Responsive polyelectrolyte complexes based on natural polysaccharides for drug delivery applications

Responsive polyelectrolyte complexes based on natural polysaccharides for drug delivery applications

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Benjamin D. Emmanuel*, Nedal Y. Abu-Thabit†, Ndidi C. Ngwuluka* ⁎ University of Jos, Jos, Nigeria, †Department of Chemical and Process Engineering Technology, Jubail Industrial College, Jubail Industrial City, Saudi Arabia

10.1 Introduction Responsive drug delivery attempts to deliver drugs to target sites in a “smart,” “intelligent,” or “environmentally sensitive” manner that mimics biological systems [1]. The appeal for such a drug delivery system stems from the need to deliver drugs unchanged to the target site of action, and have the drug released at that site in the right quantity, time, and duration. Drug action is often required in one particular part or section of the body as opposed to the systemic action of conventional drug delivery. Such is the case in cancer and gene therapy. Therefore, to get to the target site, the drug will have to overcome possible denaturing, pass through impermeable membranes, and evade uptake where it is not required. Therapeutically relevant drugs may yet remain impotent if a suitable means of delivering them to the target site is not available. Hence, drug delivery as a field has continued to evolve from conventional techniques to newer, more efficient ones, with the vehicles of drug delivery, namely polymers, being the central focus [2]. In the face of ever-growing concerns over the safety of synthetic polymers, natural polysaccharides have enjoyed an increasing interest due to their low price, availability, nontoxicity, and biodegradability [3]. Natural polysaccharides are complex carbohydrate biopolymers made up of monosaccharide units linked by glycosidic bonds into linear or branched chains of varying lengths [4]. They are obtained mainly from plants where they serve as structural ­(cellulose), reserve (starch), or protective (pectin and hemicelluloses) components [4]. Others are obtained from seaweeds (e.g., alginate from brown algae), shells of crustaceans (chitosan), and microorganisms by genetic engineering. The usefulness of natural polysaccharides is enhanced by different chemical modifications [5] involving reactive amino, carboxylic acid, or hydroxyl groups. Various functional groups can be added to backbone polysaccharides by postmodification methodology including esterification, etherification, and cross-linking reactions [6]. Polysaccharides bearing ionizable groups in their monomeric repeating units are called polyelectrolytes (PELs). PELs are divided into polycations and polyanions. The electrostatic interaction between a polyanion and a polycation gives rise to a Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications. https://doi.org/10.1016/B978-0-08-101997-9.00014-X Copyright © 2018 Elsevier Ltd. All rights reserved.

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Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications

p­ olyelectrolyte complex (PEC) [7], which has great value in the design of drug delivery systems that can respond in a predetermined way to temperature, pH, light, biomolecules, or other stimuli. The special attraction for PECs based on natural PELs is that they are formed without the use of chemical cross-linking agents and, being themselves of natural origin, are biocompatible [8]. The areas of possible application are numerous, and reflect the ­cutting-edge advances in drug delivery technology affording improved safety and efficacy of otherwise deleterious or labile active pharmaceutical ingredients (APIs). PECs are applicable for different uses such as coatings on films and fibers, implants for medical use, microcapsules, beads, fibers, films, hydrogels, supports for catalysts, and binders [9].

10.2 Polysaccharides in drug delivery From the most conventional to the recent drug delivery technologies, polysaccharides are inevitable components. Bulking agents, binders, disintegrants, capsule shells, which are made up of starch, cellulose, alginate, and other polysaccharides, are commonplace components of drugs. Polysaccharides with adhesive properties such as pregelatinized starch and cellulose make ideal binders [10]. This binding property affords easy tabletting and controls drug release. Pharmaceutical disintegrants are usually polysaccharides which exhibit good swelling property in contact with water as well as capillarity, particle repulsive properties, deformation recovery, and enzymatic activity [11]. Chitosan, corn starch, gellan gum, and agar are examples of disintegrants. Where modified release of drugs is desired, the polysaccharides often require some measure of modification. For example, croscarmellose, carboxymethyl cellulose, sodium starch glycolate are examples of modified polysaccharides used as superdisintegrants [12]. As the need for delayed-release formulations came up, polysaccharides remained the major resource of excipients. Driven by the need to minimize side effects, improve margins of safety and patient outcomes in general, formulators used polysaccharides such as guar gum, xanthan gum, locust bean gum, and chitosan to make sustained-­ release formulations [13]. More recently, site-specific delivery and targeted delivery have come to the fore, with the aim of delivering drugs directly to target sites thereby reducing the administered dose and side effects and generally increasing drug utilization. Drugs that are poorly absorbed or unstable require special delivery [14]. In such areas of drug delivery requiring precision, tailor-made synthetic polymers have gained some popularity. However, natural polysaccharides have remained prominent, since they can lend themselves to varying degrees of modification, for instance, cross-linked chitosan for colon delivery [15], cross-linked alginate-chitosan blend gel beads [16], cross-linked hybrid nanogels of alginate and PAMAM for cancer targeting [17], and cross-linked chondroitin sulfate [18]. From the instances given, it may be said that natural polymers in their crude form may not be suitable for the newer “smart” drug delivery systems. With varying degrees of modification, however, natural polysaccharides continue their foray into every area of drug delivery.

Responsive polyelectrolyte complexes based on natural polysaccharides for drug delivery applications269

10.3 Polyelectrolyte complexes PELs are charged macromolecules with positive or negative charges, which are termed as cationic PELs and anionic PELs, respectively. A PEC is formed when cationic polyelectrolyte is mixed with the oppositely charged anionic polyelectrolyte macromolecule. The mixing process of polyanions and polycations results in the formation of polysalts. The main driving force for the polyelectrolyte complexation (Fig. 10.1) is the increase in entropy due to the release of low-molecular weight counterions [19,20]. The contribution from enthalpy due to electrostatic interactions (e.g., hydrogen bonding and hydrophobic interactions) is considered to be a minor contribution [19]. The physical/ionic interaction during the formation of the PECs is referred as “ionic cross-linking” due to the involvement of positively and negatively charged ions in the cross-linking process. As opposed to chemical cross-linking that employs permanent covalent bonds, ionic cross-linking produces labile and flexible ionic networks in a reversible process [21–23]. PECs have been used in a variety of applications such as self-healing coatings [21], sensors [24], biosensors [25], and biomedical applications [26]. PECs have been used for different medical and pharmaceutical applications including tissue engineering [27], target and controlled drug delivery [8,28–30], gene delivery [31], vaccine delivery [32], imaging, and diagnostic applications [33]. In case of targeted drug delivery application, PECs prepared via ionic cross-linking route offer the following advantages: ●

●

The reduced toxicity and enhanced biocompatibility of PECs due to the avoidance of using toxic cross-linking reagents, organic precursors, and catalysts during the formation of covalently cross-linked hydrogels or cross-linked semi/full interpenetrating networks (IPNs) [34,35]. Enhanced biodegradability of some PELs. For instance, certain human enzymes such as lysozyme metabolize chitosan [35].

Fig. 10.1  Schematic illustration for the release of counterions during the formation of polyelectrolyte complex.

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●

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Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications

The ability of PECs to interact with a variety of organic/inorganic molecules through ­electrostatic interactions and hydrogen bonding, which facilitates the loading of different drugs for targeted drug delivery applications. The ability of PECs to encapsulate and entrap different hydrophilic and hydrophobic drug molecules. PECs provide enhanced stability for therapeutics against chemical and enzymatic degradation. The ability of PECs to respond reversibly to different stimuli based on the conditions of the surrounding environment. The stimuli-responsive feature of PECs allows the use of PECs for targeted and controlled release of drugs and therapeutic agents in response to exogenous stimulus (temperature, light, electric pulses) or endogenous stimuli (pH, enzyme concentration or redox gradient). The stimuli-responsive PECs can be utilized to enhance the bioavailability of drugs by controlling the release of payloads at certain points in the human body.

The formation and stability of PECs depend on many factors such as the degree of ionization of each of the oppositely charged PELs, the density of the charges on the PELs, the charge distribution over the polymeric chains, the concentration of the PELs, their mixing ratio, the mixing order, the duration of the interaction, the nature of the ionic groups, the position of the ionic groups on the polymeric chains, the molecular weight of the PELs, the polymer chain flexibility as well as the temperature, ionic strength, and pH of the reaction medium [28]. As illustrated in Fig. 10.2, PECs can be used in different forms for a variety of drug delivery systems such as fibrous membranes/films, hydrogels/beads, micro/nanoparticles, nanogels, and cryogels [29]. Depending on multiple factors, the PEC system can separate into a dilute phase and a concentrated complex coacervate phase, or it may produce a more-or-less compact precipitate or gel [9,35]. The type of the resulted PEC system depends on parameters such as the chain length of the two PELs, their chemical structure, the type of the polyelectrolyte pairs (strong/strong, weak/weak, or strong/weak) as well as the distribution of the charged groups along polyelectrolyte chains [36]. The fabrication method of PECs plays an important role for the resulted system. For example, layer-by-layer (LbL) assembly is used for the preparation of PEC films/membranes [32,37]. In contrast, direct mixing of oppositely charged PELs can lead to the formation of precipitates, water-soluble PECs, microparticles, beads,

Fig. 10.2  Different drug delivery systems based on the formation of PECs between chitosan and anionic polysaccharides [29].

Responsive polyelectrolyte complexes based on natural polysaccharides for drug delivery applications271

or gels. Precipitation results from strong interactions which hinders the formation of hydrogels. However, strong electrostatic interactions can be weakened by the addition of salts such as NaCl, which lead to the formation of a viscous and macroscopically homogeneous blend that may gel as the temperature is lowered [35]. Water-soluble PECs are formed by mixing PELs having weak charge densities, large differences in molecular dimensions, and nonstoichiometric mixing ratio. In the former case, the excess polyion charges act as counterions for stabilizing the aggregated PECs and prevent their precipitation [36,38]. The formation of micro/nanoparticles requires nonstoichiometric mixing of PELs bearing high charge density and/or similar high molar masses [38]. In contrast, gels often result from mixing equal ratios from cationic and anionic PELs.

10.4 PECs based on natural polysaccharides PECs can be prepared from natural or synthetic PELs. However, for drug delivery applications, PELs derived from natural biopolymers are preferred due to their low toxicity, biocompatibility, and intrinsic biodegradability by enzymes. Biopolymers from different natural origins represent the major source for different types of derived PELs with cationic/anionic functionality. Natural biopolymers such as proteins, nucleic acids, polypeptides, lipids, and polysaccharides bearing positive or negative charges on their polymeric backbone are referred to as polyampholytes or PELs [39]. Polysaccharides, the most abundant natural biopolymers, represent the major source for the selection of a wide range of biocompatible and biodegradable cationic/ anionic PELs. Two classes of polysaccharide-based PELs can be distinguished. The first class is the naturally occurring charged ionic polysaccharides that can be used directly as natural PELs. This class includes anionic PELs such as alginates, pectin, and hyaluronic acid. The second class is related to those PELs derived from neutral, natural polysaccharides. Examples of this class are chitosan and sulfated dextran. Chitosan, which is the most used cationic polysaccharide, is prepared by deacetylation of chitin. Similarly, sulfated dextran is prepared by sulfonation of dextran. Among the different polysaccharide PELs, chitosan have been used as the major cationic polyelectrolyte for the preparation of a variety of PECs via ionic cross-­linking with different anionic PELs for various biomedical applications (Table 10.1). The formation of chitosan hydrogels by polyelectrolyte complexation is an interesting alternative to covalently cross-linked hydrogels. One of the interesting properties of ionic PELs is their pH-responsiveness n­ ature. This is due to the presence of ionizable acidic (carboxylic/sulfonic acids) or basic (e.g., a­mmonium salts) groups on their polymer backbone (Table  10.1). The pH-­responsiveness of PELs and their PECs has been used for the preparation of ­stimuli-responsive ­hydrogels for targeted and controlled release of drug molecules inside the human body. PECs/hydrogels can be designed to respond to a specific pH range to deliver their payloads into a certain tissue or cellular compartment (Table 10.2). Hydrogels ­prepared from PECs can respond to different triggers/stimuli such as temperature

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Chitosan-based PECs with anionic polyelectrolytes derived from natural polysaccharides for different biomedical applications [29,35] Table 10.1 

Origin

Preparation method

PEC forms

Alginate (COO−)

Brown seaweeds and marine algae

Nanoparticles; microparticles; hydrogel beads; gels; tablets; films/ membranes

Drug delivery; enzyme immobilization; tissue engineering

Hyaluronic acid (COO−)

Extracellular matrix throughout connective, epithelial and neural tissues Plant cell wall (a family of complex heterogeneous olig- and polysaccharides) Sulphated polysaccharides obtained from certain species of red seaweeds Exopolysaccharide secreted from Xanthomonas campestris

Extrusion; one-stage: alginate into chitosan w/or w/o calcium; two-stage: alginate into calcium followed by chitosan coating Extrusion: w/or w/o TPP; layer-by-layer assembly Extrusion, w/or w/o calcium

Nanoparticles; microparticles; films/ membranes Beads; tablet; films/ membranes

Drug delivery; tissue engineering

Extrusion, w/or w/o TPP; composite with nanotubes Extrusion; cryogelation

Nanoparticles; microparticles; hydrogel beads; fibers Hydrogel beads; tablets; cryogel

Drug delivery; enzyme immobilization

Extrusion; layer-bylayer assembly

Hydrogel beads; films

Extrusion method

Nanoparticles; hydrogel beads

Pectin (COO−) Carrageenan (-OSO3 -2 ) Xanthan gum (COO−) Gellan gum (COO−) Cashew gum (COO−)

Exopolysaccharide produced by the bacterium Pseudomonas elodeac Exudate polysaccharide from Anacardium occidentale tree, mainly grown in Brazil

Biomedical applications

Drug delivery

Drug delivery; enzyme immobilization; tissue engineering Drug delivery; tissue engineering Drug delivery

Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications

Anionic polysaccharide/ acidic functionality

Carboxymethyl cellulose (COO−) Konjac glucomannan Gum kondagogu Dextran sulfate (-OSO3 -2 )

Derived from the stems and branches of two species of acacia tree Carboxymethylation of cellulose

Extrusion; composite

Nanoparticles; tablets

Drug delivery

Extrusion

Nanoparticles; hydrogel

Drug delivery

Extracted from tubes of Amorphophallus konjac plant Exudate from the tree Cochlospermum gossypium Sulfated dextran

Extrusion

Nanoparticles; microparticles Nanoparticles

Drug delivery

Chondroitin sulfate (COO−), (-OSO3 -2 ) Heparin (-OSO3 -2 ) Xylan (COO−)

Sulfated chondroitin

Chitin derivatives bearing negative charges (COO−), (-OSO3 -2 ), (-OPO 4 -3)

Modified chitosan

Animal Plant cell walls and some algae

Extrusion

Precipitate. Hydrogel with NaCl Hydrogel Precipitate Hydrogel; film microparticles with additional cross-linking Hydrogel; film

Drug

Responsive polyelectrolyte complexes based on natural polysaccharides for drug delivery applications273

Gum Arabic (COO−)

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Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications

Physiological pH range for various tissue and cellular compartment [40] Table 10.2 

Tissue/cellular compartment

pH

Blood Stomach Duodenum Colon Early endosome Late endosome Lysosome Golgi Tumor, extracellular

7.35–7.45 1.0–3.0 4.8–8.2 7.0–7.5 6.0–6.5 5.0–6.0 4.5–5.0 6.4 7.2–6.5

[41–43], ­enzymes [44,45], light [41,46,47], and electrical changes [41,44]. A detailed discussion regarding different types of trigger-release mechanism of natural PECs/ hydrogels will be discussed in the next section.

10.5 Polysaccharide-based PECs as a class of stimuliresponsive polymers for drug delivery The need to deliver the exact amount of drugs to the exact physiological location, over an exact span of time, and the need to turn on/off drug release to match the circadian rhythms that determine drug needs are the basic drivers for stimuli-responsive or smart drug delivery systems [48]. Of the many designs for smart drug delivery systems, PECs based on natural polysaccharides present the advantages of being nonimmunogenic and biocompatible [49]. Jeong and Gutowska [50] classified the different stimuli the polymers can respond to into three, namely chemical (pH, redox potential), physical (temperature, light, and magnetism), and biological (illness marking enzymes and biomolecules). Fig.  10.3 is a schematic illustration for different stimuli and the possible responses by drug ­devices formulated with stimuli-responsive polymers.

10.5.1 Temperature-responsive polysaccharide-based PECs Some natural polysaccharides in their unmodified state show limited temperature responsiveness. For instance, xanthan gum shows thermoresponsive conformational changes [51] and cellulose sheets respond to heat by swelling [52]. Temperature is a convenient and easy stimulus to be used as a trigger for responsive drug release. The response to temperature depends on the critical solution temperature of a polymer [53]. Temperature-responsive polymers typically display a lower critical solution temperature (LCST) or upper critical solution temperature (UCST) which is a function of their hydrophilicity or hydrophobicity. An UCST means that the polymer is soluble above the critical solution temperature, while LCST means the polymer is

Responsive polyelectrolyte complexes based on natural polysaccharides for drug delivery applications275 Enzymes

Swelling

pH

Bending

Redox potential

Magnetic field Drug Delivery Device

Responses Electric field

Light

Temperature

Permeability

Drug release Drug Delivery Device Shrinking

Gelling

Conversion

Biomarkers

Erosion

Fig. 10.3  A schematic diagram of different stimuli and possible responses.

soluble only below the critical solution temperature [40]. For drug delivery purposes, thermoresponsive polymers with LCST are more relevant. According to Sanchez and Stone [54] polymer dissolution at LCST occurs due to interactions between the polymer and the solvent (hydrogen bonding and strong polar interactions) which limit random mixing. This leads to a negative entropy change for the mixing process; thus, LCST is entropically driven unlike UCST which is enthalpy driven [55]. As shown in Fig. 10.4A, polymers with LCST homogeneously mixes with the solvent below the LCST, while above it, demixing occurs. The most closely studied polymer with regard to thermoresponsiveness is the synthetic polymer poly(N-isopropylacrylamide) or PNIPAAM, a synthetic polymer with LCST conveniently close to body temperature [53]. PNIPAAM-derivatized polymers show a sharp hydrophilic-hydrophobic transition above an LCST of 32°C, hence switching off the drug release. Recillas et  al. [56] demonstrated that PEC membranes of PNIPAAM-derivatized chitosan and pectin were thermoresponsive and capable of switching off drug release above 33.1°C. The complex was prepared by a nonstoichiometric reaction. Below the LCST, the PNIPAAM chains are hydrated and fully stretched, but above the LCST, the chains shrink and expel water from the polymer matrix leading to a fully t­ hermoreversible

T

Two-phase region

T UCST

LCST

Two-phase region

Single-phase region

(A)

f

Single-phase region

(B)

f

Fig. 10.4  Temperature vs polymer volume fraction, Ø. Schematic illustration of phase diagrams for a polymer solution showing (A) LCST and (B) UCST [53].

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Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications

phase change. Chitosan and other natural polysaccharides play limited roles in thermoresponsiveness as reported by Shi et  al. [57] that chitosan complexation had little effect on drug release by alginate/PNIPAAM beads. In their study, Shi et al. [57] prepared ­alginate-PNIPAAM complex beads and compared their drug loading efficiency, swelling, pH, and temperature-dependent drug-release profile, with that of alginate-­PNIPAAM beads PEC-coated with chitosan. At 25°C, the drug-release rate was 25% higher for the uncoated beads than that for the coated beads. This shows that the PEC played a role in delayed release. Natural polysaccharides are therefore often used to delay release or add pH-responsiveness in a thermoresponsive drug delivery system [56,58,59].

10.5.2 pH-Responsive PECs based on natural polysaccharides The main requirement for pH-responsiveness is for a polymer to have ionizable acidic or basic functional groups. In an undissolved state, PELs exist as compact folded chains. But in a suitable solvent environment, the polymer accepts protons like ammonium groups of chitosan, or donates protons such as carboxylic and sulfonic moieties, and becomes ionized [60]. The presence of several ionized groups within the polymer then causes electrostatic repulsions leading to swelling of the polymer and subsequent drug release [61] as shown in Fig. 10.5. Hence the name “PEC” in itself explains the almost ubiquitous pH-responsiveness among this class of polymers. The degree of pH sensitivity is proportional to the concentration of ionizable functional groups and the flexibility of polyelectrolyte chains [62]. It has been shown that the pH affects drug release by many natural polysaccharide-based PECs such as chitosan/carrageenan [63], chitosan/hyaluronic acid [64], and chitosan/gum kondagogu [65]. A chitosan/carrageenan PEC prepared by salt-induced impeding of polyplex formation showed pH-responsive release of bovine serum albumin by 16 times greater release in simulated intestinal pH (7.5) than simulated gastric pH (1.2) [66]. This shows potential for intestinal delivery of peptide drugs. A large proportion of PECs are designed for drug delivery to the intestines and colon. Microcapsule IPECs of chitosan and alginate showed colon-selective delivery for albendazole [67]. However, the pH difference between cancer cells and other body compartments (Table 10.2) has been exploited for the design of PEC nanoparticles of chitosan and hyaluronic acid-Paclitaxel conjugate for oral delivery of paclitaxel [68]. The PEC released paclitaxel optimally at a tumor cell pH of 7.4 in vitro.

pH change

Fig. 10.5  Schematic illustration of drug release by a pH-responsive polymer matrix. The matrix responds to pH change by swelling thereby facilitating the release of the incorporated drug.

Responsive polyelectrolyte complexes based on natural polysaccharides for drug delivery applications277

There is a strong interest in designing drug delivery systems that have dual responsiveness as evidenced by the large number of works investigating not only pH- or thermoresponsive behavior, but jointly investigating the two [56,59]. Yoshizawa et al. [69] prepared PEC films composed of chitosan and anionic polyalkylene oxide/malic acid (PAOMA) copolymer for the delivery of salicylic acid and phenol as model drugs. The films were found to increase the rate of drug release when the pH was raised from 3.8 to 7.2, or when the temperature was raised to 50°C. These release behaviors were attributed to the phase transition of PAOMA (thermoresponsiveness) and the repulsive forces between carboxyl groups in PAOMA and anionic groups in the model drugs. PEC micelles assembled from chitosan-g-poly(N-isopropylacrylamide) and sodium alginate-g-poly(N-isopropylacrylamide-co-N-vinylpyrolidone) were found to be good candidates for the thermo- or pH-responsive delivery of 5-fluorouracil [66]. These dual-responsive drug delivery systems have relevance in cancer chemotherapy as both the pH and temperature of cancer microenvironments are different from those of healthy tissues. Chitosan-based PECs due to the presence of amine groups facilitate adsorption to tumors, and once inside, both pH and temperature play a synergistic role in drug release.

10.5.3 Light-responsive PECs based on natural polysaccharides Light is an easy stimulus to use in responsive drug delivery. A drug delivery system that responds by conformational and dimensional changes leading to the triggering or withholding of drug release when UV-visible light is applied is said to be light responsive [70]. Natural polymers are little inherently light responsive and to render them so, light-responsive moieties have to be appended [71]. Such light-responsive moieties include anthracene, azobenzene, triphenylmethane, spiropyran, and cinnamonyl [71]. These groups undergo reversible photoisomerization (azobenzene), dissociation (triphenylmethane), or heterocyclic ring cleavage (spiropyran) as shown in Fig. 10.6, leading to changes in the containing polymer matrix that switches drug release on or off [72]. This drug delivery approach is suitable for topical drug delivery where the safer and noninvasive visible light serves as a trigger [73]. Photo-assisted gene therapy and chemotherapy are other areas of application. A PEC of nanoparticulate dimensions made from chitosan and hyaluronic acid coupled with photolabile gold nanoparticles were shown to deliver single-stranded DNA responsively following short exposure to 365 nm light in vitro [74]. The monomeric building blocks of natural PELs may affect the light responsiveness of their PECs because it has been shown, for example, that mannuronic-rich alginates were more photoreactive than guluronic acid-rich alginates and more photoreactive than pectates [75]. Chitosan/alginate PEC nanoparticles have been used for encapsulation of a photosensitizer, meso-tetra(N-methyl-4-pyridyl) porphine tetra tosylate (TMP) (Fig. 10.6), for photodynamic treatment of colorectal tumors. The delivery strategy showed improved cytotoxic effect of the photosensitizer compared with free TMP. The chitosan/ alginate PEC nanoparticle afforded better tumor penetration, controlled release, and did not impede the photosensitizer [76].

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Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications

Fig. 10.6  (I) Photoinduced structure change in the azobenzene molecule; (II) photoinduced structural rearrangement of triphenylmethane leading to ionization; and (III) Photoinduced structure change of spiropyran [70].

10.5.4 Redox-responsive PECs based on natural polysaccharides This triggering mechanism is useful in diseases that cause proliferation of reactive oxygen species such as cardiovascular disease, diabetes mellitus, stroke, and cancer [77]. Cancer cells have high redox potential due to aberrantly high levels of glutathione of between 2 and 10 mM [78]. The affinity of such cells to redox substrates is therefore used as the basis for the design of targeted delivery systems [79]. Since the intracellular space is reducing in nature compared with the oxidizing extracellular milieu, the polymers are designed with disulfide bridges (Fig. 10.7) or diselenide groups which ferry across the intracellular space unchanged but become rapidly cleaved once they enter the intracellular space where they deliver a payload of therapeutic agents [33,80,81]. Shu et al. [82] prepared gradient shell cross-linked hollow polyelectrolyte nanocapsules with cysteamine-conjugated chitosan and dextran sulfate using the LbL technique. The nanocapsules were redox sensitive and could serve as biodegradable carriers for protein drugs.

Responsive polyelectrolyte complexes based on natural polysaccharides for drug delivery applications279 Tumor cell

Tumor tissue

Cytosol 2-10 mM GSH

Endocytosis

Disulfide bond cleavage Intracellular drug release Nucleus

Redox sensitive NPs Disulfide bond

Blood vessel • Long circulation • Stealthy

NPs

PEG shell

Tumor cell

Hydrophobic core

• Intracellular

Therapeutic payload

• NPs

drug delivery

dissociation

Fig. 10.7  Schematic illustration of redox-sensitive nanoparticles with a disulfidelinked polyethylene glycol (PEG) shell which can respond to tumor intracellular GSH microenvironments for controlled release of therapeutic agents [79].

10.5.5 Electric field responsive PECs based on natural polysaccharides Since humans can tolerate direct current densities of up to 0.5 mA/cm2 for up to 10 min [83], electric field can be used as an actuator for implantable polymeric drug delivery systems. This system required the gel to be capable of reversible swelling or erosion when electric charge is applied [84]. The drug is released by syneresis, diffusion along a concentration gradient, electrophoresis of a charged drug toward an oppositely charged electrode, and subsequent release of entrapped drug as the gel complex erodes [84]. A chitosan/hyaluronic acid PEC swollen in NaCl solution was shown to bend toward the cathode of an electric field [85]. This electroresponsiveness is likely attributable to salt, which serves as an electrolyte. Although the mechanism for this is not yet fully understood, such a PEC shows potential for use in muscle-like contractile structures as well as in drug delivery, the PEC serving to delay drug release.

10.5.6 Biomarker-responsive PECs based on natural polysaccharides A biomarker is a measurable parameter or substance specifically associated to a disease state that can be used to show the presence of or to estimate the severity of the disease state. Examples of biomarkers include C-reactive protein (inflammation marker), cardiac troponin (myocardial infarction marker), p53 gene (tumor marker) and HbA1c (blood glucose marker). Biomarker-responsive drug delivery promises

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Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications

Glucose

R

HO

R

OH

R

OH B HO

OH

HO

B OH

OH

HO

B O

O

os

uc

Gl

e

Fig. 10.8  Glucose-dependent equilibrium of phenylboronic acid; the addition of glucose drives equilibrium to the right, thereby distorting the structure of the PBA-containing delivery system which then leads to insulin release [86].

better improvement of quality of life especially in chronic illnesses like diabetes mellitus. Glucose-sensitive drug delivery systems have gained much interest due to the ever-increasing burden of diabetes mellitus and the need to make its management easier and more convenient [86]. Several attempts have been made to fabricate polymers with glucose-sensing moieties like glucose oxidase (GOD) and phenylboronic acid (Fig. 10.8). Shi and coworkers [87] prepared glucose-responsive polyelectrolyte capsules using an LbL assembly of phenylboronic acid-derivatized chitosan and alginate. The capsules displayed glucose-responsive swelling and good insulin encapsulation, showing promise for use in intelligent sustained-release insulin therapy. The polysaccharide-binding protein concanavalin A has been investigated for possible intelligent glucose sensitive delivery. One study coupled concanavalin A with dextran, and found that the resulting gel system could deliver insulin in a dose-related response to glucose through a polysaccharide displacement mechanism [88]. Further investigations by Sahota et  al. [89] showed that the responsiveness of the dextran-­ concanavalin A gel depends on the molecular weight of dextran, with 70 kDa being the optimum average molecular mass that produces gels with reduced component leaching, good glucose responsiveness, and insulin transport. Another approach in glucose-responsive drug delivery is based on the enzyme, GOD. This approach is mainly useful for vesicle and micellar delivery systems [90]. Abu-Rabeah and Marks [91] designed an amperometric glucose biosensor based on pyrrole-modified alginate and GOD attached covalently and pyrrole polymerized. The biosensor was said to exhibit a fast response time and high glucose responsiveness attributable to pyrrole polymerization, while the alginate played a role in controlling matrix permeability.

10.6 Underutilized polysaccharides for possible complexation The relative ease with which tailor-made synthetic polymers can be obtained has put proper optimization of natural polysaccharides at somewhat of a disadvantage.

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Ngwuluka and coworkers [92] mentioned a plethora of promising African natural gums and mucilages including those of Ocimum gratissimum, Hibiscus rosa sinensis, and Abelmoschus esculentus, which are potential candidates for advanced drug delivery including smart systems. Choudhary and Pawad [93] similarly reported a gold mine of natural polysaccharide-containing gums highlighting the colon-targeted delivery potentials of abelmochus gum, albizia gum, tamarind seed polysaccharide, locust bean gum, and gum copal. Colon-targeted release is often an indicator of pH-­ responsiveness, which means with the right modifications, smart PECs might be obtained from these highly safe natural polysaccharides. The majority of newly characterized natural polysaccharides are being investigated for conventional applications as tablet binders, suspending agents, emulsifiers, and disintegrants [94]. Much like chitosan, alginate, carrageenan, and xanthan gums which were once mainly exploited for conventional applications, these newcomers deserve more attention for possible applications in advanced systems. As such, polyelectrolyte complexation offers an easy way to attempt the modification of our natural polysaccharides.

10.7 Future trends Safety concerns over synthetic polymers will remain a major driver for research into natural polysaccharides in the design of responsive drug delivery systems. The field itself continues to evolve rapidly, and with new techniques for optimal characterization, natural polysaccharides will eventually become prominent components of responsive drug delivery. With progression into clinical trials, researchers will appreciate the better acceptability of natural polysaccharides. Cancer, AIDS, and many other diseases remain at large; however, smart drug delivery systems and natural polysaccharide stand a good chance of providing some solutions. New advances in bioengineering have made it possible to decode some gene families and associated biochemical pathways responsible for the production of several natural polysaccharides. As a result, bioengineered production of some polysaccharides has been made possible, for instance, bioengineered production of heparin and heparin sulfates [19] and α-d-glucan [95], among others. As conservation issues emerge, bioengineering may gain more prominence for sourcing of future polysaccharides. Such bioengineered polysaccharides may have the advantage of being designed to have bioactive properties as in some mushroom polysaccharides such as lentinan, schizophyllan, active hexose correlated compound (AHCC), maitake D-fraction, ­polysaccharide-K, and polysaccharide-P [43], among other desirable properties. As the potential therapeutic benefits of having fully elucidated the human genome are brought to bear, gene therapy will become increasingly popular, and so will safe gene delivery. The use of PECs as nonviral gene carriers seems to have a bright ­future prospect for gene therapy. The polyanionic nature of DNA has been exploited in polyelectrolyte complexation with polycationic chitosan [74,96,97]. This gene delivery mechanism is said to be more effective than naked DNA, and safer than viral transfection [98].

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10.8 Conclusion Natural polysaccharide-based PECs are promising, less toxic, and affordable components of responsive drug delivery systems. They are being exploited for different ­stimuli-responsive drug delivery technologies, but seem to lend themselves more easily to pH-responsive systems, which are a reflection of the properties of component polysaccharides. However, more needs to be done to uncover fully the hidden potential of these systems for actual therapeutic applications.

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