Biomimetic nanoparticles and self-propelled micromotors for biomedical applications

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Biomimetic nanoparticles and self-propelled micromotors for biomedical applications

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Marta Pacheco-Jerez and Beatriz Jurado-Sa´nchez Department of Analytical Chemistry, Physical Chemistry, and Chemical Engineering, University of Alcala, Madrid, Spain

1.1 Introduction Nanoparticles (NPs) are currently a subject of an intense research due to their considerable potential for therapeutic and diagnostic applications (Ngoˆ and Van de Voorde, 2014; Zhang et al., 2017). The “on-body” applications of synthetic NPs is hampered due to such entities are subjected to immune attack and clearance upon entering the bloodstream and can turn out to be cytotoxic (Yang et al., 2010a; Lunov et al., 2011; Blanco et al., 2015). A convenient strategy to overcome this challenge relies on the surface functionalization of NPs with natural or artificial biomolecules mimicking the composition and functionality of the cell’s external membrane (Gong and Winnik, 2012; Weingart et al., 2013). The remarkable performance of natural-protein motors has inspired scientists to create nanomotors capable of converting energy into movement and forces (Wang, 2013). Such nanoscale devices consist of a self-propelled structure equipped with sensing and/or actuating attachments (Paxton et al., 2004; Ozin et al., 2005; Mei et al., 2011; Wilson et al., 2012; Wang, 2009; Gao and Wang, 2014; Magdanz and Schmidt, 2014; Wang et al., 2014). Fuel-free micromotors based on ultrasound propulsion are particularly attractive for directed drug delivery, nanosurgery, biodetoxification, and localized diagnosis (Garcia-Gradilla et al., 2013). Surface functionalization of micromotors with red blood cells (Wu et al., 2015d), liposomes (Mhanna et al., 2014; Qiu et al., 2014a), or lipoplexes (Qiu et al., 2015) is a convenient way to evade the immune system. Natural red blood cells (RBCs) loaded with iron oxide NPs (Wu et al., 2014, 2015c,a) or hybrid “spermbot” micromotors (Magdanz and Schmidt, 2014; Magdanz et al., 2015) are other “biocompatible” examples of these propelled payloads.

Materials for Biomedical Engineering: Organic Micro and Nanostructures. DOI: https://doi.org/10.1016/B978-0-12-818433-2.00001-7 Copyright © 2019 Elsevier Inc. All rights reserved.

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CHAPTER 1 Biomimetic nanoparticles and self-propelled micromotors

This chapter will discuss recent advances in the biomimetic engineering of NPs and self-propelled nanomomotors and their use in various biomedical applications, including drug and cellular cargo delivery, nanosurgery, and biodetoxification. Current challenges and prospects of this exciting research area will be provided in the conclusion.

1.2 Strategies for the biofunctionalization of nanoparticles 1.2.1 Inorganic and organic nanoparticles for biomedical applications A large variety of nanomaterials have been synthetized as “building blocks” for complex biomimetic assemblies (see Table 1.1).

1.2.1.1 Inorganic nanoparticles Gold and silver NPs with inherent surface plasmon resonance absorption properties allow for new developments in photothermal therapy and biological imaging; whereas the unique surface functionalization properties are ideal for specific ligand functionalization (Keren et al., 2008; Murphy et al., 2008; Qian et al., 2008). AuNPs can be easily synthetized via the aqueous reduction of HAuCl4 by sodium citrate or NaBH4 in the presence of organomercaptans (Ravindran et al., 2013; Piella et al., 2016). Metal oxides, particularly magnetic Fe3O4, can be guided to a specific target site for drug delivery or bioimaging applications. The most suitable synthetic techniques include the coprecipitation of iron salts (Laurent et al., 2008), thermaldecomposition of iron precursors (Park et al., 2004), and the formation of microemulsions (Wu et al., 2016). To avoid agglomeration and hence to increase the stability of the resulting NPs, polymers or biocompatible coatings are used to passivate its surface (Zhou et al., 2011). Polymeric NPs represent an important set of controlled-release systems with great compatibility and suitable degradation properties for drug delivery and imaging applications (Kamaly et al., 2012). The most commonly used polymeric NPs are poly D,L-lactide-co-glycolide (PLGA), polylactic acid, polyglutamic acid, and polycaprolactone (Kamaly et al., 2016). Polymeric NPs are normally prepared by top down approaches, mainly nanoprecipitation (Hornig et al., 2009) or oilin-water emulsification solvent evaporation (Xu et al., 2014; Othman et al., 2015). Mesoporous silica NPs are normally synthetized by sol gel chemistry approaches (Tang et al., 2012). However, due to the low biocompatibility of silica NPs, surface modification is required, normally by attaching specific ligands, membrane-mimicking components, or polyethylene glycol (Tang et al., 2012; Weingart et al., 2013).

Table 1.1 Composition of inorganic and organic nanoparticles for biomedical applications. Material

Example

Properties

Applications

References

Surface plasmon resonance Charged groups Magnetic attraction

Ravindran et al. (2013) and Weingart et al. (2013)

Inorganic nanoparticles Metal

Au, Ag

Metal oxide

Fe3O4

Polymers and silica

PLGA, polystyrene, polycaprolactone, silica CdS, CdSe

Encapsulation

Drug delivery Bioimaging Drug delivery Bioimaging Drug delivery

Fluorescence

Bioimaging

Sharma et al. (2006) and Weingart et al. (2013)

Liposomes

Egg phosphatidylethanolamine

Encapsulation

Allen and Cullis (2013) and Fang et al. (2015)

Polymer

Dextran, chitosan

Encapsulation

Polymer-lipid

Phosphatidylethanolaminedextran sulfate

Encapsulation Charged groups

Drug delivery Biodetoxification Drug delivery Bioimaging Biodetoxification Drug delivery Bioimaging Biodetoxification

Quantum dots

Zhou et al. (2011) and Weingart et al. (2013) Weingart et al. (2013)

Organic particles

Banerjee and Bandopadhyay (2016) Zhang et al. (2017)

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CHAPTER 1 Biomimetic nanoparticles and self-propelled micromotors

Quantum dots (QDs) are semiconductor nanocrystals with a size-dependent bandgap and hence controllable size fluorescence emission properties (Smith and Nie, 2010). Their high photostability and strong luminescence allow for their use to probe and track single biomolecules in living cells. Many semiconductors including InP, GaAs, and Cd-based QDs (CdSe, CdTe, CdS, CdSe ZnS) of about B20 nm are commonly used. However, as its surface is passivated with toxic trioctylphosphine oxide and trioctylphosphine selenide groups, selective modification is mandatory to enhance its biocompatibility. (Weingart et al., 2013; He and Ma, 2014).

1.2.1.2 Organic nanoparticles Solid lipid NPs are particles made from solid lipids with a mean diameter between B50 and 1000 nm. Such NPs hold considerable promise for in vivo therapy and drug delivery applications owing to their ability to entrap poorly water-soluble drugs, high stability at physiological temperatures, and high biocompatibility. Lipids used include natural fatty acids, triplamitin, and others. Synthetic routes include cold and hot homogenization techniques, microemulsion, and precipitation (Sussman et al., 2008). Liposomes are small artificial vesicles (with sizes from 0.025 to 2.5 μm) composed by a bilayer of cholesterol or natural nontoxic phospholipids. The choice of bilayer components determines the “rigidity” or “fluidity” and the charge of the bilayer determines its composition. Thus unilamellar liposomes have a single phospholipid bilayer sphere enclosing the aqueous solution, whereas multilamellar liposomes are composed by the arrangement of several unilamellar vesicles in an onion-like structure. Several approaches have been developed for liposomes preparation, mainly by passive or active loading techniques (Akbarzadeh et al., 2013; Allen and Cullis, 2013). Once in the human body, nonspecific accumulation of liposomes in organs such as the liver or spleen can reduce its target abilities and result in adverse effects. Convenient surface engineering of liposomes with polyethylene glycol or small molecules (sugar, folic acid) are suitable strategies to avoid such drawbacks (Liu et al., 2014).

1.2.2 Nanoparticle surface functionalization with single-cell membrane components For many years, scientists have been inspired by the structure and function of the components of human cell membranes for engineering NPs’ surface to enhance biocompatibility or toward long circulation and specific targeting purposes. As illustrated in Fig. 1.1, the cell membrane compromises an integral phospholipid bilayer with embedded proteins and carbohydrates. As can be seen, four types of ligands or specific cell membrane components can be used for the biomimetic functionalization of engineered NPs, namely

1.2 Strategies for the biofunctionalization of nanoparticles

FIGURE 1.1 Schematic representation of the cell membrane and its components.

phospholipids, phosphorylcholine (PC) polymers, proteins, and carbohydrates (Tu et al., 2016a). A brief description of the common strategies used will be described next.

1.2.2.1 Phospholipid layers The coating of NPs with phospholipids is a convenient strategy to obtain core shell hybrid “biomedical” vehicles with high mechanical stability (related to the solid core) and biocompatibility (via the external bilayer). The inherent surface charge of the phospholipid layer exerts a strong influence on the interaction mechanism and the type of “core” NPs employed. As such, three different strategies can be adopted, namely electrostatic, hydrophobic van der Waals interactions, and chemical bonding. For instance, colloidal gold NPs along Raman dye molecules have been encapsulated with nonthiolated phospholipid bilayers for bioimaging applications (Tam et al., 2010). Similarly, the surface of silica NPs has been coated with small unilamellar vesicles composed of 1,2-dioleolyl-sn-glycero-3-phosphotidylcholine and 1,2-dioleoyl-sn-glycero-3-phosphatidylserine (Mornet et al., 2005). Similar strategies have been adopted for the preparation of encapsulated silica NPs for gene and drug delivery, and bioimaging applications (Savarala et al., 2011a,b; Bringas et al., 2012). The coating of polymer NPs with lipid monolayers involves melding the lipid alkylchains with the hydrophobic portions of the carbon backbone of the polymer (Fang et al., 2010). Other lipids commonly used for coating polymeric NPs are 1,2-dipalmitoyl-3-trimethylammonium propane chloride, 1,2-dipalmitoyl3-trimethylammonium propane chloride, cholesterol, and others. For instance, PLGA has been wrapped with mixed monolayers of 1,2-dilauroylphosphatidylocholine and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] for targeted drug (docexatel) delivery (Liu et al., 2010).

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Other similar configurations can be found in the literature (Zhang et al., 2008; Messerschmidt et al., 2009; Fang et al., 2012). Hydrophobic self-assembly of neutral phospholipids (i.e., dipalmitoylphosphatidylcholine) on the surface of hydrophobic NPs occurs in order to reduce the free energy of the system. Thus hydrophobic tails of lipids adsorb onto the hydrophobic NP surface, with the hydrophilic head groups projecting away into the aqueous external environment. Due to an excess of lipids in the dispersion, vesicles can be formed for its subsequent interaction with the lipid surface monolayer via van der Waals interactions. A solvent exchange method has been used to fabricate 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)] copolymer (DSPE-mPEG)-coated iron oxide NPs. Iron oxide cores (previously coated with oleic acid oleylamine) and DSPE-mPEG are initially dispersed in chloroform. Then, the solvent is replaced with DSMO and water sequentially. In aqueous solutions, DSPE-mPEG is firmly attached to the iron oxide core through hydrophobic interaction between DSPE and oleic acid/oleylamine. The resulting NPs display excellent performance for in vivo tumor imaging (Tong et al., 2010). Phospholipid polymer hybrid NPs have been reported and used in drug delivery applications, including lipid-supporting particles based on poly(lactic-co-glycolic acid) and poly-L-lactide (Chan et al., 2009; Aryal et al., 2011). Phospholipids containing phosphoethanolamine head groups are widely used for coating silica NPs via van der Waals and hydrophobic interactions. Applications range from photodynamic therapy to small RNA delivery for gene silencing (Yang et al., 2010b; Ashley et al., 2012). Trioctylphosphine oxide capped QDs can be modified with phospholipids via van der Waals interactions with alkyl and hydrophobic hydrophilic interactions (Luccardini et al., 2006; Murcia et al., 2008; Weingart et al., 2013). The most frequently applied phospholipids are 1,2-dioleoyl-sn-glycero-3-phosphatidylethanolamine, 1,2-dioleoyloxy-3-(trimethylammonium) propane chloride, among others. Phospholipids bearing thiols can be incorporated on the surface of gold and silver NPs via chemical bonding, forming a stable self-assembled monolayer. As such, 1,2-dipalmitoylsn-glycero-3-phosphoethanolamine-N-[3-(2-pyridyldithio) propionate] modified with a disulfide bridged head group can assemble on the surface of AuNPs, leading to a hybrid structure for on-body cholesterol removal (Chung et al., 2008; Thaxton et al., 2009; Ravindran et al., 2013). It should be noted that, in all cases, targeting ligands such as antibodies, aptamers, or small molecules can be bound to the capping phospholipid layer for additional functionalities (Katagiri and Caruso, 2004).

1.2.2.2 Phosphorylcholine polymers Amphiphilic copolymers containing hydrophilic PC groups and hydrophobic moieties in their structures have been used as alternatives to phospholipids (Wang et al., 2011b; Gong and Winnik, 2012). The assembly can be achieved by direct adsorption of hydrophilic PC groups onto the hydrophobic surface of the NPs. For example, iron oxide NPs have been coated with a double-hydrophilic di-block

1.2 Strategies for the biofunctionalization of nanoparticles

copolymer comprising poly[2-(methacryloyloxy)ethylphosphorylcholine] (MPC)block-(glycerol monomethacrylate) for bioimaging applications (Yuan et al., 2006). In a similar manner, poly(L-lactic acid) NPs can be coated with MPC for medical diagnosis and bioimaging (Konno et al., 2004; Ito et al., 2006). This strategy has also been applied to modify peptide-coated liposomes with MPC polymer for enhanced DNA release (Ukawa et al., 2010). As a second approach, the coating relies on the surface-initiated grafting of a PC-containing polymer onto the particle surface. For example, silica NPs with poly-MPC have been prepared via radical graft polymerization (Yokoyama et al., 2006). In a third strategy, an amphiphilic PC-containing copolymer is used alone with the self-assembly driven by hydrophobic interactions between the hydrophobic groups of the NPs while the hydrophilic PC groups distribute themselves on the water micelle interface (Samanta et al., 2008; Thompson et al., 2010).

1.2.2.3 Proteins Gold NPs have been coated with a short peptide to promote intracellular delivery of membrane-impermeable proteins (Ghosh et al., 2010). Similarly, amyloid protein antibodies were coated onto iron oxide NPs functionalized with a phospholipid monolayer for the detection and treatment of cerebrovascular amyloid deposits (Poduslo et al., 2011).

1.2.2.4 Carbohydrates It is well-known that carbohydrates in the cell membrane play a critical role for stabilization by both hydrophilicity and steric repulsion. Similarly, coating NPs with such a functional group is useful for its stabilization. For example, N-acetylD-glucosamine and D-mannose have been coupled onto the surface of magnetic NPs via amidation of the amine groups in the outer shell of apoferritin-containing magnetic NPs (Valero et al., 2011). Metal NP-based biomimetic strategies using conjugated carbohydrates have been reviewed as potential replacements for native biomolecules in immunoassays and catalysis applications (Cliffel et al., 2009).

1.2.2.5 Nanoparticle coating with cell membranes Cell membrane coating of a core material with a membrane derived from a source cell is particularly attractive because the resulting hybrid preserves the natural structures of the cell membranes (Tan et al., 2015; Kroll et al., 2017; Zhou et al., 2016). Due to the easy availability of RBCs, RBC membrane-coated NPs have been extensively studied (Hu et al., 2011; Parodi et al., 2013; Li et al., 2014). The preparation protocol is depicted in Fig. 1.2 and consists of a RBC membrane derived by hypotonic treatment which is coated onto negatively charged polymeric NPs by extrusion. As the first step, RBCs are isolated from whole blood and subjected to hypotonic treatment to remove their intracellular components. Next, the RBCs are extruded through porous membranes to create RBC membranederived vesicles. For the second step, the RBC vesicles are fused with

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FIGURE 1.2 Coating polymeric nanoparticles with red blood cells. Reprinted with permission from Hu, C.M., Zhang, L., Aryal, S., Cheung, C., Fang, R.H., Zhang, L., 2011. Erythrocyte membrane-camouflaged polymeric nanoparticles as a biomimetic delivery platform. Proc. Natl. Acad. Sci. U.S.A., 108, 10980 10985. Copyright 2011, Natural Academy of Sciences of the United States of America.

preformed poly(lactic-co-glycolic acid) NPs through mechanical extrusion. By translocating cellular membranes in their entirety to NPs, the properties of cell surfaces are translocated as well (Hu et al., 2011). Thus RBC-NPs possess the same density of CD47 as its RBC source and the proteins were shown to be oriented almost exclusively in the right-side-out fashion, with the extracellular portion displayed on the RBC-NP surface (Oldenborg et al., 2000). This can be attributed to the electrostatic repulsion between the negatively charged poly (lactic-co-glycolic acid) NPs core and the negatively charged sialyl moieties on the extracellular side of the source RBC membranes. The coating confers the particles with remarkably high biocompatibility. RBC NPs have been also applied for detoxification (Fang et al., 2015; Hu et al., 2013a) to deliver antibiotics or drugs (Guo et al., 2015; Luk and Zhang, 2015) and as emerging platforms for vaccines (Hu et al., 2013b). Cell membrane coating strategies have been expanded by using other cell types such as leukocyte or cancer cells. For example, leukocyte membranes silica NPs hybrids retain the original sialic acid and N-acetylglucosamineglycans content of the original leukocyte membrane, which is crucial for cellular self-recognition and to reduce binding to similar immune cells (see Fig. 1.3). Thus the particles display prolonged blood circulation times for several biomedical applications (Parodi et al., 2013).

1.2 Strategies for the biofunctionalization of nanoparticles

FIGURE 1.3 Schematic of leukocyte-coated nanoparticles. Enlargement of the area outlined with the red box shows a schematic of the relevant proteins in the membrane, interspersed in the porous structure of the nanoparticle. The right part displays the possible interactions between the APTES group on the NPs surface and a membrane phospholipid (left) and protein (right). SEM images at the bottom part of the figure shows (from left to right) an uncoated particle, a leukocyte prior coating, and a biomimetic nanoparticle coated with the membrane completely. Scale bar, 1 mm. Reprinted with permission from Parodi, A., Quattrocchi, N., Van de ven, A.L., Chiappini, C., Evangelopoulos, M., Martinez, J.O., et al., 2013. Synthetic nanoparticles functionalized with biomimetic leukocyte membranes possess cell-like functions. Nat. Nanotech., 8, 61 68. Copyright 2013, Srpinger Nature.

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Cancer cell membrane functionalized PLGA NPs offer a robust platform with applicability toward multiple modes of anticancer therapies. Similar to RBC NPs preparation, membranes from B16 2 F10 mouse melanoma cells were extracted by emptying harvested cells and used to coat PLGA particles (Fang et al., 2014). Potential applications include vaccination or highly specific drug delivery to tumor cells. Stem cell membrane-coated gelatin nanogels (SCMGs) have also been proposed as highly efficient tumor-targeted drug delivery platforms (Gao et al., 2016a). Similarly, biomimetic photodynamic therapy NPs have been fabricated by fusing mesoporous-silica-encapsulated β-NaYF4:Yb31:Er31 NPs with stem-cell membranes. The resulting platforms have long circulation and tumor-targeting capabilities for photodynamic therapies (Gao et al., 2016b).

1.2.3 Nanoparticle biomimetic coating for specific targeting Antibody targeting holds considerable promise for a myriad of drug delivery, imaging, and photothermal therapy applications. Chemical immobilization of antibodies onto NPs can be achieved by using NPs previously modified with reactive groups, which are then mixed with purified antibodies (Haun et al., 2010; Ling et al., 2011; Poduslo et al., 2011). Peptides targets can be included to enhanced and promote functionalized NPs penetration into cells (Goto et al., 2008). Folate (vitamin B9), which displays a high affinity for the folate receptor glycosylphosphatidylinositol-linked protein overexpressed in most cancers, has been conjugated to the surface of QDs and magnetic NPs for specific bioimaging (Wang et al., 2011a; Zhao et al., 2011). Polymer NPs bearing hydrazide groups have been coated with carbohydrates present on human cervical carcinoma cell (HeLa) surfaces for specific drug delivery (Iwasaki et al., 2007). Waterdispersible rhamnose-coated iron oxide NPs display highly specific targeting properties since this sugar is a substrate of lectins of the skin (Lartigue et al., 2011). For more detail, see Table 1.2.

1.3 Strategies for the biofunctionalization of self-propelled micromotors Compared with the huge progress in the development and applications of NPs for biomedical applications, the field of nanomotors is still in its infancy with early development started in 2004. However, recent works based on the use of fuel-free (magnetic and ultrasound fields), RBC-derived and water-driven micromotors has proven the particular promise of such nanovehicles for biomedical applications (see Table 1.3). The active movement of self-propelled micromotors allow for target delivery to the proximity of tumor cells or other sites of interest.

Table 1.2 Strategies for biomimetic surface functionalization of nanoparticles. Modification

Type of interaction

Nanoparticles

References

AuNPs Polymeric

Tam et al. (2010) Mornet et al. (2005), Savarala et al. (2011a,b), Bringas et al. (2012) Zhang et al. (2008), Messerschmidt et al. (2009), Fang et al. (2010, 2012), Liu et al. (2010)

Single-cell membrane components Phospholipid bilayers

Electrostatic interactions

Silica

Hydrophobic-Van der Waals

Lipid vesicles Metal oxide Polymeric Silica Quantum dots

Phosphorylcholine polymers

Chemical bonding

AuNPs AgNPs

Adsorption

Surface-initiated grafting Hydrophobic interactions

Metal oxide Polymeric Liposome Silica Polymeric

Amidation

AuNPs Metal oxide Metal oxide

Proteins Carbohydrates

Tong et al. (2010) Chan et al. (2009), Aryal et al. (2011) Yang et al. (2010b), Ashley et al. (2012) Luccardini et al. (2006), Murcia et al. (2008), Weingart et al. (2013) Thaxton et al. (2009) Chung et al. (2008), Ravindran et al. (2013) Yuan et al. (2006) Konno et al. (2004), Ito et al. (2006) Ukawa et al. (2010) Yokoyama et al. (2006) Samanta et al. (2008), Thompson et al. (2010) Ghosh et al. (2010) Poduslo et al. (2011) Valero et al. (2011) (Continued)

Table 1.2 Strategies for biomimetic surface functionalization of nanoparticles. Continued Modification

Type of interaction

Nanoparticles

References

PLGA Polymeric (gelatin) Silica nanoparticles PLGA Gelatin nanoparticles Mesoporous silica

Hu et al. (2011) Li et al. (2014) Parodi et al. (2013) Fang et al. (2014) Gao et al. (2016a) Gao et al. (2016b)

Iron oxide Polymeric Polymeric Iron oxide Polymeric

Haun et al. (2010), Ling et al. (2011) Goto et al. (2008) Zhao et al. (2011) Lartigue et al. (2011) Iwasaki et al. (2007)

Cell membranes Red blood cells Leukocyte Cancer cell Stem cells

Electrostatic and hydrophobic

Specific targets Antibodies Peptides Folate Carbohydrate

Chemical bonding Covalent conjugation

Table 1.3 Composition of nanomotors and micromotors for biomedical applications. Type of motor

Example

Applications

References

Ni-(Au50/Ag50) Ni Pt nanowires Au Pt rolled-up micromotors (Chitosan/alginate)18-PtNP tubular micromotors Polymeric stomatocyte nanomotors

Drug delivery Drug delivery, nanosurgery Drug delivery, photothermal therapy Drug delivery

Kagan et al. (2010) Xi et al. (2013) Wu et al. (2013, 2015b)

Polycaprolactone-PtNPs Janus micromotors Catalase and urease-polystyrene Janus micromotors Urease-silica mesoporous Janus micromotors Polymer-Zn tubular micromotors Multicargo zinc loaded catalytic micromotors Mg/Pt poly(N-isopropylacrylamide) Janus micromotors Mg-red blood cell coated micromotors

Drug delivery

Wilson et al. (2012), Tu et al. (2016a,b) Gao et al. (2015b)

Bioimaging, drug delivery

Dey et al. (2015)

Drug delivery

Ma et al. (2015)

Drug delivery Bioimaging Drug delivery

Gao et al. (2012b, 2015a) Sattayasamitsathit et al. (2014) Mou et al. (2014)

Biodetoxification

Wu et al. (2015c)

Fuel-powered motors Self-electrophoretic motors Hydrogen peroxide-powered micromotors

Biohybrid micromotors

Micromotors powered by body fluids

(Continued)

Table 1.3 Composition of nanomotors and micromotors for biomedical applications. Continued Type of motor

Example

Applications

References

Ni Ag nanowire motor Plant-derived helical micromotors Artificial bacterial flagella Ti/Ni polymer coated helices Au Ru nanowires Nanoporous Au Ag nanowires Red blood cell coated gold nanowires Red blood cells-iron oxide

Drug delivery Nanosurgery Drug delivery Sperm delivery Drug delivery Drug delivery Biodetoxification Biodetoxification, bioimaging, drug delivery Drug delivery, nanosurgery

Gao et al. (2012a) Srivastava et al. (2016) Venugopalan et al. (2014) Medina-Sánchez et al. (2016) Wang et al. (2014) Garcia-Gradilla et al. (2014) Wu et al. (2015d) Wu et al. (2014, 2015a)

Fuel-free motors Magnetic micromotors

Ultrasound micromotors

Perfluorocarbon-loaded conical-tube microbullets

Kagan et al. (2012)

1.3 Strategies for the biofunctionalization of self-propelled micromotors

FIGURE 1.4 Self-propelled micromotors for biomedical applications according to its propulsion mechanism and relevant structures. US-RBC, ultrasound-propelled red blood cell micromotors.

1.3.1 Micromotors for biomedical applications: synthesis and propulsion mechanisms Fig. 1.4 shows a schematic of the different micromotors used for biomedical applications.

1.3.1.1 Fuel-powered catalytic micromotors Catalytically powered micro- or nanoscale motors rely on the catalytic decomposition of a catalyst, usually hydrogen peroxide, on a platinum surface (Paxton et al., 2004; Wang et al., 2006; Kagan et al., 2010). The high towing force (B1000 body lengths second) of such fuel-driven make them particularly attractive for cargo towing (drug delivery) applications. In addition, on-demand control and magnetic guidance of such micromotors can be achieved by the incorporation of magnetic layers or specific external stimulate. Catalytic tubular engines display independent propulsion in high ionic strength media, thus opening new avenues for their use in biological media (Ozin et al., 2005; Solovev et al., 2009; Mei et al., 2011; Li et al., 2016a). Rolled-up microengines can be used to drill into biomaterials such as cells, which can be potentially used to address the endosome escape challenge and deliver the drug or gene inside the cell (Xi et al., 2013). Manganese oxide based catalytic tubular micromotors operating on very low levels of fuel (down to 0.4%) exhibit efficient locomotion in different biological settings and has been used for camptothecin

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delivery (Wang et al., 2016). Layer-by-layer assembled tubular nanorockets have proven to be very useful for direct transport of drugs into cancer cells. Thus (chitosan/alginate)18-PtNPs nanorockets were shown to partially penetrate into HeLa cells and release doxorubicin (Wu et al., 2013). Such micromotors can also be used for photothermal therapy in cancer treatment (Wu et al., 2015b). Similarly, supramolecular assembled stomatocyte nanomotors have been prepared by selfassembly of amphiphilic block-copolymers into a bilayer vesicular structure named polymersome (Wilson et al., 2012; Tu et al., 2016b). Such motors require ultra-low levels of hydrogen peroxide (0.3%) for efficient propulsion. Polymer single crystal based micromotors (5 nm size) were designed by self-assembly of three types of NPs on the surface, namely AuNPs, Fe3O4 NPs, and PtNPs. These motors are very promising for cell separation and targeted drug delivery since functional groups and receptors can be easily attached onto their surfaces (Dong et al., 2013). Janus micromotors prepared by oil-in-water emulsion have been used for doxorubicin delivery. The micromotors are prepared by mixing a biodegradable polymer, polycaprolactone, the drug, PtNPs, and iron oxide NPs. Slow drug release is achieved due to lipase action on the polycaprolactone body of the micromotor (Gao et al., 2015b). Biohybrid catalytic motors employ a similar propulsion mechanism to that of peroxide-powered micromotors, but in this case the metal catalyst is replaced by an enzyme. For example, Feringa and coworkers described a biohybrid propulsion fuel system formed from multiwalled carbon nanotubes. Autonomous movement was induced by the in situ formation of hydrogen peroxide through the oxidation of glucose to glucolactone and further decomposition of hydrogen peroxide through the enzymatic cycle of glucose oxidase. Subsequently, H2O2 was immediately consumed by catalase. The resulting oxygen bubbles were able to propel the motors at a maximum speed of 800 μm/s (Pantarotto et al., 2008). Rolled-up Ti/Au micromotors where modified with catalase via self-assembled monolayers of 3-mercaptopropionic acid in the gold layer, being able to propel at low hydrogen peroxide levels (1.5%) (Sanchez et al., 2010). Recent attempts in the biofunctionalization of Janus micromotors have been directed toward the search for biocompatible fuels. Sen and coworkers demonstrated the enhanced diffusion of both catalase and urease-coated Janus micromotors under the presence of its respective substrates, H2O2 and urease, respectively (Dey et al., 2015). Similarly, glucosefueled Janus micromotors prepared by wax-in-water Pickering emulsion displayed enhanced diffusivity and movement under the presence on glucose substrate (Schattling et al., 2015). Sanchez’s group also reported on the enhanced diffusivity of catalase, urease, and glucose oxidase hollow mesoporous Janus nanomotors in the presence of its corresponding substrate due to a chemophoretic mechanism (Ma et al., 2015). Recent efforts have been directed at expanding the scope of fuels for synthetic nanomotors by exploring the use of natural biofluids as fuel. Acid-driven polymer or zinc micromotors can propel autonomously and efficiently in gastric acid and, thus can be operated in the stomach environment

1.3 Strategies for the biofunctionalization of self-propelled micromotors

(Gao et al., 2012b; Sattayasamitsathit et al., 2014). In vivo evaluation of the distribution, retention, cargo delivery, and acute toxicity profile of such synthetic motors in mouse stomach via oral administration demonstrates the practical applicability of such micromotors (Gao et al., 2015a). Magnesium-based Janus micromotors which utilize galvanic corrosion and chloride pitting corrosion processes to generate hydrogen bubbles that propel the microparticles are attractive for in vivo drug delivery in salt-rich media (Mou et al., 2013). Thus drug-loaded, magnesium-based Mg/Pt poly(N-isopropylacrylamide) (PNIPAM) Janus micromotors has been used for the loading, transport, and delivery of drug molecules by taking advantage of the partial surface-attached thermoresponsive PNIPAM hydrogel layers (Mou et al., 2014). Magnesium microparticles have also been employed as fuel for tubular catalytic micromotors after entrapment by filtration of the structure (Li et al., 2016b). Water-powered RBC mimicking motors consisting of Mg microparticles covered by RBCs hold considerable promise for detoxification applications (Wu et al., 2015c).

1.3.1.2 Fuel-free micromotors Magnetic-propelled micromotors are noninvasive and are relatively easy to manipulate and control for directed delivery and nanosurgery applications (Xu et al., 2016). Indeed, magnetic nanomotors based on conformal ferrite coatings were shown to be cytocompatible with mouse myoblast cells for successful navigation in human blood (Venugopalan et al., 2014). Biotemplate is a simple method for the mass production of magnetic helical microswimmers for important nanosurgery applications (Gao et al., 2014; Srivastava et al., 2016). Flexible template prepared Ni Ag micromotors have been used for the precise delivery of doxorubicin-encapsulated magnetic PLGA microparticles (Gao et al., 2012a). Nelson’s group have made important advances in magnetically actuated helical micromachines for diverse biomedical applications (Zhang et al., 2009b; Peyer et al., 2013). Artificial bacterial flagella with a ferromagnetic metal head containing chromium/nickel/gold layers was obtained by a self-scrolling technique (Zhang et al., 2009a). After exposition to a rotating magnetic field, the magnetically induced rotation of the head was converted into translational motion in the direction dependent on the chirality of the helix. Artificial bacterial flagella consisting of titanium helical structures coated with liposomes have the ability to load both hydrophilic and hydrophobic drugs and to release the cargo (Mhanna et al., 2014). Microhelices coated with Ni/Ti and functionalized with Pluronic F-127 have been used for the coupling, transport, and release of microsperm cells (Medina-Sa´nchez et al., 2016). Mallouk et al. pioneered the use of continuous or pulsed ultrasound for the autonomous motion of Au Ru bimetallic nanowires (2 μm in length and 330 nm in diameter) with a concave end and synthesized via a template electrodeposition (Wang et al., 2012, 2014; Ahmed et al., 2016). Ultrasound-propelled Au Ni Au nanowire motors prepared using sphere lithography can be magnetically controlled for cell isolation and controlled drug delivery (Garcia-Gradilla et al., 2013).

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Au Ag alloy micromotors with high loading abilities have been used for doxorubicin loading. Ultrasound-driven transport of the loaded drug toward cancer cells was followed by near-infrared light triggered release (Garcia-Gradilla et al., 2014). Gold nanowires coated with RBCs are also particularly promising for biodetoxification applications (Wu et al., 2015d). Wu et al. demonstrated that erythrocytes can serve as functional micromotors in an ultrasound field. The RBCs were loaded with iron oxide NPs for magnetic guidance and propulsion (Wu et al., 2014). Additionally, QDs and drugs can be loaded for theragnostic (drug delivery and bioimaging) applications (Wu et al., 2015a). Pulsed ultrasound waves have been reported to induce propulsion of perfluorocarbon-loaded microbullets for penetrating and deforming cellular tissue for potential targeted drug delivery and precision nanosurgery (Kagan et al., 2012).

1.3.2 Biomimetic surface functionalization of micromotors and nanomotors The main strategies involve the use of biocompatible gel coating, liposomes or RBCs, either alone or as coating for the micromotors, as can be seen in Table 1.4. For example, OrmoComp—a commercially available gel composed of inorganic (Si O Si) organic groups—was used to coat Fe/Ti/SU-8 helices (Qiu et al., 2014b). Similarly, poly(L-lysine) was also use to coat the micromotors as an alternative to OrmoComp. HEK 293 cell-culture experiments revealed the biocompatibility of the poly(L-lysine) and the SU-8 material of the micromotors (Kim et al., 2013). A third approach for coating the helical micromotors relies on the use of dipalmitoylphosphatidylcholine liposomes (Qiu et al., 2014a). Ferrite was also used as a highly efficient coating for helical nanomotors. C2C12 mouse myoblast cells systematically increased on the substrates in a culture for up to 72 hours, indicating the great biocompatibility of these nanomotors in promoting Table 1.4 Strategies for biomimetic surface functionalization of selfpropelled micromotors. Type of motor

Modification

References

Magnetic SU-8 helices coated with Ti/Ni layers

OrmoComp, hybrid ceramic polymer Poly(L-lysine) Dipalmitoylphosphatidylcholine liposomes Ferritine Lipoplexes Red blood cells

Qiu et al. (2014b)

Red blood cells

Wu et al. (2015c)

Ultrasound-propelled Au nanowires Magnesium Janus micromotors

Kim et al. (2013) Qiu et al. (2014a) Venugopalan et al. (2014) Qiu et al. (2015) Wu et al. (2015d)

1.3 Strategies for the biofunctionalization of self-propelled micromotors

myoblast proliferation (Venugopalan et al., 2014). More sophisticated recent configurations consisted of integrating lipoplexes with the helical micromotors for successful wirelessly targeted and single-cell gene delivery to human embryonic kidney (HEK 293) cells (Qiu et al., 2015). RBC membranes have also been used to coat self-propelled micromotors. As a first example, water-driven Mg microparticles were covered with RBC (Wu et al., 2015c). Fig. 1.5 illustrates the fabrication process of RBC membrane-coated gold nanomotors, consisting of the preparation of gold nanowires and coating with a functional layer of RBC membranes. Negatively charged gold nanowires were incubated with RBC membrane-derived vesicles (diameter 50 100 nm) under ultrasonication. The high-surface tension of RBC vesicles and their electrostatic

FIGURE 1.5 Synthesis of RBC membrane-coated gold nanomotors. (A) Schematic of the preparation process of an ultrasound-propelled gold nanowire motors coated with RBC membranes. (B) Scanning electron microscope image of a fabricated motor sponge. (C) Fluorescent image of a motor sponge in which the RBC membranes were stained with Rhodamine B. Reprinted with permission from Wu, Z., Li, T., Gao, W., Xu, T., Jurado-Sa´nchez, B., Li, J., et al., 2015d. Cellmembrane-coated synthetic nanomotors for effective biodetoxification. Adv. Func. Mater., 25, 3881 3887. Copyright 2015, Wiley.

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repulsion with the citrate-modified gold nanowires resulted in effective fusion and coverage of RBC vesicles onto the nanowires with a right-side-out orientation, similar to what has been observed on the RBC membrane-coated polymeric NP system (Wu et al., 2015d). Wu et al. created a new fully biocompatible micromotor which utilized RBCs as functional micromotors with the aid of magnetic guidance and ultrasound propulsion. The RBC micromotors were prepared by endocytosis of magnetic NPs in RBCs (Wu et al., 2014, 2015a).

1.4 Biomedical applications of biomimetic nanoparticles and self-propelled micromotors 1.4.1 Drug delivery Many excellent reviews have given a comprehensive overview of the different strategies and applications of NPs and micromotors as drug delivery systems (Davis et al., 2008; Alvarez-Lorenzo and Concheiro, 2014; Gao and Wang, 2014; Sun et al., 2014; Liu et al., 2016). We will only give a brief overview of selected examples. As a first example, pH-sensitive polymeric micelles have been successfully used for targeted drug delivery to treat metastatic breast cancer (Tang et al., 2017). The chemotherapeutic agent paclitaxel was loaded with the dual-pH sensitive micelle, which consisted of a pH-sensitive core, an acidcleavable anionic shell, and a polyethylene glycolcorona. Biologically friendly Mg/Pt poly(N-isopropylacrylamide) can effectively uptake, transport, and control release (via temperature changes) drug molecules by taking advantage of the partial surface-attached thermoresponsive PNIPAM hydrogel layers (Mou et al., 2014).

1.4.2 Biodetoxification Toxins secreted from pathogenic bacteria and venomous animals represent ranged attack mechanisms to aid their survival. As protein toxins rely on multiple mechanisms to overcome the cell membrane barrier to inflict their virulence effect, a promising therapeutic antitoxin platform is to administer cell membrane mimics as decoys to sequester these virulence factors. Cell membrane-coated NPs and micromotors are ideal candidates given their structural similarity to cellular membranes (Hu et al., 2013a; Fang et al., 2015; Wu et al., 2015c,d; Dehaini et al., 2016). Zhang’s group showed that polymeric NPs wrapped in a RBC membrane were able to act as toxin “nanosponges” and divert pore-forming toxins away from their healthy cellular targets (Hu et al., 2013a). Ultrasound-powered biomimetic nanosponge motors were able to efficiently remove mellitin toxin (Wu et al., 2015d).

1.4 Biomedical applications of biomimetic nanoparticles

1.4.3 Cellular cargo delivery Gene or protein therapy, represent novel medical strategies in which protein or DNA are utilized as a therapeutic substance, delivering into a patient’s cells to treat diseases such as cancer. For example, highly biocompatible electrically propelled protein-functionalized gold-nanowire motors could deliver on-the-fly tumor necrosis factor alpha, a type of cytokine involved in cell-inflammation processes to a target cell (Fan et al., 2010). Au nanowires have been employed for gene ´ vila et al., 2016). Single-cell gene intracellular delivery (Esteban-Ferna´ndez de A delivery to an HEK using a lipoplexes-based magnetic micromotor has also been demonstrated (Qiu et al., 2015). Another impressive application involves the cellular delivery of sperm using magnetic helical micromotors for assisted fertilization, as shown in Fig. 1.6 (Medina-Sa´nchez et al., 2016).

1.4.4 Nanosurgery Ultrasound-propelled, self-folded Ti Ni Au micromotors functionalized with perfluorocarbon can efficiently penetrate into lamb kidney tissue for precision nanosurgery (Kagan et al., 2012). Rolled-up, magnetically powered microdrillers consisting of Ti/Cr/Fe could drill into a porcine liver tissue sample (Xi et al., 2013). Schmidt group reported on the first example of “dual-action microdaggers” where plant-derived biogenic micromotors were used for creating a cellular incision followed by the drug release or other therapeutics for highly localized drug administration or nanosurgery (Srivastava et al., 2016).

FIGURE 1.6 Magnetic helical microswimmer carrying sperm toward an oocyte for fertilization. Reproduced with permission from Medina-Sa´nchez, M., Schwarz, L., Meyer, A.K., Hebenstreit, F., Schmidt, O.G., 2016. Cellular cargo delivery: toward assisted fertilization by sperm-carrying micromotors. Nano Lett., 16, 555 561. Copyright 2015, Wiley.

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1.5 Conclusion In this chapter we have described the synthesis and surface functionalization strategies for the preparation of biomimetically engineered NPs and micromotors. A plethora of materials have been explored for the design of NPs, including Au, Ag, metal oxides, polymers, silica, QDs, solid lipids, liposomes, and hybrid combinations. However, for most in vivo applications adequate surface functionalization is mandatory to avoid clearance from the immune systems while imparting enhanced cellular internalization ability. The main strategies involve biomimetic functionalization with cell membrane components, including phospholipid bilayers, PC polymers, proteins, and carbohydrates. Such strategies have proven to be effective to extend NP residence time in vivo, particularly to bypass macrophage uptake and systemic clearance. More sophisticated configurations involve top down biomimetic approaches by coating NPs with natural cell membranes (including RBCs and stem-cells) for long-circulating cargo delivery. Further modification of the as-prepared NPs with bioactive molecules facilitate targeted delivery for specific functions. Considerable progress over the past decade has been aimed at the design of micromotors for diverse biomedical applications and strategies. Common peroxide driven micromotors are hampered by the requirement of toxic fuels and the low biocompatibility of its components (metals). As an alternative, Mg-based and Zn-based micromotors and fuel-free (magnetic and ultrasound) micromotors have several advantages such as on-demand motion control, long lifetime, and great biocompatibility. Indeed, these artificial nanomachines can achieve predetermined tasks, targeted drug and gene delivery, and exciting nanosurgery applications. Key challenges still remain to translate the proven potential of nanomachines into real-world clinical applications. Current efforts are directed to improve their compatibility via surface biomimetic functionalization with polymers, liposomes, or RBCs.

Acknowledgment B.J.-S is grateful for support from the Spanish Ministry of Economy and Competitiveness (Ramon y Cajal contract, RYC-2015-17558).

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Further reading

Zhou, L., Yuan, J., Wei, Y., 2011. Core shell structural iron oxide hybrid nanoparticles: from controlled synthesis to biomedical applications. J. Mater. Chem. 21, 2823 2840. Zhou, H., Fan, Z., Lemons, P.K., Cheng, H., 2016. A facile approach to functionalize cell membrane-coated nanoparticles. Theranostics 6, 1012 1022.

Further reading Gao, W., Sattayasamitsathit, S., Orozco, J., Wang, J., 2011. Highly efficient catalytic microengines: template electrosynthesis of polyaniline/platinum microtubes. J. Am. Chem. Soc. 133, 11862 11864. He, P., Urban, M.W., 2005. Phospholipid-stabilized au 2 nanoparticles. Biomacromolecules 6, 1224 1225. Xu, T., Gao, W., Xu, L.-P., Zhang, X., Wang, S., 2016. Fuel-free synthetic micro-/nanomachines. Adv. Mater. Available from: https://doi.org/10.1002/adma.201603250.

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