be highly pH-dependent

She et al. (2013)

Five- to eightfold enhancement in the in vitro antitumor activity against OVCAR-3 and RAW 264.7 cells

Zou et al. (2013)

PCL on the surface of drug NPs protects drugs from degradation, allows the release of drugs at the target site because of biodegradation at acidic pH 6. Trastuzumab was conjugated to the NR surface for breast cancer cell targeting

Laemthong et al. (2016)

Quader et al. (2014)

Guo et al. (2013)

Gu et al. (2013b)

concentration of GTH in the cytoplasm (1
11 mM) from that in the plasma (about 10 μM), the concentration in tumor cells is elevated and is several times higher than in normal cells. GTH is a tripeptide of γ-glutamyl-cysteinyl-glycine acting as a biological reducing agent. The reductionbioresponsive NPs are systems developed to achieve targeted cytosolic drug and gene release (Sufi et al., 2018). They also assure high stability against hydrolytic degradation and a fast response to the intracellular reducing environment (Sawant and Jhaveri, 2014). The simplest approach for reduction-responsive nanocarriers is shell-sheddable micelles containing a disulfide bond between hydrophilic (like PEG and Dex) and hydrophobic blocks of

2.3 INTERNAL STIMULI-SENSITIVE NANOSYSTEMS

91

polypeptides (Ding et al., 2013), polyanhydride (Wang et al., 2014), polyesters (Ko and Oh, 2014), hexadecyl (Cui et al., 2013), and small hydrophobic molecules (Xu et al., 2014). The drug/DNA encapsulated in the nanocarrier is held together by disulfide (S
S) bonds under normal conditions. Once disulfide bonds (SS) are reduced to thiols due to the high GSH within cells the carrier is destabilized and can release the entrapped cargo (Torchilin, 2009; Ganta et al., 2008). The second approach consists of incorporation of multiple disulfide bonds in the main chain of the hydrophobic polymer or conjugation of drugs to the side chain of the polymer via multiple disulfide linkers. The third approach is a reversible crosslinking strategy able to construct reduction-responsive nanotherapeutics by crosslinking of the polymeric NPs with disulfide bonds, which renders nanotherapeutics particularly stable during circulation, while being prone to quick decrosslinking in the cytosol. Redox-sensitive micelles utilizing the crosslinking approach have been extensively investigated for delivery of small molecules and nucleic acids using core-crosslinked, shell-crosslinked, or micelles crosslinked at the core
shell interface (Li et al., 2011; Koo et al., 2012). Different possibilities to obtain reduction-responsive polymeric nanotherapeutics are presented in Table 2.4.

Table 2.4 Some Examples of Reduction-Responsive Polymeric Nanotherapeutics Reduction-Responsive Nanotherapeutics Atorvastatin calcium loaded mPEG-SSvitamin E succinate

Gal-decorated shell-sheddable micelles based on PEG-SS-PCL and Gal-PEGPCL block copolymers

Folic acid
functionalized shell-sheddable micelles based on 4-armPEG-SS-PCL copolymer Gal-PEG-PCL, PEG-PCL-poly(2(diethylamino)ethylmethacrylate) and PEG-SS-PCL Disulfide-linked glycol NPs (SS-GNs) with sheddable saccharide shells PCLgraft-SS-lactobionic acid copolymer DOX-loaded pullulan-SS-cholesterol NPs PEG-poly(Lys)-SS-CPT as reductionsensitive micelles α-Amino acid-based poly(ester amide)

PEG-b-poly(disulfide urethane)-b-PEG triblock copolymer micelles

Effects

References

Encapsulation efficiency of 99.09%; shell-sheddable micelles completely block the lung and liver metastasis of breast cancer with minimal toxicity; enhanced Ator accumulation in tumor and lung Release more than 75% of DOX in 12 h; cellular DOX level was much greater than that with reduction-insensitive PEGPCL/Gal20 and nontargeting PEG-SSPCL controls Better specificity and therapeutic efficiency

Xu et al. (2014)

Facile loading and triggered intracellular delivery of proteins

Wang et al. (2013b)

DOX-loaded SS-GNs exhibited high antitumor activity toward HepG2 cells; 18-fold higher nontoxicity Better antitumor effect and biosafety for hepatocellular carcinoma Prolonged blood circulation and high accumulation in urothelial carcinoma DOX-loaded enzymatically and reductively degradable NPs showed 10 times higher in vitro antitumor activity Efficiently transport and release DOX

Chen et al. (2014a)

Zhong et al. (2013)

Shi et al. (2014)

Li et al. (2014b,) Yen et al. (2014) Sun et al. (2015)

Lu et al. (2015) (Continued)

92

CHAPTER 2 RESPONSIVE POLYMERIC NANOTHERAPEUTICS

Table 2.4 Some Examples of Reduction-Responsive Polymeric Nanotherapeutics Continued Reduction-Responsive Nanotherapeutics Shell-crosslinked biodegradable micelles based on methoxy PEG-(cysteine)4PDLLA copolymer Bioreducible shell-crosslinked HA NPs based on HA-b-PCL block copolymers via disulfide linkages HA-Lys methyl ester-lipoic acid conjugates reversibly crosslinked HA NPs Disulfide-crosslinked NGs from watersoluble PEG-b-poly(HEMA-co-acryloyl carbonate) block copolymers Bioreducible NGs obtained by copolymerization of heparinmethacrylate derivative and cystamine bisacrylamide Disulfide-containing prodrug of CPT covalently linked to a polymer (CPT-SSPEG-SS-CPT)

HA
deoxycholic acid conjugates

Reversible disulfide-crosslinked micellar system, cysteine containing telodendrimers (a linear dendritic polymer composed of PEG and dendritic clusters of cholic acids) PEG-b-poly(L-Lys)-b-poly(L-phenyl alanine). Shell crosslinking by disulfide bonds (SS) Micelles based on green fluorescent protein-targeted siRNA reversibly modified with phosphothioethanol via a reducible disulfide bond; electrostatic association of siRNA with cationic carriers

Effects

References

Delivered sevenfold higher DOX drug to the tumor almost completely inhibited M109 tumor growth Effective in suppressing tumor growth among all the treatments

Lee et al. (2013b)

Prolonged circulation time and markably high accumulation in the tumor; effective inhibition of MCF-7/ADR tumor growth and increase of survival rate Loading efficiencies (up to 98.2%) of cytochrome C

Zhong et al. (2015)

High DOX loading content of 30% and a high loading efficiency of 90%

Wu et al. (2015)

PEG provided the hydrophilic component and CPT formed the hydrophobic portion disulfide linker and ester bond were incorporated between PEG and CPT which, when cleaved, generated native CPT due to ester degradation; pharmacological efficacy of CPT released Rapid drug release, increased uptake in breast cancer cells via HA-receptormediated endocytosis under reducing conditions in vitro; higher tumor-targeting capacity Targeted PTX delivery more efficacious for ovarian cancer; improved stability, prolonged circulation, preferential tumor targeting, and controlled release

Boissiere et al. (2011)

DTX for cancer therapy, enhanced efficacy after crosslinking

Koo et al. (2012)

50-fold effective, nontoxic, redoxsensitive micellar system, stable delivery of genes and siRNA. siRNA protected against degradation

Musacchio et al. (2010)

Han et al. (2015a)

Chen et al. (2013)

Liu et al. (2012)

Li et al. (2011)

2.3 INTERNAL STIMULI-SENSITIVE NANOSYSTEMS

93

Table 2.4 Some Examples of Reduction-Responsive Polymeric Nanotherapeutics Continued Reduction-Responsive Nanotherapeutics Antisense oligonucleotide conjugated to PEG with a disulfide linkage and assembled into polyion complex (PIC) micelles through complexation with branched PEI Disulfide-crosslinked PIC micelles from iminothiolane-modified PEG-block-poly (L-Lys) and siRNA Poly(ethylene glycol)-block-poly{N-[N(2-aminoethyl)-2-aminoethyl] aspartamide}; (PEG-SS-P[Asp(DET)]) with plasmid DNA, disulfide-crosslinked Supramolecular nanosystem based on PEG-β-cyclodextrin and a disulfidecontaining adamantine-terminated DOX prodrug

Effects

References

Plasmid DNA, antisense oligonucleotides, and siRNA delivery; active antisense oligonucleotide molecules released in cell interior

Takae et al. (2008)

Effective siRNA delivery; 100-fold higher transfection efficacy

Matsumoto et al. (2009)

Gene carriers by forming PEG-detachable

Kumagai et al. (2012)

Efficient codelivery of doxorubicin and sorafenib for treating hepatocellular carcinoma

Xiong et al. (2018)

2.3.5 LYSOSOMAL ENZYME-RESPONSIVE NANOTHERAPEUTICS Several lysosomal enzymes are known as glycosidases, proteases, and sulfatases. Lysosomal enzyme-responsive nanotherapeutics are constituted from copolymer
anticancer drug conjugates (Table 2.5). They are stable during circulation and are able to release drugs under the action of specific enzymes.

2.3.6 REACTIVE OXYGEN SPECIES
RESPONSIVE NANOTHERAPEUTICS ROS involved in physiological and pathological (atherosclerosis, aging, and cancer) processes are produced in the mitochondria from an incomplete reduction of oxygen and NADPH (nicotinamide adenine dinucleotide phosphate) oxidase (NOX) in the plasma membrane. Excessive amounts of ROS cause oxidative stress and damage to DNA, proteins, and lipids by oxidation. ROS-responsive nanocarriers (Table 2.6) have the ability of triggered hydrophilic/hydrophobic switch or cleavage of the ROS-sensitive bonds in the polymer chain destruction of the nanocarriers and facilitate drug release in tumor cells. ROS-responsive units, such as arylboronic ester, ferrocenyl, selenium, and thioether groups, are usually integrated into polymer for stimuli-responsive drug release.

2.3.7 ADENOSINE TRIPHOSPHATE
RESPONSIVE NANOTHERAPEUTICS It is well known that ATP, as the most abundant ribonucleotide in cells, exists in all living organisms, and the concentration of ATP changes in many key physiological and pathological processes (Gorman et al., 2007). ATP-responsive nanocarriers for codelivering drugs and genes have been

94

CHAPTER 2 RESPONSIVE POLYMERIC NANOTHERAPEUTICS

Table 2.5 Examples of Polymeric Lysosomal Enzyme-Responsive Nanotherapeutics Lysosomal Enzyme-Responsive Nanotherapeutics PHPMA copolymer
anticancer drug conjugates with lysosomally cleavable peptide spacers like GFLG (Gly-Phe-LeuGly tetra-peptide) Dual enzyme-responsive HPMA copolymer-DOX conjugates (P-DOXPLGLAG-iRGD), via GFLG linker mPEGylated dendron-GFLG-DOX conjugate NPs

Effects

References

Susceptible to cathepsin B

Kopeˇcek and Kopeˇckov´a, 2010

Enhanced tumor accumulation, penetration, and cytotoxicity in 2D and 3D prostate cancer cells Much faster drug release in the presence of papain; 80% vs 30% drug release in 15 h; improved proliferation inhibition against 4T1 murine breast cancer

Peng and Kopeˇcek, 2015 Li et al. (2014e) and Zhang et al. (2014c)

Table 2.6 Examples of ROS-Responsive Polymeric Nanotherapeutics ROS-Responsive Nanotherapeutics

Effects

References

Amphiphilic hyperbranched polyphosphates of alternative hydrophobic selenide groups and hydrophilic phosphate segments in the dendritic backbone 4-Phenylboronic acid pinacolester (PBAP) conjugated β-cyclodextrin (Ox-β-CD)

Fast intracellular DOX release under exclusive oxidative microenvironment within cancer cells

Liu et al. (2013b)

Antitumor potential of DTX was greatly enhanced with Ox-β-CD NPs in the presence of H2O2 Promptly release cisplatin; enhanced efficiency of cancer chemotherapy

Zhang et al. (2014a)

Hydrogen peroxide (H2O2) concentrationdependent drug release Antitumor effect by enhancing the cell apoptosis

Liu et al. (2015)

Micelles readily cleaved into free copolymers under reducing environment. Higher anticancer efficacy and faster DOX release from redox-sensitive micelles vs nonsensitive controls High stability and rapid destabilization of micelles in reducing conditions, GSHdependent cytotoxicity of DOX-loaded formulations in vitro Micellar rearrangement due to reductive cleavage of disulfide-linked PEG causes rapid release of encapsulated DOX. DOX release from micelles accelerated under increasing GSH concentrations

Sun et al. (2011)

H2O2-responsive nanocarriers constituted from PLGA NPs, catalase, and platinum anticancer agents SN38 was conjugated onto hydrophilic hyperbranched polyglycerol (HPG) via a H2O2-responsive thioether linkage resulting in HPG-2S-SN38 nanomicelles, which were encapsulated with cinnamaldehyde PEO-b-poly(N-methacryloyl-N0 (tbutyloxycarbonyl) cystamine) (PEO-bPMABC). Intermediate disulfide linkages in the core of micelles (formed by PMABC units) Hexa-arm star-shaped (6sPCL-SS-PEG). Intermediate disulfide linkages between the core and shell result in shedding of PEG shell under reductive conditions mPEG-SS-poly(ε-benzyloxycarbonyl-L-Lys)

Chen et al. (2014c)

Ren et al. (2011)

Wen et al. (2011)

2.3 INTERNAL STIMULI-SENSITIVE NANOSYSTEMS

95

Table 2.6 Examples of ROS-Responsive Polymeric Nanotherapeutics Continued ROS-Responsive Nanotherapeutics

Effects

References

Monomethoxy-poly(ethylene glycol)-SShexadecyl (mPEG-SS-C16). Disulfide bridge linkage between mPEG and C16 imparts redox sensitivity in reducing environment

Faster DOX release, significantly enhanced cytotoxicity and efficient internalization into HeLa cells along with DOX release in the cytoplasm and entry into nuclei for the redox-sensitive micelles compared to the nonredox-sensitive counterparts As arylboronic ester in the nanoprodrug was susceptible to H2O2, selective drug release could be realized at the tumor site and rearrangement of HPBA into quinone methide (QM) was supposed to attenuate the detoxication system in cancer cells via scavenging GSH, thus synergistically improving the therapeutic efficiency of CHL

Cui et al. (2013)

Nanoprodrug (120 nm) of antitumor agent, chlorambucil (CHL), by integrating CHL into a diols-containing polymer (PEG-gpoly (acrylic acid)) via self-immolative linker 4-(hydroxymethyl) phenylboronic acid (HPBA)

Luo et al. (2018)

successfully developed, based on the higher ATP concentration in the intracellular fluids (1
10 mM) than in the extracellular environment (,0.4 mM) (Gribble et al., 2000). ATP binding aptamers have been screened for gene delivery and sensing platform (Meng et al., 2014a). According to previous studies, the doxorubicin (DOX)
aptamer complex could effectively inhibit DOX release, while in the presence of ATP, the complex formation causes the dissociation of aggregates, which promotes the release of DOX in the environment with a high ATP concentration compared with that in ATP-deficient extracellular fluid (Mo et al., 2015). Cationic polymers, like polyethylenimine (PEI) (Wang et al., 2016a), have been involved in the preparation of stable complexes with ATP-responsive aptamer duplex (ARAD). The obtained nanocarrier displayed ATP-responsive controlled release of the anticancer drug (DOX) and high gene transfection efficiency. This preparation method, based only on electronic interactions and no chemical reactions or complex modifications, can be further applied to the design of analogous responsive nanocarriers, such as cytidine triphosphate (CTP), guanosine triphosphate (GTP), and uridine triphosphate (UTP) (Zuo et al., 2007; Huizenga and Szostak, 1995). Hybridized aptamer was found to enable the self-assembly of drug-conjugated polymer by forming a drug
conjugates
aptamer complex. Thus, in a recent study (Zhang et al., 2016d), ATP and pH dual-responsive active targeting NPs of 70 nm were formed through the intercalation effect between PEG-poly(aspartic acid)-DOX conjugates and hybridized aptamer in addition to the mere hydrophobic interaction among drug molecules like micelles.

2.3.8 GLUCOSE-RESPONSIVE NANOTHERAPEUTICS In glucose-responsive nanomaterials, the system responds to a change in the glucose concentration of the surroundings. This has a promising future in the application of diabetes treatment.

96

CHAPTER 2 RESPONSIVE POLYMERIC NANOTHERAPEUTICS

Recently, work on glucose sensitivity in physiological conditions has been widely reported and includes concanavalin (Chang et al., 2018), glucose oxide, and phenylboronic acid (PBA), but concanavalin and glucose oxide are both based on proteins and so exhibit certain defects, such as antigenicity, instability, and high cost. PBA-containing materials have been most widely studied and used in the construction of a glucose-responsive system. However, because the pKa of PBA is much higher than the pH of physiological conditions, most PBA are modified with other polymers. Biodegradable and biocompatible PNIPAm-based NGs were synthesized with nitrilo-triacetic acid and PBA as functional groups and ethylene glycol dimethacrylate (EGDMA) as crosslinker (Li et al., 2017a). The role of nitrilotriacetic acid groups was to specifically bind imidazolecontaining protein drugs such as insulin via chelated zinc ions, leading to an efficient loading of insulin. Glucose-triggered insulin release was achieved based on the glucose-responsiveness of PBA groups that caused the swelling of NGs. In another study, shell-crosslinked NPs were fabricated by the complexation of poly(3-methacrylamido phenylboronic acid) (PMAPBA) and thiolated chitosan via boronic acid-related reactions (Wang et al., 2016d). Owing to the crosslinking of the NP shell, insulin was encapsulated in the NPs, with a loading capacity of up to 18%. The release of insulin from the NPs slowed down because of the presence of disulfide bonds and increased with increasing glucose level in the medium.

2.3.9 INTERNAL THERMO-RESPONSIVE NANOTHERAPEUTICS The idea of internal thermo-sensitive systems came from the temperature difference between diseased and healthy tissues. Gota et al. (2009) reported polymer NGs obtained by emulsion copolymerization of NIPAm with a fluorescent methacrylamide derivative in the presence of a crosslinker, that can be used as intracellular thermometers. In this way, the intracellular temperature variations associated with biological processes can be monitored with a temperature resolution .0.5 C.

2.4 RESPONSIVE DENDRIMERS Smart dendrimers are more effective, more convenient, and much safer, showing constant release profiles for specific therapies. They respond either to endogenous (acid, enzyme, and redox potentials) or exogenous (light, US, and temperature change) stimuli, mainly because of assembly/disassembly into micelles by change in the balance between hydrophilic and hydrophobic units, driven by protonation/deprotonation, possess labile groups at the stimuli action, or can be conjugated with stimuli-activable ligands (acid labile, reduction-labile bonds) (Wang et al., 2016b). Responsive dendrimers proved to be more efficient in cancer drug or protein delivery, showing an interesting pH-responsive gene expression. Dendrimer
drug conjugates via acid-labile bonds such as hydrazone linkage, boronate ester bond, acid-labile amides, thiol-disulfide, enzyme-labile as specific peptide linkers and collagen, light-labile bonds (e.g., ortho-nitrobenzyl or visible light cleavable perylen-3-yl methanol group), which can be introduced in core, shell, or as a spacer between dendrimer and shielding ligands. pH-responsive dendrimeric nanosystems are stable against hydrolysis at physiological pH but are cleavable at extracellular acidity (pH 6.5
6.8), and the cancer drug release rate is accelerated

2.4 RESPONSIVE DENDRIMERS

97

after endocytosis of the prodrug by cancer cells (pH 5.0
6.0). The “off
on” drug release behavior improves the therapeutic efficacy and minimizes the adverse effects. PAMAM dendrimers were conjugated with different polymeric compounds, like PEG (Hu et al., 2016) or heparin (Nguyen et al., 2017), to obtain pH and redox dual-responsive drug nanocarriers (see Table 2.7) in order to achieve a long circulation time and effective intracellular drug release. pH-responsive dendrimers with embedded acetal repeating units and POSS core were obtained (Huang et al., 2016). The alkene-terminated dendrimer was produced by azo-Michael addition of octaamine polyhedral oligomeric silsequioxanes (POSS-[NH2]8) and acetal monomer N-(2-(1-(allyloxy)ethoxy)ethyl)acrylamide (AEEAA). Subsequently, the peripheral alkenes selectively reacted with the thiol in cysteamine hydrochloride to obtain amine-terminated dendrimers. Then, the second and third generations of dendrimers were prepared by alternately adding AEEAA and cysteamine hydrochloride accordingly. Their rich surface functionalities could be conveniently modified by PEG or zwitterion, producing acid-labile amphiphiles that could assemble into micelles and nanofibers. Zhang et al. (2017) obtained PEGylated lysine peptide dendrimer
hydrophilic gemcitabine (GEM) conjugates with enzyme-responsiveness. The small drug GEM was conjugated to the PEGylated peptide dendritic polymeric scaffold owing to the GFLG, an enzyme-cleavable linker. The prepared NPs (80
110 nm) were able to release GEM significantly faster in the tumor cellular environments, which specifically contains secreted Cathepsin B, quantifiably more than 80% GEM was released with Cathepsin B compared to the condition without Cathepsin B at 24 h. In another study, similar PEGylated peptide dendrimers were involved in the conjugation with hydrophobic drugs, like PTX, via the same enzyme-responsive linker (GFLG) (Li et al., 2017b). Hence, dendrimers are capable of carrying and releasing both hydrophilic and hydrophobic drugs. When a drug molecule is conjugated to the dendrimer via a disulfide-containing linker, its release can be triggered by abundant intracellular GSH. Prodrugs like valproic acid (Mishra et al., 2014), doxorubicin, paclitaxel (Lee et al., 2013c), and N-acetyl cysteine (Nance et al., 2015) were used for this purpose. Reduction-responsive dendrimers can also be designed by introducing disulfide bonds into a dendrimers core (Feng et al., 2011), into a dendrimer shell (Beloor et al., 2014), or as a spacer between dendrimer and shielding ligands, such as PEG (Hu et al., 2014), and crosslinking ligands among dendrimers (Li et al., 2014a). Dendrimers can also be involved in the preparation of external stimuli-responsive nanocarriers. For example, light-responsive dendrimeric nanotherapeutics can be obtained by conjugation with a light cleavable group, such as ortho-nitrobenzyl (Choi et al., 2012a,b). The strategies for providing thermo-sensitive properties to dendrimers with core
shell nanostructure consist of the modification of the outer dendrimer surface with thermo-sensitive polymers as PNIPAm (Shao et al., 2011), conjugation with small compounds such as isobutyl amide, NIPAm, oligo-ethylene glycol (OEG), phenylalanine, and peptides to the dendrimer surface, and constructing dendrimers or dendrons using amphiphilic components such as OEG and β-aminoester (Shao et al., 2011). Various LCSTs of thermo-sensitive dendrimers are ensured by the different ratios of hydrophilic and hydrophobic units in their backbone (Amirova et al., 2017). The first and second generation of well-defined thermo-responsive amphiphilic linear
dendritic diblock copolymers based on hydrophilic linear poly(N-vinylcaprolactam) and hydrophobic dendritic aromatic polyamide have been synthesized via RAFT polymerization of N-vinylcaprolactam by employing dendritic chain-transfer agents possessing a single dithiocarbamate moiety at the focal point (Bi et al., 2013). The thermo-sensitive dendrimers exhibit poor solubility above LCST and difficult control during the phase transition process, which may generate safety concerns for in vivo applications.

98

CHAPTER 2 RESPONSIVE POLYMERIC NANOTHERAPEUTICS

2.5 DUAL-RESPONSIVE NANOTHERAPEUTICS In dual-responsive nanocarriers, two different stimuli are combined, such as pH and redox stimuli, to enhance the response rate and achieve fast and complete drug release into the cancer cells. At the same time, enhanced tumor targetability and therapeutic efficacy are achieved by improving in vivo stability, tumor cell uptake, tumor penetration, and intracellular drug release (Cheng et al., 2013). Some examples of dual-responsive nanotherapeutics are presented in Table 2.7.

Table 2.7 Examples of Dual-Responsive Nanotherapeutics Stimuli pH and redox

Dual-Responsive Nanotherapeutics Polyplex micelles from PEGpoly[(N-dimethylmaleoyl-2aminoethyl) aspartamide] (PEGPAsp(EDA-DM)) and platinum (IV)-conjugated cationic poly (amidoamine) (PAMAM—Pt (IV)) dendrimer prodrugs

Polymer-modified nanoliposomes (100
200 nm) prepared by conjugating a eudragit E100/cystamine dihydrochloride polymer with a phospholipid bilayer

NGs (80
115 nm) based on a random copolymer that contains OEG and pyridyldisulfide (PDS) units as side-chain functionalities

Effects

References

At tumor pH (B6.8), polyplex micelles were disassembled by conversion of negatively charged PEG-PAsp(EDA-DM) copolymer into positively charged PEG-PAspEDA; efficient penetration into the dense tumor tissue; PAMAM— Pt(IV) prodrugs released at tumor pH; high cellular uptake; IC50 value was 88 times lower than cisplatin against drugresistant A549R cells; potent inhibition on the growth of MCTS at pH 6.8 Treatment of chronic inflammation When the nanoliposomes penetrate the inflamed cells, they will first encounter a low pH in the ECM where they will undergo an initial degradation (swelling). Upon reaching the ICM cytosol, the nanoliposomes will fully degrade due to an increase in GTH concentration during inflammation and release the therapeutic agent to the cell nucleus (site of action) High DOX encapsulation efficiency (70%, w/w) and pH and redox-controlled drug release

Li et al. (2014c)

Mavuso et al. (2016)

Asadi and Khoee, 2016

2.5 DUAL-RESPONSIVE NANOTHERAPEUTICS

99

Table 2.7 Examples of Dual-Responsive Nanotherapeutics Continued Stimuli

Dual-Responsive Nanotherapeutics PTX prodrug NPs from polypeptide-PTX conjugate, PTX was linked to EG-b-poly(LLys) via 3,3-dithiodipropionic acid; 15.6% drug loading content Disulfide-crosslinked polymersomes (B35 nm) from water-soluble PEG-poly(acrylic acid)-poly(2-(diethylamino)ethyl methacrylate) triblock copolymer thiol derivative Core-crosslinked polypeptide micelles from lipoic acid and cis-1,2-cyclohexanedicarboxylic acid decorated PEG-b-poly(LLys) block copolymers Reversibly core-crosslinked micelles (58 nm) from PEGpoly(TMBPEC-co-PDSC) copolymers DOX-loaded PEGylated dualresponsive poly(methacrylic acid-co-PEG methyl ether methacrylate-co-N,N-bis (acryloyl) cystamine) NGs Supramolecular NGs crosslinked by disulfide bonds and host
guest interaction between Dex-graft-benzimidazole and thiol-β-CD DOX prodrug NGs based on biocompatible hyperbranched polyglycerol; DOX conjugated to the polymer via an acid-labile hydrazone linker Heparin (Hep) conjugated to PAMAM dendrimer G3.5 via redox-sensitive disulfide bond

Disulfide linkage between PAMAM dendrimers and PEG. DOX was loaded into the hydrophobic core of the conjugates to prepare PAMAMSS-PEG/DOX complexes (PSSP/DOX)

Effects

References

Accelerated drug release at pH 5.0; superior tumor inhibition effect

Lv et al. (2014)

Excellent colloidal stability; potent cancer cell apoptosis

Sun et al. (2014)

DOX release amount was doubled under endosomal pH of 5.0 than at pH 7.4

Wu et al. (2013)

DOX-loaded crosslinked micelles showed high antitumor activity and biodegradability

Chen et al. (2015b)

DOX released was more than 85% within 30 h at pH 5.0

Zhou et al. (2015a)

Enhanced DOX release under acidic conditions and intracellular reduction environment

Chen et al. (2014b)

Efficient drug release at pH 5.0; very low drug leaching at physiological condition

Zhang et al. (2014b)

Diameter of 11 nm; loaded with more than 20% letrozole; enhances the effectiveness of cancer therapy after removing Hep from the surface Redox and acid-triggered DOX release, which increased with the PEGylation degree

Nguyen et al. (2017)

Hu et al. (2016)

(Continued)

100

CHAPTER 2 RESPONSIVE POLYMERIC NANOTHERAPEUTICS

Table 2.7 Examples of Dual-Responsive Nanotherapeutics Continued Stimuli

Dual-Responsive Nanotherapeutics

GSH and ROS

SN38 prodrug nanocapsules OEG-2S-SN38

GSH and enzyme

NG prepared from human hair keratin and alginate

Redox and thermo

Micelles obtained by the triblock copolymer mPEG2k-b400DTPA-b-mPEG2 selfassembly in aqueous media and encapsulated with Nile Red

pH and thermo

NGs based on PNIPAm, HEAA, and tert-butyl 2-acrylamidoethyl carbamate (2AAECM)

Spherical NGs with poly(N,N(diethylamino ethyl methacrylate) (DEAEM) core and PEG shell, was achieved by a simple “surfactant free” emulsion polymerization method with the aid of PEG methylether methacrylates (PEGMA) as polymerizable stabilizers

Nanohydrogels (140
190 nm) consisting of CS and the monomers acrylic acid (AA), methyl methacrylate (MMA), and NIPAm

Effects

References

Decompose and quickly release in the presence of GSH or H2O2; high in vitro cytotoxicity in human cancer cell lines— breast tumor Promising vectors for DOX hydrochlorin with super-high drug-loading rate of 52.9% (w/ w) and dual-stimuli responsive behavior to GSH and trypsin • Exhibit thermo-responsive size variations (due to the thermo-caused collapse of the 400DTPA segment in the micellar core), as manifested by the decrease of size from 108.8 nm at 10 C to 55.6 nm at 37 C • Can release drugs by reduction triggering Passive targeting of PTX; faster drug release at acid pH (pH 5), similar to those observed at lysosome compartment; rapid penetration and intracellular accumulation of NGs in MCF7, HeLa, and T47D cells after 48 h incubation NGs with more DEAEM show larger shrinkages as a function of pH, however their dispersability in water is limited to the use of high acid concentration The swelling of the NGs at a pH value lower than 7.4, comparable to the extracellular pH of tumors, is a promising behavior precluding its application in loading and release of anticancer drugs Uniform spherical morphology and carried obvious positive surface charges. 5-FU-loaded nanohydrogels showed loading efficiencies of 5-FU

Wang et al. (2013a)

Sun et al. (2017)

Song et al. (2018)

P´erez et al. (2014)

Manzanares-Guevara et al. (2017)

Liu et al. (2016)

2.5 DUAL-RESPONSIVE NANOTHERAPEUTICS

101

Table 2.7 Examples of Dual-Responsive Nanotherapeutics Continued Stimuli pH and GSH

Dual-Responsive Nanotherapeutics NGs of NIPAm, HEAA, and 2acrylamidoethyl carbamate, and crosslinked with N,N-cystamine bisacrylamide or N-methylene bisacrylamide

PVA-based NGs from PVA-(SSalkynyl)-COOH and PVA-azide obtained by inverse nanoprecipitation and click reaction

pH and magnetic

Citric-coated Fe3O4 functionalized with poly (ethylene glycol) bis (carboxymethyl ether) and conjugated with DOX

Effects

References

No modifications of fibrinogen concentration; increased antithrombin III; histology showed no tissue damage, inflammation, or morphological change in liver, kidney, and spleen 95% of DOX was released in 10 h at pH 5.5 because of a decrease of electrostatic interaction between COOH and DOX and cleavage of the intervening disulfide bonds; low IC50 values of 0.32 and 0.45 μg DOX equiv./mL Cancer chemotherapy

P´erez et al. (2015)

Chen et al. (2015a)

Ji et al. (2018)

Other multifunctional micelles have also integrated multiple functions, including the ability to codeliver siRNA and DOX, passive and active cancer targeting, cell membrane translocation, and pH-triggered drug release simultaneous imaging and gene delivery applications, or as “theranostics” (Sawant and Jhaveri, 2014). Dual pH- and redox-responsive NGs were prepared by crosslinking of polymer chains through both imine and disulfide bonds. If only one stimulus (low pH or presence of reducing agent) acts on the NGs, they do not disaggregate and a minor increase in the drug release rate is observed because there is still sufficient crosslinking density. By contrast, when both stimuli are present, the particles disassemble (Jackson and Fulton, 2012). Glucose- and temperature-sensitive polymeric NPs were prepared by the self-assembly of poly N-vinylcaprolactam-co-acrylamidophenylboronic acid p(NVCL-co-AAPBA) (Wu et al., 2016). The normal range of blood glucose is 3.9
6.0 mmol/L compared to that of diabetes patients with 9.0
18.0 mmol/L. The prepared copolymers responded to a high concentration of glucose by significantly increasing particle sizes, thus they have great potential in the application of drug-delivery systems with glucose sensitivity. Also, the diameters of NPs decrease with an increase in temperature. The NPs have a good insulin-loading capacity of approximately 15% due to hydrophilic
hydrophobic interactions, do not affect the conformation of the insulin, and show low toxicity to cells and animals. A photo/thermo-responsive NG was recently reported (Lee et al., 2017). The thermoresponsiveness was provided by PNIPAm and photo-responsiveness was provided by the

102

CHAPTER 2 RESPONSIVE POLYMERIC NANOTHERAPEUTICS

photochromic SP and nitrobenzoxadiazole (NBD) derivatives. SP undergoes a reversible structural interconversion between the nonfluorescent ring-closed SP and fluorescent ring-opened merocyanine states. SP was used as FRET (Fo¨rster resonance energy transfer) acceptors and physically incorporated into the thermo-responsive PNIPAm-based NGs containing green-emissive NBD derivatives as FRET donors. Therefore, the NG emits green fluorescence corresponding to the fluorescence of the NBD derivatives; however, when irradiated with UV light, the C
O spiro bond in the SP form is broken and the molecule adopts the merocyanine form, resulting in a light-pink coloremitting NG. Notably, the selective fluorescence intensity of the NGs in water was modulated by thermo-responsive FRET processes between the NBD and SP dyes. Multistimuli-responsive systems. Multistimuli-responsive delivery systems are more interesting for drug delivery because of the coexistence of acidity, hypoxia microenvironment, and enzymes in tumors (Chen et al., 2015a,b,c). Examples include PAMAM dendrimers conjugated to macrophages via acid-responsive hydrazone linkages (Holden et al., 2010) or collagen-modified dendrimer conjugated with doxorubicin via hydrazone linkages showing both acid- and enzyme-responsive behaviors (Kojima et al., 2013). Also, the internal triggers are combined with external ones to design multistimuli-responsive dendrimers. Thermo- and light-responsive dendrimers are produced from encapsulated gold NPs into elastin-mimetic dendrimers (Fukushima et al., 2015).

2.6 FUNCTIONALIZATION OF NANOPARTICLES TO CREATE STIMULI RESPONSIVENESS NPs can be functionalized either in bulk or by modifying their surfaces.

2.6.1 BULK MODIFICATIONS The introduction of the stimuli-responsive elements into homogeneous spherical NPs results in particular morphologies such as simple spherical, core
shell, hollow, concentric, or more complex as Janus, gibbous/inverse gibbous, and cocklebur morphologies with variable properties for each phase within one particle (Liu et al., 2017). Spherical shapes can be synthesized by emulsion or controlled reversible-deactivation radical polymerization methods. Functionalization is achieved by copolymerization with stimuli-responsive monomers into them. The photochromic moieties, such as azobenzene, spiropyrans, diaryethenes, or fulgides can be used because they offer volume and reversible color changes. For example, azobenzene moieties undergo reversible isomerization from cis- to trans-conformations in response to pH changes and/or UV/vis radiation. Their incorporation into poly(2-(N,N-dimethylamino) ethyl methacrylate-co-butylacrylate-co-N,N-(dimethylamino) azobenzene acrylamide) (P(DMAEMA/nBA/DMAAZOAm) leads to pH-responsiveness, shifting from red at pH , 4 to yellow at higher pHs. Other polymers/copolymers utilized in the synthesis of the responsive NPs are poly(dimethylaminoethyl methacrylate), PNIPAm, polyacrylic acid (PAA) for pH-responsive, PHEMA, poly(glycidyl methacrylate), poly(4-vinylpyridine), poly(methacrylic acid), PCL, polythioether ketal, β-CD, PAMAM, for dual magnetic-responsive NPs, PEGylated phospholipids (PEG phospholipids), PLGA, SP for electric field-responsive NPs. If a small drug

2.6 FUNCTIONALIZATION OF NANOPARTICLES

103

molecule is entrapped inside the interior core of the core
shell NP, upon external stimuli, its release is controlled by volume and diffusivity changes, or disassembly of the shell. Hollow NPs can be obtained from core
shell ones with different solubility and thermal properties by applying the solvation, etching, calcination, or spatially controlled polymerization (Liu et al., 2017; Men et al., 2013; Shi et al., 2016). The amphiphilic Janus NPs are from polymers with different physical and/or chemical properties by sequential “living” ring-opening metathesis polymerization emulsion polymerization, seeding polymerization, and self-assembly. Multifunctional nanomaterials with phase-separated morphologies result. The cocklebur and urchin NPs, obtained using a nanoextruder, exhibit a spiky surface morphology with very high surface area. These features enable the attachment of localized stimuliresponsive components, and the incorporation of molecular entities into spikes acting as receptors or molecular recognition sites (Lestage and Urban, 2005).

2.6.2 SURFACE MODIFICATION The responsive surfaces change their properties upon the application of an external stimulus. Moreover, the multiresponsive surfaces allow mimicking of the cooperativity encountered in systems, and are very attractive for drug delivery (Pasparakis and Vamvakaki, 2011). Surface modification is one of the fundamental approaches used to increase the time NPs remain in the circulation to ensure accumulation at the tumor. The aim is to make NPs “invisible” to the reticulo-endothelial system (RES), to avoid rapid clearance. Surface functionalization with hydrophilic polymers is one of the most used strategies, especially with PEG and their derivatives (Meng et al., 2011; Karakoti et al., 2011). PEG not only reduces RES uptake but also improves the stability of the NPs in biological fluids (Cauda et al., 2010). The basis of active targeting relies on “decorating” the periphery of the nanocarriers with targeting ligands, which are specifically selected for a given receptor overexpressed in the surface of cancer cells or vasculature and poorly expressed in healthy cells or vessels. Selected surface reactions can be applied to decorate NPs with stimuli-responsive polymers. The grafting to, grafting from, and “grafting through” (copolymerization) are the most applied approaches (Radhakrishnan et al., 2006). The “grafting-to” approach involves a chemical reaction between (end-) functionalized polymers and complementary reactive groups on the functionalized substrate surface. In the grafting-from method, the macromolecular backbone is chemically modified in order to introduce active sites capable of initiating functionality. The initiating sites can be incorporated by copolymerization, can be incorporated in a post-polymerization reaction, or can already be a part of the polymer. Different conjugation strategies have been developed to graft targeting ligands to NPs, such as carbodiimide-mediated COOH/NH2 coupling, maleimide/SH coupling, click chemistry, pyridyldithiol and thiol reactions, avidin
biotin interactions capable of attaching proteins or nucleic acids, etc. Modified NPs surfaces with stimuli-responsive polymer shells can undergo reversible processes controlled by stimuli as collapsing/swelling, assembly/disassembly of NPs, binding selectivity, which is critical for precise targeting (hydrogen bonding, van der Waals interactions, and spatial geometry of the ligands play a critical role in these processes), labile linkages cleavage (such as

104

CHAPTER 2 RESPONSIVE POLYMERIC NANOTHERAPEUTICS

disulfides, orthoesters, boroesters, o-nitrobenzyl esters, reversible macromolecular interactions in DNA double helix interactions), etc. (Liu et al., 2017). By grafting a PNIPAm
poly(acrylamido phenylboronic acid) copolymer onto a rough silicon substrate, Xia et al. (2007) obtained a surface with wettability variations changing between superhydrophilicity and super-hydrophobicity in response to three different stimuli: pH, temperature, and glucose concentration. Such coatings are promising in diagnostics, drug delivery, or cell culture applications. A combination of organic and inorganic (metal, metal oxides, or ceramic) phases is also of great interest because it combines the unique properties of inorganic NPs with functional and stimuliresponsive polymeric shells. Bioresponsive polymer-coated drug NRs as a thin layer (10.3 6 1.4 nm) of PCL polymer coating of 500.9 6 91.3 nm length 3 122.7 6 10.1 nm width was deposited on the surface of camptothecin (CPT) (Laemthong et al., 2016). The PCL polymer coating was biodegradable at acidic pH 6. Trastuzumab, a humanized IgG monoclonal antibody, was conjugated to the NR surface for breast cancer cell targeting and it was found to decrease breast cancer cell growth by 66.9 6 5.3% in vitro. In mesoporous silica NPs, smart nanosystems with a honeycomb-like porous structure, the drug is enclosed within the mesopores and its output is blocked by using capping agents or gatekeepers that prevent any premature cargo departure. Drug release takes place once the system has been exposed to a given stimulus, which provokes the gatekeeper removal and triggers the release of the entrapped cargo. The release is triggered only upon exposure to stimuli, which induce the removal of gatekeepers and then the release of the entrapped drug molecules. As an example, in Table 2.8 are summaries of representative stimuli-responsive drug-delivery NPs, polymeric or modified with polymer systems, which have been classified into two groups depending on the stimulus that acts as a release trigger, namely internal and external stimuli (Blanco-Fernandez et al., 2014).

Table 2.8 Stimuli-Responsive Strategies for Smart Drug Delivery Using Mesoporous Silica as the Core NP Stimuli

Responsive Linker

Capping Agent

References

Octadecyl (C18) chains PNIPAm DNA strands

Paraffins PNIPAm Biotin

Coiled-coil peptide motifs

Coiled-coil peptide motifs

4(3-cyanophenyl)butylene dipolar molecule




Aznar et al. (2011) Jadhav et al. (2015) Schlossbauer et al. (2010) Martelli et al. (2013) Zhu et al. (2010)

External stimuli Temperature

Electric field

2.6 FUNCTIONALIZATION OF NANOPARTICLES

105

Table 2.8 Stimuli-Responsive Strategies for Smart Drug Delivery Using Mesoporous Silica as the Core NP Continued Stimuli

Responsive Linker

Capping Agent

References

Magnetic field

Hybridization of 2 ssDNA

γ-Fe2O3 NPs

Alkylammonium chains (NH3 1
(CH2)
NH21
R) PEI/PNIPAm polymer Azo bonds (
N 5 N
)

Cucurbituril

Ruiz-Hernández et al. (2011) Thomas et al. (2010) Baeza et al. (2012) Saint-Cricq et al. (2015) Martı´nez-Carmona et al. (2015)

Light

PEI/PNIPAm chains 1 catalase PEG

4-[4-(1-(Fmoc)methyl)-2-methoxy-5nitrophenoxy] butanoic acid photolinker DNA aptamer Azobenzene/coumarin dimer

Protein shell (avidin estreptavidin-biotin-transferrin) DNA aptamer Coumarin dimer

Azobenzene derivatives

β-CDs

Yang et al. (2012) Zhu and Fujiwara (2007) Ferris et al. (2009)

Internal stimuli pH

Redox potential

Enzymes

Small molecules

Ferrocenyl moieties PAH-PSS PEM Aromatic amines Benzoic-imine bonds
S
S

S
S


β-CD-modified CeO2 NPs PAH-PSS PEM CDs Polypseudorotaxanes ssDNA PEG


S
S


Poly(propylene imine) dendrimer

β-Galactosidase-cleavable oligosaccharide MMP9-sensitive peptide sequence (RSWMGLP) Protease-sensitive peptide sequences (CGPQGIWGQGCR) α-Amylase and lipase cleavable stalks HRP-polymer nanocapsule Ionizable benzimidazole group

β-Galacto-oligosaccharide

PNIPAm-PEGDA shell

Xu et al. (2013) Feng et al. (2013) Meng et al. (2010) Gao et al. (2011a) Ma et al. (2012) Zhang et al. (2014d) Nadrah et al. (2013) Agostini et al. (2012) van Rijt et al. (2015) Singh et al. (2011)

CDs

Park et al. (2009)


CD-modified glucose oxidase

Baeza et al. (2014) Aznar et al. (2013)

Avidin

PAH, poly(allylamine hydrochloride); PEM, polyelectrolyte multilayers; HRP, enzyme horseradish peroxidase.

106

CHAPTER 2 RESPONSIVE POLYMERIC NANOTHERAPEUTICS

2.7 CONCLUSION In this chapter, we have summarized and discussed the use of stimuli-responsive nanotherapeutics in different biomedical fields, especially as nanocarriers for drug and gene delivery for cancer therapy or other diseases. The introduction of biocompatible stimuli-responsive polymeric materials, that can be designed to make smart drug nanocarriers, has motivated many investigations. Many recent researches have presented the importance of using stimuli response nanosystems in this area. Special attention was accorded to micelle and NG nanotherapeutics due to their unique and excellent characteristics and special behavior in response to an appropriate stimulus, which can be internal or external. Also, other types of responsive nanosystems, such as nanofibers, NPs, dendrimers, polymeric nanoliposomes, nanovehicles, etc., have been presented. The smart nanosystems, mainly multiresponsive ones allow delivery of a payload in spatial-, temporal-, and dosage-controlled ways is very efficient for specific therapies. Many different stimuli have been developed, such as pH, redox, thermo-, light-, and so on, but how to integrate these different stimuli together well to ensure a synergistic effect is still a big challenge. However, numerous multifunctionalized nanosystems with high sensitivity and specificity have been designed for diagnostic applications.

REFERENCES Abreu, C., Paula, H., Seabra, V., Feitosa, J., Sarmento, B., de Paula, R., 2016. Synthesis and characterization of non-toxic and thermo-sensitive poly(N-isopropylacrylamide)-grafted cashew gum nanoparticles as a potential epirubicin delivery matrix. Carbohydr. Polym. 154, 77
85. Agostini, A., Mondrago´n, L., Coll, C., Aznar, E., Marcos, M., Martı´nez-M´an˜ez, R., et al., 2012. Dual enzymetriggered controlled release on capped nanometric silica mesoporous supports. ChemistryOpen 1 (1), 17
20. Aili, D., Stevens, M., 2010. Bioresponsive peptide
inorganic hybrid nanomaterials. Chem. Soc. Rev. 39 (9), 3358
3370. Akimoto, J., Nakayama, M., Sakai, K., Okano, T., 2010. Thermally controlled intracellular uptake system of polymeric micelles possessing poly(N-isopropylacrylamide)-based outer coronas. Mol. Pharm. 7 (4), 926
935. Alatorre-Meda, M., Alvarez-Lorenzo, C., Concheiro, A., Taboada, P., 2013. UV and near-IR triggered release from polymeric micelles and nanoparticles. In: Alvarez-Lorenzo, C., Concheiro, A. (Eds.), Smart Materials forDrug Delivery.. RSC Publishing, Cambridge, UK, pp. 304
348. Alvarez-Lorenzo, C., Bromberg, L., Concheiro, A., 2009. Light-sensitive intelligent drug delivery systems. Photochem. Photobiol. 85 (4), 848
860. Amirova, A., Rodchenko, S., Milenin, S., Tatarinova, E., Kurlykin, M., Tenkovtsev, A., et al., 2017. Influence of a hydrophobic core on thermoresponsive behavior of dendrimer-based star-shaped poly(2-isopropyl-2oxazoline) in aqueous solutions. J. Polym. Res. 24 (8), 124. Antoniraj, M., Kumar, C., Kandasamy, R., 2015. Synthesis and characterization of poly (N-isopropylacrylamide)-g-carboxymethyl chitosan copolymer-based doxorubicin-loaded polymeric nanoparticles for thermoresponsive drug release. Colloid Polym. Sci. 294 (3), 527
535. Asadi, H., Khoee, S., 2016. Dual responsive nanogels for intracellular doxorubicin delivery. Int. J. Pharm. 511 (1), 424
435.

REFERENCES

107

Aw, M., Losic, D., 2013. Ultrasound enhanced release of therapeutics from drug-releasing implants based on titania nanotube arrays. Int. J. Pharm. 443 (1
2), 154
162. Aznar, E., Mondrago´n, L., Ros-Lis, J., Sanceno´n, F., Marcos, M., Martı´nez-M´an˜ez, R., et al., 2011. Finely tuned temperature-controlled cargo release using paraffin-capped mesoporous silica nanoparticles. Angew. Chem. Int. Ed. 50 (47), 11172
11175. Aznar, E., Villalonga, R., Gim´enez, C., Sanceno´n, F., Marcos, M., Martı´nez-M´an˜ez, R., et al., 2013. Glucosetriggered release using enzyme-gated mesoporous silica nanoparticles. Chem. Commun. 49 (57), 6391
6393. Babin, J., Pelletier, M., Lepage, M., Allard, J., Morris, D., Zhao, Y., 2009. A new two-photon-sensitive block copolymer nanocarrier. Angew. Chem. Int. Ed. 48 (18), 3329
3332. Bae, K., Choi, S., Park, S., Lee, Y., Park, T., 2006. Thermosensitive pluronic micelles stabilized by shell cross-linking with gold nanoparticles. Langmuir 22 (14), 6380
6384. Bae, Y., Alani, A., Rockich, N., Lai, T., Kwon, G., 2010. Mixed pH-sensitive polymeric micelles for combination drug delivery. Pharm. Res. 27 (11), 2421
2432. Baeza, A., Guisasola, E., Ruiz-Hern´andez, E., Vallet-Regı´, M., 2012. Magnetically triggered multidrug release by hybrid mesoporous silica nanoparticles. Chem. Mater. 24 (3), 517
524. Baeza, A., Guisasola, E., Torres-Pardo, A., Gonz´alez-Calbet, J., Melen, G., Ramirez, M., et al., 2014. Hybrid enzyme-polymeric capsules/mesoporous silica nanodevice for in situ cytotoxic agent generation. Adv. Funct. Mater. 24 (29), 4625
4633. Beloor, J., Ramakrishna, S., Nam, K., Seon Choi, C., Kim, J., Kim, S., et al., 2014. Effective gene delivery into human stem cells with a cell-targeting peptide-modified bioreducible polymer. Small 11 (17), 2069
2079. Bi, Y., Yan, C., Shao, L., Wang, Y., Ma, Y., Tang, G., 2013. Well-defined thermoresponsive dendritic polyamide/poly(N-vinylcaprolactam) block copolymers. J. Polym. Sci. A Polym. Chem. 51 (15), 3240
3250. Biswas, Y., Jana, S., Dule, M., Mandal, T.K., 2017. Chapter 6: Responsive polymer nanostructures. In: Lin, Z., Yang, Y., Zhang, A. (Eds.), Polymer-Engineered Nanostructures for Advanced Energy Applications. Engineering Materials and Processes. Springer, Cham, pp. 173
304. Blanco-Fernandez, B., Concheiro, A., Alvarez-Lorenzo, C., 2014. Chapter B3: Stimuli-sensitive nanostructured systems for biomedical applications. In: Torchilin, V. (Ed.), Handbook of Nanobiomedical Research, Volume 4: Biology, safety and novel concepts in nanomedicine. World Scientific, Singapore, pp. 309
348. Blum, A., Kammeyer, J., Rush, A., Callmann, C., Hahn, M., Gianneschi, N., 2015. Stimuli-responsive nanomaterials for biomedical applications. J. Am. Chem. Soc. 137 (6), 2140
2154. Boissiere, O., Han, D., Tremblay, L., Zhao, Y., 2011. Flower micelles of poly(N-isopropylacrylamide) with azobenzene moieties regularly inserted into the main chain. Soft Matter 7 (19), 9410
9515. Bou, S., Ellis, A., Ebara, M., 2016. Synthetic stimuli-responsive ‘smart’ fibers. Curr. Opin. Biotechnol. 39, 113
119. Cauda, V., Argyo, C., Bein, T., 2010. Impact of different PEGylation patterns on the long-term bio-stability of colloidal mesoporous silica nanoparticles. J. Mater. Chem. 20 (39), 8693
8699. Chang, R., Li, M., Ge, S., Yang, J., Sun, Q., Xiong, L., 2018. Glucose-responsive biopolymer nanoparticles prepared by co-assembly of concanavalin A and amylopectin for insulin delivery. Ind. Crops Prod. 112, 98
104. Chen, Y., Liang, H., Zhang, Q., Blomley, M., Lu, Q., 2006. Pluronic block copolymers: novel functions in ultrasound-mediated gene transfer and against cell damage. Ultrasound Med. Biol. 32 (1), 131
137. Chen, W., Zheng, M., Meng, F., Cheng, R., Deng, C., Feijen, J., et al., 2013. In situ forming reductionsensitive degradable nanogels for facile loading and triggered intracellular release of proteins. Biomacromolecules 14 (4), 1214
1222.

108

CHAPTER 2 RESPONSIVE POLYMERIC NANOTHERAPEUTICS

Chen, W., Zou, Y., Meng, F., Cheng, R., Deng, C., Feijen, J., et al., 2014a. Glyco-nanoparticles with sheddable saccharide shells: a unique and potent platform for hepatoma-targeting delivery of anticancer drugs. Biomacromolecules 15 (3), 900
907. Chen, X., Chen, L., Yao, X., Zhang, Z., He, C., Zhang, J., et al., 2014b. Dual responsive supramolecular nanogels for intracellular drug delivery. Chem. Commun. 50 (29), 3789
3791. Chen, H., He, W., Guo, Z., 2014c. An H2O2-responsive nanocarrier for dual-release of platinum anticancer drugs and O2: controlled release and enhanced cytotoxicity against cisplatin resistant cancer cells. Chem. Commun. 50 (68), 9714
9717. Chen, W., Achazi, K., Schade, B., Haag, R., 2015a. Charge-conversional and reduction-sensitive poly(vinyl alcohol) nanogels for enhanced cell uptake and efficient intracellular doxorubicin release. J. Control. Release 205, 15
24. Chen, W., Meng, F., Cheng, R., Deng, C., Feijen, J., Zhong, Z., 2015b. Facile construction of dualbioresponsive biodegradable micelles with superior extracellular stability and activated intracellular drug release. J. Control. Release 210, 125
133. Chen, H., Feng, Y., Deng, G., Liu, Z., He, Y., Fan, Q., 2015c. Fluorescent dendritic organogels based on 2-(20 hydroxyphenyl)benzoxazole: emission enhancement and multiple stimuli-responsive properties. Chem. A Eur. J. 21 (31), 11018
11028. Cheng, R., Meng, F., Deng, C., Klok, H., Zhong, Z., 2013. Dual and multi-stimuli responsive polymeric nanoparticles for programmed site-specific drug delivery. Biomaterials 34 (14), 3647
3657. Cheng, R., Meng, F., Deng, C., Zhong, Z., 2015. Bioresponsive polymeric nanotherapeutics for targeted cancer chemotherapy. Nano Today 10 (5), 656
670. Choi, S., Lee, S., Park, T., 2006. Temperature-sensitive pluronic/poly(ethylenimine) nanocapsules for thermally triggered disruption of intracellular endosomal compartment. Biomacromolecules 7 (6), 1864
1870. Choi, S., Verma, M., Silpe, J., Moody, R., Tang, K., Hanson, J., et al., 2012a. A photochemical approach for controlled drug release in targeted drug delivery. Bioorg. Med. Chem. 20 (3), 1281
1290. Choi, S., Thomas, T., Li, M., Desai, A., Kotlyar, A., Baker, J., 2012b. Photochemical release of methotrexate from folate receptor-targeting PAMAM dendrimer nanoconjugate. Photochem. Photobiol. Sci. 11 (4), 653
660. Chountoulesi, M., Kyrili, A., Pippa, N., Meristoudi, A., Pispas, S., Demetzos, C., 2015. The modulation of physicochemical characterization of innovative liposomal platforms: the role of the grafted thermoresponsive polymers. Pharm. Dev. Technol. 22 (3), 330
335. Crucho, C.I.C., 2015. Stimuli-responsive polymeric nanoparticles for nanomedicine. ChemMedChem 10 (1), 24
38. Cui, W., Lu, X., Cui, K., Wu, J., Wei, Y., Lu, Q., 2011. Photosensitive nanoparticles of chitosan complex for controlled release of dye molecules. Nanotechnology 22 (6), 065702. Cui, C., Xue, Y., Wu, M., Zhang, Y., Yu, P., Liu, L., et al., 2013. Cellular uptake, intracellular trafficking, and antitumor efficacy of doxorubicin-loaded reduction-sensitive micelles. Biomaterials 34 (15), 3858
3869. Daniel-da-Silva, A., Ferreira, L., Gil, A., Trindade, T., 2011. Synthesis and swelling behavior of temperature responsive κ-carrageenan nanogels. J. Colloid Interface Sci. 355 (2), 512
517. Ding, J., Chen, J., Li, D., Xiao, C., Zhang, J., He, C., et al., 2013. Biocompatible reduction-responsive polypeptide micelles as nanocarriers for enhanced chemotherapy efficacy in vitro. J. Mater. Chem. B 1 (1), 69
81. Ding, L., Wang, C., Jiang, R., Wang, L., Song, W., 2016. Preparation of small and photoresponsive polymer nanoparticles by intramolecular crosslinking of reactive star azo-polymers. React. Funct. Polym. 109, 56
63. Duan, X., Xiao, J., Yin, Q., Zhang, Z., Yu, H., Mao, S., et al., 2013. Smart pH-sensitive and temporalcontrolled polymeric micelles for effective combination therapy of doxorubicin and disulfiram. ACS Nano 7 (7), 5858
5869.

REFERENCES

109

Edinger, D., Wagner, E., 2010. Bioresponsive polymers for the delivery of therapeutic nucleic acids. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 3 (1), 33
46. Feng, X., Cheng, Y., Wu, Q., Zhang, J., Xu, T., 2011. Stimuli response of cystamine-core dendrimer revealed by diffusion and NOE NMR studies. J. Phys. Chem. B 115 (14), 3777
3783. Feng, W., Zhou, X., He, C., Qiu, K., Nie, W., Chen, L., et al., 2013. Polyelectrolyte multilayer functionalized mesoporous silica nanoparticles for pH-responsive drug delivery: layer thickness-dependent release profiles and biocompatibility. J. Mater. Chem. B 1 (43), 5886
5898. Feng, A., Yan, Q., Zhang, H., Peng, L., Yuan, J., 2014. Electrochemical redox responsive polymeric micelles formed from amphiphilic supramolecular brushes. Chem. Commun. 50 (36), 4740
4742. Ferris, D., Zhao, Y., Khashab, N., Khatib, H., Stoddart, J., Zink, J., 2009. Light-operated mechanized nanoparticles. J. Am. Chem. Soc. 131 (5), 1686
1688. Fukushima, D., Sk, U., Sakamoto, Y., Nakase, I., Kojima, C., 2015. Dual stimuli-sensitive dendrimers: photothermogenic gold nanoparticle-loaded thermo-responsive elastin-mimetic dendrimers. Colloid Surf. B Biointerfaces 132, 155
160. Fundueanu, G., Constantin, M., Ascenzi, P., 2008. Preparation and characterization of pH- and temperature-sensitive pullulan microspheres for controlled release of drugs. Biomaterials 29 (18), 2767
2775. Fundueanu, G., Constantin, M., Ascenzi, P., 2010. Poly(vinyl alcohol)microspheres with pH- and thermosensitive properties as temperature-controlled drug delivery. Acta Biomater. 6 (10), 3899
3907. Ganta, S., Devalapally, H., Shahiwala, A., Amiji, M., 2008. A review of stimuli-responsive nanocarriers for drug and gene delivery. J. Control. Release 126 (3), 187
204. Gao, Z., Fain, H., Rapoport, N., 2004. Ultrasound-enhanced tumor targeting of polymeric micellar drug carriers. Mol. Pharm. 1 (4), 317
330. Gao, Z., Fain, H., Rapoport, N., 2005. Controlled and targeted tumor chemotherapy by micellar-encapsulated drug and ultrasound. J. Control. Release 102 (1), 203
222. Gao, Y., Yang, C., Liu, X., Ma, R., Kong, D., Shi, L., 2011a. A multifunctional nanocarrier based on nanogated mesoporous silica for enhanced tumor-specific uptake and intracellular delivery. Macromol. Biosci. 12 (2), 251
259. Gao, Z., Tian, L., Hu, J., Park, I., Bae, Y., 2011b. Prevention of metastasis in a 4T1 murine breast cancer model by doxorubicin carried by folate conjugated pH sensitive polymeric micelles. J. Control. Release 152 (1), 84
89. Gao, G., Li, Y., Lee, D., 2013. Environmental pH-sensitive polymeric micelles for cancer diagnosis and targeted therapy. J. Control. Release 169 (3), 180
184. Gao, Y., Zhou, Y., Zhao, L., Zhang, C., Li, Y., Li, J., et al., 2015. Enhanced antitumor efficacy by cyclic RGDyK-conjugated and paclitaxel-loaded pH-responsive polymeric micelles. Acta Biomater. 23, 127
135. Gohy, J., Zhao, Y., 2013. Photo-responsive block copolymer micelles: design and behavior. Chem. Soc. Rev. 42 (17), 7117
7129. Gorman, M., Feigl, E., Buffington, C., 2007. Human plasma ATP concentration. Clin. Chem. 53 (2), 318
325. Gota, C., Okabe, K., Funatsu, T., Harada, Y., Uchiyama, S., 2009. Hydrophilic fluorescent nanogel thermometer for intracellular thermometry. J. Am. Chem. Soc. 131 (8), 2766
2767. Gribble, F., Loussouarn, G., Tucker, S., Zhao, C., Nichols, C., Ashcroft, F., 2000. A novel method for measurement of submembrane ATP concentration. J. Biol. Chem. 275 (39), 30046
30049. Gu, G., Xia, H., Hu, Q., Liu, Z., Jiang, M., Kang, T., et al., 2013a. PEG-co-PCL nanoparticles modified with MMP-2/9 activatable low molecular weight protamine for enhanced targeted glioblastoma therapy. Biomaterials 34 (1), 196
208.

110

CHAPTER 2 RESPONSIVE POLYMERIC NANOTHERAPEUTICS

Gu, Y., Zhong, Y., Meng, F., Cheng, R., Deng, C., Zhong, Z., 2013b. Acetal-linked paclitaxel prodrug micellar nanoparticles as a versatile and potent platform for cancer therapy. Biomacromolecules 14 (8), 2772
2780. Guo, X., Shi, C., Wang, J., Di, S., Zhou, S., 2013. pH-triggered intracellular release from actively targeting polymer micelles. Biomaterials 34 (18), 4544
4554. Guo, H., Jeong, J., Kim, J., 2016. Electrospun thermo-responsive nanofibers of poly(hydroxyethylacrylate-cocoumaryl acrylate-co-ethylmethacrylate). Colloid Surf. A Physicochem. Eng. Aspects 495, 1
10. Han, H., Thambi, T., Choi, K., Son, S., Ko, H., Lee, M., et al., 2015a. Bioreducible shell-cross-linked hyaluronic acid nanoparticles for tumor-targeted drug delivery. Biomacromolecules 16 (2), 447
456. Han, S., Li, Z., Zhu, J., Han, K., Zeng, Z., Hong, W., et al., 2015b. Dual-pH sensitive charge-reversal polypeptide micelles for tumor-triggered targeting uptake and nuclear drug delivery. Small 11 (21), 2543
2554. Han, Y., Wang, M., Xu, C., 2017. Chapter 11: Magnetic nanoparticles for bioseparation, biosensing, and regenerative medicine. In: Hou, Y., Sellmyer, D.J. (Eds.), Magnetic Nanomaterials
Fundamentals, Synthesis and Applications: Fundamentals, Synthesis and Applications. Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, pp. 345
363. Hang, C., Zou, Y., Zhong, Y., Zhong, Z., Meng, F., 2017. NIR and UV-responsive degradable hyaluronic acid nanogels for CD44-targeted and remotely triggered intracellular doxorubicin delivery. Colloid Surf. B Biointerfaces 158, 547
555. Hassanzadeh, F., Maaleki, S., Varshosaz, J., Khodarahmi, G., Farzan, M., Rostami, M., 2016. Thermosensitive folic acid-targeted poly (ethylene-co-vinyl alcohol) hemisuccinate polymeric nanoparticles for delivery of epirubicin to breast cancer cells. Iran. Polym. J. 25 (11), 967
976. Hayashi, H., Kono, K., Takagishi, T., 1999. Temperature sensitization of liposomes using copolymers of Nisopropylacrylamide. Bioconjug. Chem. 10 (3), 412
418. He, H., Chen, S., Zhou, J., Dou, Y., Song, L., Che, L., et al., 2013. Cyclodextrin-derived pH-responsive nanoparticles for delivery of paclitaxel. Biomaterials 34 (21), 5344
5358. Holden, C.A., Yuan, Q., Yeudall, W.A., Lebman, D.A., Yang, H., 2010. Surface engineering of macrophages with nanoparticles to generate a cell-nanoparticle hybrid vehicle for hypoxia-targeted drug delivery. Int. J. Nanomedicine 5, 25
36. Hosseini, M., Farjadian, F., Makhlouf, A.S.H., 2016. Chapter 1: Smart stimuli-responsive nano-sized hosts for drug delivery. In: Hosseini, M., Makhlouf, A. (Eds.), Industrial Applications for Intelligent Polymers and Coatings. Springer, Cham, pp. 1
26. Hu, F., Zhang, Y., You, J., Yuan, H., Du, Y., 2012. pH triggered doxorubicin delivery of PEGylated glycolipid conjugate micelles for tumor targeting therapy. Mol. Pharm. 9 (9), 2469
2478. Hu, J., Miura, S., Na, K., Bae, Y., 2013. pH-responsive and charge shielded cationic micelle of poly(l-histidine)-block-short branched PEI for acidic cancer treatment. J. Control. Release 172, 69
76. Hu, W., Cheng, L., Cheng, L., Zheng, M., Lei, Q., Hu, Z., et al., 2014. Redox and pH-responsive poly (amidoamine) dendrimer
poly (ethylene glycol) conjugates with disulfide linkages for efficient intracellular drug release. Colloid Surf. B Biointerfaces 123, 254
263. Hu, W., Qiu, L., Cheng, L., Hu, Q., Liu, Y., Hu, Z., et al., 2016. Redox and pH dual responsive poly(amidoamine) dendrimer-poly(ethylene glycol) conjugates for intracellular delivery of doxorubicin. Acta Biomater. 36, 241
253. Huang, F., Cheng, R., Meng, F., Deng, C., Zhong, Z., 2015. Micelles based on acid degradable poly(acetal urethane): preparation, pH-sensitivity, and triggered intracellular drug release. Biomacromolecules 16 (7), 2228
2236. Huang, D., Yang, F., Wang, X., Shen, H., You, Y., Wu, D., 2016. Facile synthesis and self-assembly behaviour of pH-responsive degradable polyacetal dendrimers. Polym. Chem. 7 (40), 6154
6158. Huizenga, D., Szostak, J., 1995. A DNA aptamer that binds adenosine and ATP. Biochemistry 34 (2), 656
665.

REFERENCES

111

Husseini, G., Pitt, W., 2009. Ultrasonic-activated micellar drug delivery for cancer treatment. J. Pharm. Sci. 98 (3), 795
811. Husseini, G., Myrup, G., Pitt, W., Christensen, D., Rapoport, N., 2000. Factors affecting acoustically triggered release of drugs from polymeric micelles. J. Control. Release 69 (1), 43
52. Husseini, G., Christensen, D., Rapoport, N., Pitt, W., 2002. Ultrasonic release of doxorubicin from Pluronic P105 micelles stabilized with an interpenetrating network of N,N-diethylacrylamide. J. Control. Release 83 (2), 303
305. Husseini, G., Velluto, D., Kherbeck, L., Pitt, W., Hubbell, J., Christensen, D., 2013. Investigating the acoustic release of doxorubicin from targeted micelles. Colloid Surf. B Biointerfaces 101, 153
155. Isaacson, K., Jensen, M., Watanabe, A., Green, B., Correa, M., Cappello, J., 2018. Self-assembly of thermoresponsive recombinant silk-elastinlike nanogels. Macromol. Biosci. 18 (1). Available from: http://dx.doi. org/10.1002/mabi.201700192. Jackson, A., Fulton, D., 2012. Triggering polymeric nanoparticle disassembly through the simultaneous application of two different stimuli. Macromolecules 45 (6), 2699
2708. Jadhav, S., Miletto, I., Brunella, V., Berlier, G., Scalarone, D., 2015. Controlled post-synthesis grafting of thermoresponsive poly(N-isopropylacrylamide) on mesoporous silica nanoparticles. Polym. Adv. Technol. 26 (9), 1070
1075. Jalili-Firoozinezhad, S., Mohamadzadeh Moghadam, M., Ghanian, M., Ashtiani, M., Alimadadi, H., Baharvand, H., et al., 2017. Polycaprolactone-templated reduced-graphene oxide liquid crystal nanofibers towards biomedical applications. RSC Adv. 7 (63), 39628
39634. Ji, F., Zhang, K., Li, J., Gu, Y., Zhao, J., Zhang, J., 2018. A dual pH/magnetic responsive nanocarrier based on PEGylated Fe3O4 nanoparticles for doxorubicin delivery. J. Nanosci. Nanotechnol. 18 (7), 4464
4470. Jiang, J., Tong, X., Morris, D., Zhao, Y., 2006. Toward photocontrolled release using light-dissociable block copolymer micelles. Macromolecules 39 (13), 4633
4640. Jiang, H., Chen, D., Guo, D., Wang, N., Su, Y., Jin, X., et al., 2017a. Zwitterionic gold nanorods: low toxicity and high photothermal efficacy for cancer therapy. Biomater. Sci. 5 (4), 686
697. Jiang, T., Jin, K., Liu, X., Pang, Z., 2017b. Chapter 8: Nanoparticles for tumor targeting. In: Sougata, J., Sabyasach, M., Subrata, J. (Eds.), Biopolymer-Based Composites, Drug Delivery and Biomedical Applications. Elesevier, Cambridge, pp. 221
267. Jin, Q., Mitschang, F., Agarwal, S., 2011a. Biocompatible drug delivery system for photo-triggered controlled release of 5-fluorouracil. Biomacromolecules 12 (10), 3684
3691. Jin, Y., Song, L., Su, Y., Zhu, L., Pang, Y., Qiu, F., et al., 2011b. Oxime linkage: a robust tool for the design of pH-sensitive polymeric drug carriers. Biomacromolecules 12 (10), 3460
3468. Jin, E., Zhang, B., Sun, X., Zhou, Z., Ma, X., Sun, Q., et al., 2013. Acid-active cell-penetrating peptides for in vivo tumor-targeted drug delivery. J. Am. Chem. Soc. 135 (2), 933
940. Jochum, F., Theato, P., 2010. Thermo- and light responsive micellation of azobenzene containing block copolymers. Chem. Commun. 46 (36), 6717
6719. Karakoti, A., Das, S., Thevuthasan, S., Seal, S., 2011. PEGylated inorganic nanoparticles. Angew. Chem. Int. Ed. 50 (9), 1980
1994. Karimi, M., Ghasemi, A., Sahandi Zangabad, P., Rahighi, R., Moosavi Basri, S., Mirshekari, H., et al., 2016a. Smart micro/nanoparticles in stimulus-responsive drug/gene delivery systems. Chem. Soc. Rev. 45 (5), 1457
1501. Karimi, M., Sahandi Zangabad, P., Ghasemi, A., Amiri, M., Bahrami, M., Malekzad, H., et al., 2016b. Temperature-responsive smart nanocarriers for delivery of therapeutic agents: applications and recent advances. ACS Appl. Mater. Interfaces 8 (33), 21107
21133. Kim, Y., Ebara, M., Aoyagi, T., 2013. A smart hyperthermia nanofiber with switchable drug release for inducing cancer apoptosis. Adv. Funct. Mater. 23 (46), 5753
5761.

112

CHAPTER 2 RESPONSIVE POLYMERIC NANOTHERAPEUTICS

Kim, H., Chung, K., Lee, S., Kim, D., Lee, H., 2015. Near-infrared light-responsive nanomaterials for cancer theranostics. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 8 (1), 23
45. Ko, N., Oh, J., 2014. Glutathione-triggered disassembly of dual disulfide located degradable nanocarriers of polylactide-based block copolymers for rapid drug release. Biomacromolecules 15 (8), 3180
3189. Kojima, C., Suehiro, T., Watanabe, K., Ogawa, M., Fukuhara, A., Nishisaka, E., et al., 2013. Doxorubicinconjugated dendrimer/collagen hybrid gels for metastasis-associated drug delivery systems. Acta Biomater. 9 (3), 5673
5680. Kondawar, S.B., Agrawal, S.P., 2013. Chapter 11: Nanofibers of conducting polymer nanocomposites. In: Tiwari, A., Kobayashi, H. (Eds.), Responsive Materials and Methods: State of the Art Stimuli Responsive Materials and Their Applications. John Wiley & Sons, Inc, Hoboken, NJ, pp. 169
200. Koo, A., Min, K., Lee, H., Lee, S., Kim, K., Chan Kwon, I., et al., 2012. Tumor accumulation and antitumor efficacy of docetaxel-loaded core-shell-corona micelles with shell-specific redox-responsive cross-links. Biomaterials 33 (5), 1489
1499. Kopeˇcek, J., Kopeˇckov´a, P., 2010. HPMA copolymers: origins, early developments, present, and future. Adv. Drug Deliv. Rev. 62 (2), 122
149. Kumagai, M., Shimoda, S., Wakabayashi, R., Kunisawa, Y., Ishii, T., Osada, K., et al., 2012. Effective transgene expression without toxicity by intraperitoneal administration of PEG-detachable polyplex micelles in mice with peritoneal dissemination. J. Control. Release 160 (3), 542
551. Kumar, S., Allard, J., Morris, D., Dory, Y., Lepage, M., Zhao, Y., 2012. Near-infrared light sensitive polypeptide block copolymer micelles for drug delivery. J. Mater. Chem. 22 (15), 7252
7257. Kurzhals, S., Zirbs, R., Reimhult, E., 2015. Synthesis and magneto-thermal actuation of iron oxide core
PNIPAM shell nanoparticles. ACS Appl. Mater. Interfaces 7 (34), 19342
19352. Laemthong, T., Kim, H., Dunlap, K., Brocker, C., Barua, D., Forciniti, D., et al., 2016. Bioresponsive polymer coated drug nanorods for breast cancer treatment. Nanotechnology 28 (4), 045601. Lale, S.V., Koul, V., 2018. Stimuli-responsive polymeric nanoparticles for cancer therapy. In: Thakur, V., Thakur, M., Voicu, S. (Eds.), Polymer Gels. Gels Horizons: From Science to Smart Materials. Springer, Singapore, pp. 27
54. Lee, E., Na, K., Bae, Y., 2005. Doxorubicin loaded pH-sensitive polymeric micelles for reversal of resistant MCF-7 tumor. J. Control. Release 103 (2), 405
418. Lee, S.H., Choi, S.H., Kim, S.H., Park, T.G., 2008. Thermally sensitive cationic polymer nanocapsules for specific cytosolic delivery and efficient gene silencing of siRNA: swelling induced physical disruption of endosome by cold shock. J. Control. Release 125 (1), 25
32. Lee, J., Jang, J., Choi, J., Moon, S., Noh, S., Kim, J., et al., 2011. Exchange-coupled magnetic nanoparticles for efficient heat induction. Nat. Nanotechnol. 6 (7), 418
422. Lee, S., Saito, K., Lee, H., Lee, M., Shibasaki, Y., Oishi, Y., et al., 2012. Hyperbranched double hydrophilic block copolymer micelles of poly(ethylene oxide) and polyglycerol for pH-responsive drug delivery. Biomacromolecules 13 (4), 1190
1196. Lee, I., Park, M., Kim, Y., Hwang, O., Khang, G., Lee, D., 2013a. Ketal containing amphiphilic block copolymer micelles as pH-sensitive drug carriers. Int. J. Pharm. 448 (1), 259
266. Lee, S., Kim, S., Tyler, J., Park, K., Cheng, J., 2013b. Blood-stable, tumor-adaptable disulfide bonded mPEG(Cys)4-PDLLA micelles for chemotherapy. Biomaterials 34 (2), 552
561. ¨ z, O., et al., 2013c. Design, synthesis and biological Lee, C., Lo, S., Lim, J., da Costa, V., Ramezani, S., O assessment of a triazine dendrimer with approximately 16 paclitaxel groups and 8 PEG groups. Mol. Pharm. 10 (12), 4452
4461. Lee, J., Oh, K., Kim, D., Lee, E., 2014. pH-sensitive short worm-like micelles targeting tumors based on the extracellular pH. J. Mater. Chem. B 2 (37), 6363
6370.

REFERENCES

113

Lee, S., Bui, H., Vales, T., Cho, S., Kim, H., 2017. Multi-color fluorescence of pNIPAM-based nanogels modulated by dual stimuli-responsive FRET processes. Dyes Pigments 145, 216
221. Lestage, D.J., Urban, M.W., 2005. Cocklebur-shaped colloidal dispersions. Langmuir 21 (23), 10253
10255. Li, Y., Pan, S., Zhang, W., Du, Z., 2009. Novel thermo-sensitive core
shell nanoparticles for targeted paclitaxel delivery. Nanotechnology 20 (6), 065104. Li, X., Wen, H., Dong, H., Xue, W., Pauletti, G., Cai, X., et al., 2011. Self-assembling nanomicelles of a novel camptothecin prodrug engineered with a redox-responsive release mechanism. Chem. Commun. 47 (30), 8647
8649. Li, C., Wang, H., Cao, J., Zhang, J., Yu, X., 2014a. Bioreducible cross-linked polymers based on G1 peptide dendrimer as potential gene delivery vectors. Eur. J. Med. Chem. 87, 413
420. Li, H., Cui, Y., Liu, J., Bian, S., Liang, J., Fan, Y., et al., 2014b. Reduction breakable cholesteryl pullulan nanoparticles for targeted hepatocellular carcinoma chemotherapy. J. Mater. Chem. B 2 (22), 3500
3510. Li, J., Han, Y., Chen, Q., Shi, H., ur Rehman, S., Siddiq, M., et al., 2014c. Dual endogenous stimuliresponsive polyplex micelles as smart two-step delivery nanocarriers for deep tumor tissue penetration and combating drug resistance of cisplatin. J. Mater. Chem. B 2 (13), 1813
1824. Li, M., Tang, Z., Lv, S., Song, W., Hong, H., Jing, X., et al., 2014d. Cisplatin crosslinked pH-sensitive nanoparticles for efficient delivery of doxorubicin. Biomaterials 35 (12), 3851
3864. Li, N., Li, N., Yi, Q., Luo, K., Guo, C., Pan, D., et al., 2014e. Amphiphilic peptide dendritic copolymer-doxorubicin nanoscale conjugate self-assembled to enzyme-responsive anti-cancer agent. Biomaterials 35 (35), 9529
9545. Li, L., Knickelbein, K., Zhang, L., Wang, J., Obrinske, M., Ma, G., et al., 2015. Amphiphilic sugar poly (orthoesters) as pH-responsive nanoscopic assemblies for acidity-enhanced drug delivery and cell killing. Chem. Commun. 51 (66), 13078
13081. Li, C., Wu, G., Ma, R., Liu, Y., Liu, Y., Lv, J., et al., 2017a. Nitrilotriacetic acid (NTA) and phenylboronic acid (PBA) functionalized nanogels for efficient encapsulation and controlled release of insulin. ACS Biomater. Sci. Eng. 4 (6), 2007
2017. Li, N., Cai, H., Jiang, L., Hu, J., Bains, A., Hu, J., et al., 2017b. Enzyme-sensitive and amphiphilic PEGylated dendrimer-paclitaxel prodrug-based nanoparticles for enhanced stability and anticancer efficacy. ACS Appl. Mater. Interfaces 9 (8), 6865
6877. Li, Y., Gao, J., Zhang, C., Cao, Z., Cheng, D., Liu, J., et al., 2017c. Stimuli-responsive polymeric nanocarriers for efficient gene delivery. Top. Curr. Chem. (Cham.) 375 (2), 27. Available from: https://doi.org/10.1007/ s41061-017-0119-6. Ling, D., Hyeon, T., 2017. Chapter 13: Magnetic nanomaterials for therapy. In: Hou, Y., Sellmyer, D.J. (Eds.), Magnetic Nanomaterials
Fundamentals, Synthesis and Applications: Fundamentals, Synthesis and Applications. Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, pp. 393
437. Liu, G., Chen, C., Li, D., Wang, S., Ji, J., 2012. Near-infrared light-sensitive micelles for enhanced intracellular drug delivery. J. Mater. Chem. 22 (33), 16865. Liu, T., Wu, M., Lin, M., Yang, F., 2013a. A novel ultrasound-triggered drug vehicle with multimodal imaging functionality. Acta Biomater. 9 (3), 5453
5463. Liu, J., Pang, Y., Zhu, Z., Wang, D., Li, C., Huang, W., et al., 2013b. Therapeutic nanocarriers with hydrogen peroxide-triggered drug release for cancer treatment. Biomacromolecules 14 (5), 1627
1636. Liu, J., Huang, Y., Kumar, A., Tan, A., Jin, S., Mozhi, A., et al., 2014. pH-sensitive nano-systems for drug delivery in cancer therapy. Biotechnol. Adv. 32 (4), 693
710. Liu, B., Wang, D., Liu, Y., Zhang, Q., Meng, L., Chi, H., et al., 2015. Hydrogen peroxide-responsive anticancer hyperbranched polymer micelles for enhanced cell apoptosis. Polym. Chem. 6 (18), 3460
3471. Liu, S., Zhang, J., Cui, X., Guo, Y., Zhang, X., Hongyan, W., 2016. Synthesis of chitosan-based nanohydrogels for loading and release of 5-fluorouracil. Colloid Surf. A Physicochem. Eng. Aspects 490, 91
97.

114

CHAPTER 2 RESPONSIVE POLYMERIC NANOTHERAPEUTICS

Liu, X., Yang, Y., Urban, M.W., 2017. Stimuli-responsive polymeric nanoparticles. Macromol. Rapid Commun. 38 (13), 1700030. Lu, W., Wang, X., Cheng, R., Deng, C., Meng, F., Zhong, Z., 2015. Biocompatible and bioreducible micelles fabricated from novel α-amino acid-based poly(disulfide urethane)s: design, synthesis and triggered doxorubicin release. Polym. Chem. 6 (33), 6001
6010. Luckanagul, J., Pitakchatwong, C., Bhuket, P., Muangnoi, C., Rojsitthisak, P., Chirachanchai, S., et al., 2017. Chitosan-based polymer hybrids for thermo-responsive nanogel delivery of curcumin. Carbohydr. Polym. 181, 1119
1127. Luckanagul, J., Pitakchatwong, C., Ratnatilaka Na Bhuket, P., Muangnoi, C., Rojsitthisak, P., Chirachanchai, S., et al., 2018. Chitosan-based polymer hybrids for thermo-responsive nanogel delivery of curcumin. Carbohydr. Polym. 181, 1119
1127. Luo, T., David, M., Dunshee, L., Scott, R., Urello, M., Price, C., et al., 2017. Thermoresponsive elastin-bcollagen-like peptide bioconjugate nanovesicles for targeted drug delivery to collagen-containing matrices. Biomacromolecules 18 (8), 2539
2551. Luo, C., Zhou, Y., Zhou, T., Xing, L., Cui, P., Sun, M., et al., 2018. Reactive oxygen species-responsive nanoprodrug with quinone methides-mediated GSH depletion for improved chlorambucil breast cancers therapy. J. Control. Release 274, 56
68. Lv, C., Wang, Z., Wang, P., Tang, X., 2012. Photodegradable polyurethane self-assembled nanoparticles for photocontrollable release. Langmuir 28 (25), 9387
9394. Lv, S., Tang, Z., Zhang, D., Song, W., Li, M., Lin, J., et al., 2014. Well-defined polymer-drug conjugate engineered with redox and pH-sensitive release mechanism for efficient delivery of paclitaxel. J. Control. Release 194, 220
227. Ma, X., Nguyen, K., Borah, P., Ang, C., Zhao, Y., 2012. Functional silica nanoparticles for redox-triggered drug/ssDNA co-delivery. Adv. Healthc. Mater. 1 (6), 690
697. Manouras, T., Vamvakaki, M., 2017. Field responsive materials: photo-, electro-, magnetic- and ultrasoundsensitive polymers. Polym. Chem. 8 (1), 74
96. Manzanares-Guevara, L., Licea-Claverie, A., Paraguay-Delgado, F., 2017. Preparation of stimuli responsive nanogels based on poly(N,N-diethylaminoethyl methacrylate) by a simple “surfactant-free” methodology. Soft Mater. 16 (1), 37
50. Marin, A., Muniruzzaman, M., Rapoport, N., 2001. Acoustic activation of drug delivery from polymeric micelles: effect of pulsed ultrasound. J. Control. Release 71 (3), 239
249. Marin, A., Sun, H., Husseini, G., Pitt, W., Christensen, D., Rapoport, N., 2002. Drug delivery in pluronic micelles: effect of high-frequency ultrasound on drug release from micelles and intracellular uptake. J. Control. Release 84 (1-2), 39
47. Martelli, G., Zope, H., Bro`via Capell, M., Kros, A., 2013. Coiled-coil peptide motifs as thermoresponsive valves for mesoporous silica nanoparticles. Chem. Commun. 49 (85), 9932
9934. Martı´nez-Carmona, M., Baeza, A., Rodriguez-Milla, M., Garcı´a-Castro, J., Vallet-Regı´, M., 2015. Mesoporous silica nanoparticles grafted with a light-responsive protein shell for highly cytotoxic antitumoral therapy. J. Mater. Chem. B 3 (28), 5746
5752. Matsumoto, S., Christie, R., Nishiyama, N., Miyata, K., Ishii, A., Oba, M., et al., 2009. Environmentresponsive block copolymer micelles with a disulfide cross-linked core for enhanced siRNA delivery. Biomacromolecules 10 (1), 119
127. Mavuso, S., Choonara, Y., Marimuthu, T., Kumar, P., du Toit, L., Kondiah, P., et al., 2016. A dual pH/Redox responsive copper-ligand nanoliposome bioactive complex for the treatment of chronic inflammation. Int. J. Pharm. 509 (1-2), 348
359. Men, Y., Drechsler, M., Yuan, J., 2013. Double-stimuli-responsive spherical polymer brushes with a poly(ionic liquid) core and a thermoresponsive shell. Macromol. Rapid Commun. 34 (21), 1721
1727.

REFERENCES

115

Meng, H., Xue, M., Xia, T., Zhao, Y., Tamanoi, F., Stoddart, J., et al., 2010. Autonomous in vitro anticancer drug release from mesoporous silica nanoparticles by pH-sensitive nanovalves. J. Am. Chem. Soc. 132 (36), 12690
12697. Meng, H., Xue, M., Xia, T., Ji, Z., Tarn, D., Zink, J., et al., 2011. Use of size and a copolymer design feature to improve the biodistribution and the enhanced permeability and retention effect of doxorubicinloaded mesoporous silica nanoparticles in a murine xenograft tumor model. ACS Nano 5 (5), 4131
4144. Meng, H., Zhang, X., Lv, Y., Zhao, Z., Wang, N., Fu, T., et al., 2014a. DNA dendrimer: an efficient nanocarrier of functional nucleic acids for intracellular molecular sensing. ACS Nano 8 (6), 6171
6181. Meng, F., Zhong, Y., Cheng, R., Deng, C., Zhong, Z., 2014b. pH-sensitive polymeric nanoparticles for tumortargeting doxorubicin delivery: concept and recent advances. Nanomedicine 9 (3), 487
499. Mennini, N., Mura, P., Nativi, C., Richichi, B., Di Cesare Mannelli, L., Ghelardini, C., 2015. Injectable liposomal formulations of opiorphin as a new therapeutic strategy in pain management. Future Sci. OA 1 (3), . Available from: https://doi.org/10.1002/marc.201700030FSO2, 20 pp. Menon, S., Thekkayil, R., Varghese, S., Das, S., 2011. Photoresponsive soft materials: synthesis and photophysical studies of a stilbene-based diblock copolymer. J. Polym. Sci. A Polym. Chem. 49 (23), 5063
5073. Min, K., Kim, J., Bae, S., Shin, H., Kim, M., Park, S., et al., 2010. Tumoral acidic pH-responsive MPEG-poly (β-amino ester) polymeric micelles for cancer targeting therapy. J. Control. Release 144 (2), 259
266. Mishra, M., Beaty, C., Lesniak, W., Kambhampati, S., Zhang, F., Wilson, M., et al., 2014. Dendrimer brain uptake and targeted therapy for brain injury in a large animal model of hypothermic circulatory arrest. ACS Nano 8 (3), 2134
2147. Mo, R., Jiang, T., Sun, W., Gu, Z., 2015. ATP-responsive DNA-graphene hybrid nanoaggregates for anticancer drug delivery. Biomaterials 50, 67
74. Mohamed, S., Parayath, N., Taurin, S., Greish, K., 2014. Polymeric nano-micelles: versatile platform for targeted delivery in cancer. Ther. Deliv. 5 (10), 1101
1121. Munshi, N., Rapoport, N., Pitt, W., 1997. Ultrasonic activated drug delivery from Pluronic P-105 micelles. Cancer Lett. 118 (1), 13
19. Mura, P., Mennini, N., Nativi, C., Richichi, B., 2017. In situ mucoadhesive-thermosensitive liposomal gel as a novel vehicle for nasal extended delivery of opiorphin. Eur. J. Pharm. Biopharm. 122, 54
61. Musacchio, T., Vaze, O., D’Souza, G., Torchilin, V., 2010. Effective stabilization and delivery of siRNA: reversible siRNA 2 phospholipid conjugate in nanosized mixed polymeric micelles. Bioconjug. Chem. 21 (8), 1530
1536. Nadrah, P., Porta, F., Planinˇsek, O., Kros, A., Gaberˇscˇ ek, M., 2013. Poly(propylene imine) dendrimer caps on mesoporous silica nanoparticles for redox-responsive release: smaller is better. Phys. Chem. Chem. Phys. 15 (26), 10740
10748. Nance, E., Porambo, M., Zhang, F., Mishra, M., Buelow, M., Getzenberg, R., et al., 2015. Systemic dendrimer-drug treatment of ischemia-induced neonatal white matter injury. J. Control. Release 214, 112
120. Neamtu, I., Rusu, A.G., Diaconu, A., Nita, L.E., Chiriac, A.P., 2017. Basic concepts and recent advances in nanogels as carriers for medical applications. Drug Deliv. 24 (1), 539
557. Nguyen, T., Nguyen, T., Nguyen, C., Nguyen, D., 2017. Redox and pH responsive poly (amidoamine) dendrimer-heparin conjugates via disulfide linkages for letrozole delivery. BioMed Res. Int. 2017, 1
7. Nishimura, T., Takara, M., Mukai, S., Sawada, S., Sasaki, Y., Akiyoshi, K., 2016. A light sensitive selfassembled nanogel as a tecton for protein patterning materials. Chem. Commun. 52 (6), 1222
1225. Nuhn, L., Vanparijs, N., De Beuckelaer, A., Lybaert, L., Verstraete, G., Deswarte, K., et al., 2016. pHdegradable imidazoquinoline-ligated nanogels for lymph node-focused immune activation. Proc. Natl Acad. Sci. 113 (29), 8098
8103.

116

CHAPTER 2 RESPONSIVE POLYMERIC NANOTHERAPEUTICS

Pamfil, D., Vasile, C., 2018. Chapter 4: Nanogels of natural polymers. In: Thakur, J.K., Thakur, M.K., Voicu, S. (Eds.), Polymer Gels: Science and Fundamentals. Springer, Singapore, 978-981-10-6085-4pp. 71
110. Available from: http://dx.doi.org/10.1007/978-981-10-6080-9_4. Park, C., Kim, H., Kim, S., Kim, C., 2009. Enzyme responsive nanocontainers with cyclodextrin gatekeepers and synergistic effects in release of guests. J. Am. Chem. Soc. 131 (46), 16614
16615. Pasparakis, G., Vamvakaki, M., 2011. Multiresponsive polymers: nano-sized assemblies, stimuli-sensitive gels and smart surfaces. Polym. Chem. 2 (6), 1234
1238. Peng, Z., Kopeˇcek, J., 2014. HPMA copolymer CXCR4 antagonist conjugates substantially inhibited the migration of prostate cancer cells. ACS Macro Lett. 3 (12), 1240
1243. Peng, Z., Kopeˇcek, J., 2015. Enhancing accumulation and penetration of HPMA copolymer
doxorubicin conjugates in 2D and 3D prostate cancer cells via iRGD conjugation with an MMP-2 cleavable spacer. J. Am. Chem. Soc. 137 (21), 6726
6729. Peng, L., Feng, A., Zhang, H., Wang, H., Jian, C., Liu, B., et al., 2014. Voltage-responsive micelles based on the assembly of two biocompatible homopolymers. Polym. Chem. 5 (5), 1751
1759. P´erez, E., Martı´nez, A., Teijo´n, C., Teijo´n, J., Blanco, M., 2014. Bioresponsive nanohydrogels based on HEAA and NIPA for poorly soluble drugs delivery. Int. J. Pharm. 470 (1-2), 107
119. P´erez, E., Olmo, R., Teijo´n, C., Mun˜´ız, E., Montero, N., Teijo´n, J., et al., 2015. Biocompatibility evaluation of pH and glutathione-responsive nanohydrogels after intravenous administration. Colloid Surf. B Biointerfaces 136, 222
231. Permyakova, N., Zheltonozhskaya, T., Ignatovskaya, M., Maksin, V., Iakubchak, O., Klymchuk, D., 2018. Stimuli-responsive properties of special micellar nanocarriers and their application for delivery of vitamin E and its analogues. Colloid Polym. Sci. 296 (2), 295
307. Prasad, M., Lambe, U., Brar, B., Shah, I., Ranjan, K., Rao, R., et al., 2018. Nanotherapeutics: an insight into healthcare and multi-dimensional applications in medical sector of the modern world. Biomed. Pharmacother. 97, 1521
1537. Pruitt, J., Husseini, G., Rapoport, N., Pitt, W., 2000. Stabilization of pluronic P-105 micelles with an interpenetrating network of N,N-diethylacrylamide. Macromolecules 33 (25), 9306
9309. Quader, S., Cabral, H., Mochida, Y., Ishii, T., Liu, X., Toh, K., et al., 2014. Selective intracellular delivery of proteasome inhibitors through pH-sensitive polymeric micelles directed to efficient antitumor therapy. J. Control. Release 188, 67
77. Quadir, M., Morton, S., Deng, Z., Shopsowitz, K., Murphy, R., Epps, T., et al., 2014. PEG
polypeptide block copolymers as pH-responsive endosome-solubilizing drug nanocarriers. Mol. Pharm. 11 (7), 2420
2430. Radhakrishnan, B., Ranjan, R., Brittain, W., 2006. Surface initiated polymerizations from silica nanoparticles. Soft Matter 2 (5), 386
396. Rapoport, N., 1999. Stabilization and activation of Pluronic micelles for tumor-targeted drug delivery. Colloid Surf. B Biointerfaces 16 (1-4), 93
111. Rapoport, N., 2012. Ultrasound-mediated micellar drug delivery. Int. J. Hyperther. 28 (4), 374
385. Rapoport, N., Christensen, D., Fain, H., Barrows, L., Gao, Z., 2004. Ultrasound-triggered drug targeting of tumors in vitro and in vivo. Ultrasonics 42 (1-9), 943
950. Rapoport, N., Gao, Z., Kennedy, A., 2007. Multifunctional nanoparticles for combining ultrasonic tumor imaging and targeted chemotherapy. J. Natl Cancer Inst. 99 (14), 1095
1106. Ren, T., Feng, Y., Zhang, Z., Li, L., Li, Y., 2011. Shell-sheddable micelles based on star-shaped poly(ε-caprolactone)-SS-poly(ethyl glycol) copolymer for intracellular drug release. Soft Matter 7 (6), 2329
2331. Rijcken, C., Veldhuis, T., Ramzi, A., Meeldijk, J., van Nostrum, C., Hennink, W., 2005. Novel fast degradable thermosensitive polymeric micelles based on PEG-block-poly(N-(2-hydroxyethyl)methacrylamide-oligolactates. Biomacromolecules 6 (4), 2343
2351.

REFERENCES

117

Rijcken, C., Soga, O., Hennink, W., Nostrum, C., 2007a. Triggered destabilisation of polymeric micelles and vesicles by changing polymers polarity: an attractive tool for drug delivery. J. Control. Release 120 (3), 131
148. Rijcken, C., Snel, C., Schiffelers, R., van Nostrum, C., Hennink, W., 2007b. Hydrolysable core-crosslinked thermosensitive polymeric micelles: synthesis, characterisation and in vivo studies. Biomaterials 28 (36), 5581
5593. Romasanta, L., Lopez-Manchado, M., Verdejo, R., 2015. Increasing the performance of dielectric elastomer actuators: a review from the materials perspective. Prog. Polym. Sci. 51, 188
211. Ruiz-Hernández, E., Baeza, A., Vallet-Regi,́ M., 2011. Smart drug delivery through DNA/magnetic nanoparticle gates. ACS Nano 5 (2), 1259
1266. Saint-Cricq, P., Deshayes, S., Zink, J., Kasko, A., 2015. Magnetic field activated drug delivery using thermodegradable azo-functionalised PEG-coated core
shell mesoporous silica nanoparticles. Nanoscale 7 (31), 13168
13172. Saneja, A., Kumar, R., Arora, D., Kumar, S., Panda, A., Jaglan, S., 2018. Recent advances in near-infrared light-responsive nanocarriers for cancer therapy. Drug Discov. Today 23 (5), 1115
1125. Sawant, R., Jhaveri, A., 2014. Chapter 3: Micellar nanopreparations for medicine. In: Torchilin, V. (Ed.), Handbook of Nanobiomedical Research: Fundamentals, Applications and Recent Developments. Northeastern University, Boston, MA, pp. 87
139. Sawant, R., Vaze, O., Wang, T., D’Souza, G., Rockwell, K., Gada, K., et al., 2011. Palmitoyl ascorbate liposomes and free ascorbic acid: comparison of anticancer therapeutic effects upon parenteral administration. Pharm. Res. 29 (2), 375
383. Schlossbauer, A., Warncke, S., Gramlich, P., Kecht, J., Manetto, A., Carell, T., et al., 2010. A programmable DNA-based molecular valve for colloidal mesoporous silica. Angew. Chem. Int. Ed. 49 (28), 4734
4737. Shao, P., Wang, B., Wang, Y., Li, J., Zhang, Y., 2011. The application of thermosensitive nanocarriers in controlled drug delivery. J. Nanomater. 2011, 1
12. She, W., Li, N., Luo, K., Guo, C., Wang, G., Geng, Y., et al., 2013. Dendronized heparin 2 doxorubicin conjugate based nanoparticle as pH-responsive drug delivery system for cancer therapy. Biomaterials 34 (9), 2252
2264. Shi, C., Guo, X., Qu, Q., Tang, Z., Wang, Y., Zhou, S., 2014. Actively targeted delivery of anticancer drug to tumor cells by redox-responsive star-shaped micelles. Biomaterials 35 (30), 8711
8722. Shi, J., Wang, X., Xu, S., Wu, Q., Cao, S., 2016. Reversible thermal-tunable drug delivery across nanomembranes of hollow PUA/PSS multilayer microcapsules. J. Membr. Sci. 499, 307
316. Shieh, M., Peng, C., Chiang, W., Wang, C., Hsu, C., Wang, S., et al., 2010. Reduced skin photosensitivity withmeta-tetra(hydroxyphenyl)chlorin-loaded micelles based on a poly(2-ethyl-2-oxazoline)-b-poly(d,l-lactide) diblock copolymer in vivo. Mol. Pharm. 7 (4), 1244
1253. Sim, T., Lim, C., Cho, Y., Lee, E., Youn, Y., Oh, K., 2018. Development of pH-sensitive nanogels for cancer treatment using crosslinked poly(aspartic acid-graft-imidazole)-block-poly(ethylene glycol). J. Appl. Polym. Sci. 135 (20), 46268. Singh, N., Karambelkar, A., Gu, L., Lin, K., Miller, J., Chen, C., et al., 2011. Bioresponsive mesoporous silica nanoparticles for triggered drug release. J. Am. Chem. Soc. 133 (49), 19582
19585. Soga, O., van Nostrum, C., Fens, M., Rijcken, C., Schiffelers, R., Storm, G., et al., 2005. Thermosensitive and biodegradable polymeric micelles for paclitaxel delivery. J. Control. Release 103 (2), 341
353. Song, L., Zhang, B., Jin, E., Xiao, C., Li, G., Chen, X., 2018. A reduction-sensitive thermo-responsive polymer: synthesis, characterization, and application in controlled drug release. Eur. Polym. J. 101, 183
189. Stuart, M., Huck, W., Genzer, J., Mu¨ller, M., Ober, C., Stamm, M., et al., 2010. Emerging applications of stimuli-responsive polymer materials. Nat. Mater. 9 (2), 101
113.

118

CHAPTER 2 RESPONSIVE POLYMERIC NANOTHERAPEUTICS

Sufi, S., Pajaniradje, S., Mukherjee, V., Rajagopalan, R., 2018. Redox nano-architectures: perspectives and implications in diagnosis and treatment of human diseases. Antioxid. Redox Signal. Available from: https://doi.org/10.1089/ars.2017.7412. Sun, L., Yang, Y., Dong, C., Wei, Y., 2010. Two-photon-sensitive and sugar-targeted nanocarriers from degradable and dendritic amphiphiles. Small 7 (3), 401
406. Sun, P., Zhou, D., Gan, Z., 2011. Novel reduction-sensitive micelles for triggered intracellular drug release. J. Control. Release 152, e85
e87. Sun, H., Meng, F., Cheng, R., Deng, C., Zhong, Z., 2014. Reduction and pH dual-bioresponsive crosslinked polymersomes for efficient intracellular delivery of proteins and potent induction of cancer cell apoptosis. Acta Biomater. 10 (5), 2159
2168. Sun, H., Cheng, R., Deng, C., Meng, F., Dias, A., Hendriks, M., et al., 2015. Enzymatically and reductively degradable α-amino acid-based poly(ester amide)s: synthesis, cell compatibility, and intracellular anticancer drug delivery. Biomacromolecules 16 (2), 597
605. Sun, Z., Yi, Z., Zhang, H., Ma, X., Su, W., Sun, X., et al., 2017. Bio-responsive alginate-keratin composite nanogels with enhanced drug loading efficiency for cancer therapy. Carbohydr. Polym. 175, 159
169. Takae, S., Miyata, K., Oba, M., Ishii, T., Nishiyama, N., Itaka, K., et al., 2008. PEG-detachable polyplex micelles based on disulfide-linked block catiomers as bioresponsive nonviral gene vectors. J. Am. Chem. Soc. 130 (18), 6001
6009. Talelli, M., Rijcken, C., van Nostrum, C., Storm, G., Hennink, W., 2010a. Micelles based on HPMA copolymers. Adv. Drug Deliv. Rev. 62 (2), 231
239. Talelli, M., Iman, M., Varkouhi, A., Rijcken, C., Schiffelers, R., Etrych, T., et al., 2010b. Core-crosslinked polymeric micelles with controlled release of covalently entrapped doxorubicin. Biomaterials 31 (30), 7797
7804. Talelli, M., Rijcken, C., Oliveira, S., van der Meel, R., van Bergen en Henegouwen, P., Lammers, T., et al., 2011. Nanobody—shell functionalized thermosensitive core-crosslinked polymeric micelles for active drug targeting. J. Control. Release 151 (2), 183
192. Tang, R., Ji, W., Panus, D., Palumbo, R., Wang, C., 2011. Block copolymer micelles with acid-labile ortho ester side-chains: synthesis, characterization, and enhanced drug delivery to human glioma cells. J. Control. Release 151 (1), 18
27. Tang, S., Yin, Q., Zhang, Z., Gu, W., Chen, L., Yu, H., et al., 2014. Co-delivery of doxorubicin and RNA using pH-sensitive poly (β-amino ester) nanoparticles for reversal of multidrug resistance of breast cancer. Biomaterials 35 (23), 6047
6059. Thomas, C., Ferris, D., Lee, J., Choi, E., Cho, M., Kim, E., et al., 2010. Noninvasive remote-controlled release of drug molecules in vitro using magnetic actuation of mechanized nanoparticles. J. Am. Chem. Soc. 132 (31), 10623
10625. Torchilin, V., 2009. Multifunctional and stimuli-sensitive pharmaceutical nanocarriers. Eur. J. Pharm. Biopharm. 71 (3), 431
444. Torchilin, V., 2014. Multifunctional, stimuli-sensitive nanoparticulate systems for drug delivery. Nat. Rev. Drug Discov. 13 (11), 813
827. Ugarenko, M., Chan, C., Nudelman, A., Rephaeli, A., Cutts, S., Phillips, D., 2009. Development of pluronic micelle-encapsulated doxorubicin and formaldehyde-releasing prodrugs for localized anticancer chemotherapy. Oncol. Res. Featur. Preclin. Clin. Cancer Ther. 17 (7), 283
299. van Rijt, S., Bo¨lu¨kbas, D., Argyo, C., Datz, S., Lindner, M., Eickelberg, O., et al., 2015. Protease-mediated release of chemotherapeutics from mesoporous silica nanoparticles to ex vivo human and mouse lung tumors. ACS Nano 9 (3), 2377
2389. Wajs, E., Nielsen, T., Larsen, K., Fragoso, A., 2016. Preparation of stimuli-responsive nano-sized capsules based on cyclodextrin polymers with redox or light switching properties. Nano Res. 9 (7), 2070
2078.

REFERENCES

119

Wang, Y., Guo, L., 2016. Nanomaterial-enabled neural stimulation. Front. Neurosci. 10, 69. Wang, J., Sun, X., Mao, W., Sun, W., Tang, J., Sui, M., et al., 2013a. Tumor redox heterogeneity-responsive prodrug nanocapsules for cancer chemotherapy. Adv. Mater. 25 (27), 3670
3676. Wang, X., Sun, H., Meng, F., Cheng, R., Deng, C., Zhong, Z., 2013b. Galactose-decorated reduction-sensitive degradable chimaeric polymersomes as a multifunctional nanocarrier to efficiently chaperone apoptotic proteins into hepatoma cells. Biomacromolecules 14 (8), 2873
2882. Wang, Y., Zhou, K., Huang, G., Hensley, C., Huang, X., Ma, X., et al., 2013c. A nanoparticle-based strategy for the imaging of a broad range of tumours by nonlinear amplification of microenvironment signals. Nat. Mater. 13 (2), 204
212. Wang, J., Yang, G., Guo, X., Tang, Z., Zhong, Z., Zhou, S., 2014. Redox-responsive polyanhydride micelles for cancer therapy. Biomaterials 35 (9), 3080
3090. Wang, Y., Zheng, J., Tian, Y., Yang, W., 2015a. Acid degradable poly(vinylcaprolactam)-based nanogels with ketal linkages for drug delivery. J. Mater. Chem. B 3 (28), 5824
5832. Wang, Z., Ma, G., Zhang, J., Yuan, Z., Wang, L., Bernards, M., et al., 2015b. Surface protonation/deprotonation controlled instant affinity switch of nano drug vehicle (NDV) for pH triggered tumor cell targeting. Biomaterials 62, 116
127. Wang, G., Huang, G., Zhao, Y., Pu, X., Li, T., Deng, J., et al., 2016a. ATP triggered drug release and DNA co-delivery systems based on ATP responsive aptamers and polyethylenimine complexes. J. Mater. Chem. B 4 (21), 3832
3841. Wang, H., Huang, Q., Chang, H., Xiao, J., Cheng, Y., 2016b. Stimuli-responsive dendrimers in drug delivery. Biomater. Sci. 4, 375
390. Wang, Y., Ying, X., Chen, L., Liu, Y., Wang, Y., Liang, J., et al., 2016c. Electroresponsive nanoparticles improve antiseizure effect of phenytoin in generalized tonic-clonic seizures. Neurotherapeutics 13 (3), 603
613. Wang, Y., Huang, F., Sun, Y., Gao, M., Chai, Z., 2016d. Development of shell cross-linked nanoparticles based on boronic acid-related reactions for self-regulated insulin delivery. J. Biomater. Sci. Polym. Ed. 28 (1), 93
106. Wang, Y., Luo, Y., Zhao, Q., Wang, Z., Xu, Z., Jia, X., 2016e. An enzyme-responsive nanogel carrier based on PAMAM dendrimers for drug delivery. ACS Appl. Mater. Interfaces 8 (31), 19899
19906. Weaver, C., LaRosa, J., Luo, X., Cui, X., 2014. Electrically controlled drug delivery from graphene oxide nanocomposite films. ACS Nano 8 (2), 1834
1843. Wei, X., Lv, X., Zhao, Q., Qiu, L., 2013. Thermosensitive β-cyclodextrin modified poly(ε-caprolactone)-poly (ethylene glycol)-poly(ε-caprolactone) micelles prolong the anti-inflammatory effect of indomethacin following local injection. Acta Biomater. 9 (6), 6953
6963. Wen, H., Dong, H., Xie, W., Li, Y., Wang, K., Pauletti, G., et al., 2011. Rapidly disassembling nanomicelles with disulfide-linked PEG shells for glutathione-mediated intracellular drug delivery. Chem. Commun. 47 (12), 3550
3552. Wu, L., Zou, Y., Deng, C., Cheng, R., Meng, F., Zhong, Z., 2013. Intracellular release of doxorubicin from core-crosslinked polypeptide micelles triggered by both pH and reduction conditions. Biomaterials 34 (21), 5262
5272. Wu, W., Yao, W., Wang, X., Xie, C., Zhang, J., Jiang, X., 2015. Bioreducible heparin-based nanogel drug delivery system. Biomaterials 39, 260
268. Wu, J., Bremner, D., Li, H., Sun, X., Zhu, L., 2016. Synthesis and evaluation of temperature- and glucosesensitive nanoparticles based on phenylboronic acid and N -vinylcaprolactam for insulin delivery. Mater. Sci. Eng. C 69, 1026
1035. Xia, F., Ge, H., Hou, Y., Sun, T., Chen, L., Zhang, G., et al., 2007. Multiresponsive surfaces change between superhydrophilicity and superhydrophobicity. Adv. Mater. 19 (18), 2520
2524.

120

CHAPTER 2 RESPONSIVE POLYMERIC NANOTHERAPEUTICS

Xiong, Q., Cui, M., Yu, G., Wang, J., Song, T., 2018. Facile fabrication of reduction-responsive supramolecular nanoassemblies for co-delivery of doxorubicin and sorafenib toward hepatoma cells. Front. Pharmacol. 9 (61). Available from: https://doi.org/10.3389/fphar.2018.00061. Xu, C., Lin, Y., Wang, J., Wu, L., Wei, W., Ren, J., et al., 2013. Nanoceria-triggered synergetic drug release based on CeO2-capped mesoporous silica host-guest interactions and switchable enzymatic activity and cellular effects of CeO2. Adv. Healthc. Mater. 2 (12), 1591
1599. Xu, P., Yu, H., Zhang, Z., Meng, Q., Sun, H., Chen, X., et al., 2014. Hydrogen-bonded and reduction-responsive micelles loading atorvastatin for therapy of breast cancer metastasis. Biomaterials 35 (26), 7574
7587. Xuan, J., Boissie`re, O., Zhao, Y., Yan, B., Tremblay, L., Lacelle, S., et al., 2012. Ultrasound-responsive block copolymer micelles based on a new amplification mechanism. Langmuir 28 (47), 16463
16468. Yan, B., Boyer, J., Branda, N., Zhao, Y., 2011. Near-infrared light-triggered dissociation of block copolymer micelles using upconverting nanoparticles. J. Am. Chem. Soc. 133 (49), 9714
9717. Yang, M., Ding, Y., Zhang, L., Qian, X., Jiang, X., Liu, B., 2007. Novel thermosensitive polymeric micelles for docetaxel delivery. J. Biomed. Mater. Res. A 81A (4), 847
857. Yang, J., Zhang, D., Jiang, S., Yang, J., Nie, J., 2010. Synthesis of Y-shaped poly(solketal acrylate)-containing block copolymers and study on the thermoresponsive behavior for micellar aggregates. J. Colloid Interface Sci. 352 (2), 405
414. Yang, X., Liu, X., Liu, Z., Pu, F., Ren, J., Qu, X., 2012. Near-infrared light-triggered, targeted drug delivery to cancer cells by aptamer gated nanovehicles. Adv. Mater. 24 (21), 2890
2895. Yang, X., Du, X., Liu, Y., Zhu, Y., Liu, Y., Li, Y., et al., 2013. Rational design of polyion complex nanoparticles to overcome cisplatin resistance in cancer therapy. Adv. Mater. 26 (6), 931
936. Yen, H., Cabral, H., Mi, P., Toh, K., Matsumoto, Y., Liu, X., et al., 2014. Light-induced cytosolic activation of reduction-sensitive camptothecin-loaded polymeric micelles for spatiotemporally controlled in vivo chemotherapy. ACS Nano 8 (11), 11591
11602. Yilmaz, G., Guler, E., Geyik, C., Demir, B., Ozkan, M., Odaci Demirkol, D., et al., 2018. pH responsive glycopolymer nanoparticles for targeted delivery of anti-cancer drugs. Mol. Syst. Des. Eng. 3 (1), 150
158. Yim, H., Park, S., Bae, Y., Na, K., 2013. Biodegradable cationic nanoparticles loaded with an anticancer drug for deep penetration of heterogeneous tumours. Biomaterials 34 (31), 7674
7682. Ying, X., Wang, Y., Liang, J., Yue, J., Xu, C., Lu, L., et al., 2014. Angiopep-conjugated electro-responsive hydrogel nanoparticles: therapeutic potential for epilepsy. Angew. Chem. Int. Ed. 53, 12436
12440. Zhang, H., Xia, H., Wang, J., Li, Y., 2009. High intensity focused ultrasound-responsive release behavior of PLA-b-PEG copolymer micelles. J. Control. Release 139 (1), 31
39. Zhang, D., Wei, Y., Chen, K., Zhang, X., Xu, X., Shi, Q., et al., 2014a. Biocompatible reactive oxygen species (ROS)-responsive nanoparticles as superior drug delivery vehicles. Adv. Healthc. Mater. 4 (1), 69
76. Zhang, X., Achazi, K., Steinhilber, D., Kratz, F., Dernedde, J., Haag, R., 2014b. A facile approach for dualresponsive prodrug nanogels based on dendritic polyglycerols with minimal leaching. J. Control. Release 174, 209
216. Zhang, C., Pan, D., Luo, K., She, W., Guo, C., Yang, Y., et al., 2014c. Peptide dendrimer-doxorubicin conjugate-based nanoparticles as an enzyme-responsive drug delivery system for cancer therapy. Adv. Healthc. Mater. 3 (8), 1299
1308. Zhang, J., Niemela¨, M., Westermarck, J., Rosenholm, J., 2014d. Mesoporous silica nanoparticles with redoxresponsive surface linkers for charge-reversible loading and release of short oligonucleotides. Dalton Trans. 43 (10), 4115
4126. Zhang, B., Shi, W., Jiang, T., Wang, L., Mei, H., Lu, H., et al., 2016a. Optimization of the tumor microenvironment and nanomedicine properties simultaneously to improve tumor therapy. Oncotarget 7 (38), 62607
62618. Zhang, W., Wang, F., Wang, Y., Wang, J., Yu, Y., Guo, S., et al., 2016b. pH and near-infrared light dualstimuli responsive drug delivery using DNA-conjugated gold nanorods for effective treatment of multidrug resistant cancer cells. J. Control. Release 232, 9
19.

REFERENCES

121

Zhang, Y., Huang, L., Li, Z., Ma, G., Zhou, Y., Han, G., 2016c. Illuminating cell signaling with near-infrared light-responsive nanomaterials. ACS Nano 10 (4), 3881
3885. Zhang, Y., Lu, Y., Wang, F., An, S., Zhang, Y., Sun, T., et al., 2016d. ATP/pH dual responsive nanoparticle with d-[des-Arg10]Kallidin mediated efficient in vivo targeting drug delivery. Small 13 (3), 1602494. Zhang, C., Pan, D., Li, J., Hu, J., Bains, A., Guys, N., et al., 2017. Enzyme-responsive peptide dendrimergemcitabine conjugate as a controlled-release drug delivery vehicle with enhanced antitumor efficacy. Acta Biomater. 55, 153
162. Zhao, Y., 2012. Light-responsive block copolymer micelles. Macromolecules 45 (9), 3647
3657. Zhao, A., Zhou, S., Zhou, Q., Chen, T., 2010. Thermosensitive micelles from PEG-based ether-anhydride triblock copolymers. Pharm. Res. 27 (8), 1627
1643. Zhao, B., Zhao, Y., Huang, Y., Luo, L., Song, P., Wang, X., et al., 2012. The efficiency of tumor-specific pHresponsive peptide-modified polymeric micelles containing paclitaxel. Biomaterials 33 (8), 2508
2520. Zhao, Y., Tavares, A., Gauthier, M., 2016. Nano-engineered electro-responsive drug delivery systems. J. Mater. Chem. B 4 (18), 3019
3030. Zhong, Y., Yang, W., Sun, H., Cheng, R., Meng, F., Deng, C., et al., 2013. Ligand-directed reduction-sensitive shell-sheddable biodegradable micelles actively deliver doxorubicin into the nuclei of target cancer cells. Biomacromolecules 14 (10), 3723
3730. Zhong, Y., Zhang, J., Cheng, R., Deng, C., Meng, F., Xie, F., et al., 2015. Reversibly crosslinked hyaluronic acid nanoparticles for active targeting and intelligent delivery of doxorubicin to drug resistant CD44 1 human breast tumor xenografts. J. Control. Release 205, 144
154. Zhou, T., Zhao, X., Liu, L., Liu, P., 2015a. Preparation of biodegradable PEGylated pH/reduction dual-stimuli responsive nanohydrogels for controlled release of an anti-cancer drug. Nanoscale 7 (28), 12051
12060. Zhou, Z., Badkas, A., Stevenson, M., Lee, J., Leung, Y., 2015b. Herceptin conjugated PLGA-PHis-PEG pH sensitive nanoparticles for targeted and controlled drug delivery. Int. J. Pharm. 487 (1-2), 81
90. Zhu, Y., Fujiwara, M., 2007. Installing dynamic molecular photomechanics in mesopores: a multifunctional controlled-release nanosystem. Angew. Chem. Int. Ed. 46 (13), 2241
2244. Zhu, Y., Liu, H., Li, F., Ruan, Q., Wang, H., Fujiwara, M., et al., 2010. Dipolar molecules as impellers achieving electric-field-stimulated release. J. Am. Chem. Soc. 132 (5), 1450
1451. Zhu, L., Wang, T., Perche, F., Taigind, A., Torchilin, V., 2013. Enhanced anticancer activity of nanopreparation containing an MMP2-sensitive PEG-drug conjugate and cell-penetrating moiety. Proc. Natl Acad. Sci. 110 (42), 17047
17052. Zhu, L., Perche, F., Wang, T., Torchilin, V., 2014a. Matrix metalloproteinase 2-sensitive multifunctional polymeric micelles for tumor-specific co-delivery of siRNA and hydrophobic drugs. Biomaterials 35 (13), 4213
4222. Zhu, Q., Jia, L., Gao, Z., Wang, C., Jiang, H., Zhang, J., et al., 2014b. A tumor environment responsive doxorubicin-loaded nanoparticle for targeted cancer therapy. Mol. Pharm. 11 (10), 3269
3278. Zou, J., Zhang, F., Zhang, S., Pollack, S., Elsabahy, M., Fan, J., et al., 2013. Poly(ethylene oxide)-block-polyphosphoester-graft-paclitaxel conjugates with acid-labile linkages as a ph-sensitive and functional nanoscopic platform for paclitaxel delivery. Adv. Healthc. Mater. 3 (3), 441
448. Zou, Y., Song, Y., Yang, W., Meng, F., Liu, H., Zhong, Z., 2014. Galactose-installed photo-crosslinked pHsensitive degradable micelles for active targeting chemotherapy of hepatocellular carcinoma in mice. J. Control. Release 193, 154
161. Zuo, Y., Jiao, Z., Ma, L., Song, P., Wang, R., Xiong, Y., 2016. Hydrogen bonding induced UCST phase transition of poly(ionic liquid)-based nanogels. Polymer 98, 287
293. Zuo, X., Song, S., Zhang, J., Pan, D., Wang, L., Fan, C., 2007. A target-responsive electrochemical aptamer switch (TREAS) for reagentless detection of nanomolar ATP. J. Am. Chem. Soc. 129 (5), 1042
1043.