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Keywords:

  • biological applications of polymers;
  • diblock copolymers;
  • drug delivery systems;
  • enzymes;
  • self-assembly

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Block Copolymer Vesicles
  5. Conclusion
  6. Biographical Information
  7. Biographical Information
  8. Biographical Information
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The ability of amphiphilic block copolymers to self-assemble in selective solvents has been widely studied in academia and utilized for various commercial products. The self-assembled polymer vesicle is at the forefront of this nanotechnological revolution with seemingly endless possible uses, ranging from biomedical to nanometer-scale enzymatic reactors. This review is focused on the inherent advantages in using polymer vesicles over their small molecule lipid counterparts and the potential applications in biology for both drug delivery and synthetic cellular reactors.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Block Copolymer Vesicles
  5. Conclusion
  6. Biographical Information
  7. Biographical Information
  8. Biographical Information

Polymer chemists have exploited the wide range of controlled polymerization techniques now available in order to design macromolecular analogues of nature's simple amphiphiles. In particular, advances in living radical polymerization1–3 have enabled a much broader range of functional groups to be incorporated into copolymer structures than was previously possible using anionic polymerization.4 Well-defined block copolymer amphiphiles undergo self-assembly in aqueous solution in order to minimize energetically unfavourable hydrophobe–water interactions. The various reported morphologies are primarily a result of the inherent molecular curvature and how this influences the packing of the copolymer chains: specific self-assembled nanostructures can be targeted according to a dimensionless ‘packing parameter’, p, which is defined in Equation (1):

  • equation image((1))

where v is the volume of the hydrophobic chains, ao is the optimal area of the head group, and lc is the length of the hydrophobic tail. Therefore, the packing parameter of a given molecule usually dictates its most likely self-assembled morphology. As a general rule,5 spherical micelles are favoured when equation image, cylindrical micelles when equation image, and enclosed membrane structures (vesicles, also known as polymersomes) when equation image (Figure 1).

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Figure 1. Various self-assembled structures formed by amphiphilic block copolymers in a block-selective solvent. The type of structure formed is due to the inherent curvature of the molecule, which can be estimated through calculation of its dimensionless packing parameter, p.

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Conventional micelles and vesicles based on hydrophilic–hydrophobic AB diblock copolymers have been extensively reported.6 However, a ‘Pandora's Box’ of possible morphologies has recently been opened because of the remarkably diverse and growing range of block copolymer architectures that are now available, including those based on stimulus-responsive block copolymers. Spherical micelles have been developed beyond simple core–shell particles, such as shell cross-linked micelles,7 schizophrenic diblock copolymer micelles,8 Janus micelles with two chemically distinct hemispheres,9–11 and multi-compartmental ‘hamburger’ micelles (Figure 2a).12

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Figure 2. Transmission electron micrographs of: a) ‘hamburger’ micelles,12 b) helical micelles,23 c) bilayer tubules,29 and d) mixtures of polymer vesicles and ‘octopi’ structures.18 (Reproduced with permission from ref.12, 18, 23, 29 © 2006 American Chemical, 2008 Royal Society of Chemistry and 1998, 2004 American Chemical Society respectively)

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Block copolymer cylindrical (or worm-like) micelles have also been widely reported. Infinitely long cylinders are energetically favourable relative to shortened cylinders with incorporated end-defects, since these structures allow uniform curvature across the entire aggregate. However, entropic demands and molecular frustration induces the formation of defects such as end caps (which are more energetically favourable) and branch points (which are less favourable).13 Literature reports of giant14 and short worms,15, 16 y-junction and end cap defects,17, 18 and even worm-like micellar networks19 illustrate the increasing complexity associated with macromolecular amphiphilic self-assemblies. The wide array of intramolecular and intermolecular interactions within block copolymer assemblies generates even more sophisticated structures. For example, giant segmented worm-like micelles have been reported from the secondary self-assembly of ABC triblock copolymer spherical micelles.20 Amongst the plethora of observed morphologies there have been reports of the selective formation of toroidal,21 segmented,22 and helical23 cylindrical micelles from the self-assembly of PAA-PMA-PS triblock copolymers (Figure 2b). Toroids have also been reported for various systems, and in each case the driving force for structure formation appears to be minimization of the end cap energy.24–27

Spherical vesicles are not the only possible bilayer-type structures generated through self-assembly. Bilayer tubules have been generated from direct dissolution of copolymers in solvent mixtures followed by dialysis28, 29 (Figure 2c) and also in pure organic solvents,30 with tubes up to centimetres in length being obtained.31 Unfortunately, there are few reports that describe the formation of colloidally stable, self-assembled tubes in purely aqueous solution, since the energetically favoured fate of a copolymer bilayer under these conditions is the spherical vesicle. A thermo-reversible transition between tubes and vesicles was reported for poly(ethylene oxide)-poly(butadiene) (PEO-PBD) diblock copolymers in aqueous sugar solution, which was attributed to the thermal effect on membrane bending elasticity.32 Kinetically metastable neuron-like myelin tubes and ‘myelinsomes’ have recently been reported. However, these were energetically unstable and readily collapsed to form vesicles.33 Stable nanotubes have also been reported that form by the self-assembly of an amphiphilic triblock copolymer through aqueous rehydration.34 This allows encapsulation of a water-soluble dye within the tube interior and increased stability can be achieved through coronal chain cross-linking. However, ‘pure’ dispersions of tubes were not obtained: the co-existence of vesicles was always observed.

In a seminal paper,18 the Bates group reported the non-ergodic nature of copolymer amphiphile self-assemblies, with many intermediate structures being observed. Non-ergodicity is the failure to achieve global equilibration, i.e., exchange of polymer chains between aggregates (because the almost negligible critical micelle concentration (CMC) is vanishingly small) is not observed within the experimental time scales. At certain hydrophilic volume fractions, these ‘mixed’ assemblies were attributed to the interfacial tension mis-match because of either copolymer binary mixtures or an increased molecular weight. Bilayer sheets with pendulous worm-like micelle arms (known as ‘octopi structures’) and undulating worm-like micelles were widely observed at specific copolymer molar ratios (Figure 2d). These bilayer budded-type structures and laterally nanostructured vesicles have also been reported for the self-assembly of an amphiphilic µ-ABC miktoarm copolymer.35

For a summary of the polymer chemical identities and abbreviations used herein, please refer to Table 1 and Figure 3.

Table 1. Polymer chemical identities and abbreviations used herein.
AbbreviationPolymer
PAAPoly(acrylic acid)
PMAPoly(methyl acrylate)
PSPolystyrene
PEOPoly(ethylene oxide)
PBDPoly(butadiene)
PBOPoly(butylene oxide)
PMOXAPoly(2-methyloxazoline)
PDMSPoly(dimethyl siloxane)
PCLPoly(ε-caprolactone)
PPSPoly(propylene sulphide)
PNIPAMPoly(N-isopropylacrylamide)
P2VPPoly(2-vinylpyridine)
PDEAPoly(2-(diethylamino)ethyl methacrylate)
PDPAPoly(2-(diisopropylamino)ethyl methacrylate)
PMPCPoly(2-(methacryloyloxy)ethyl phosphorylcholine)
PLAPoly(lactic acid)
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Figure 3. Chemical structures of the polymers detailed in Table 1.

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Block Copolymer Vesicles

  1. Top of page
  2. Abstract
  3. Introduction
  4. Block Copolymer Vesicles
  5. Conclusion
  6. Biographical Information
  7. Biographical Information
  8. Biographical Information

Just over a decade ago, Eisenberg and co-workers reported36 the first observations of polymer vesicles from the self-assembly of polystyrene–poly(acrylic acid) (PS-PAA) block copolymers. At first it was speculated that polymer vesicles were non-equilibrium structures because of the glassy nature of the PS membrane, but their thermodynamic stability was subsequently established.37–40 Further work confirmed that vesicular morphologies are not dictated by the kinetically frozen glassy nature of the hydrophobic block, since vesicles could be formed with low glass transition temperature (Tg) hydrophobes such as PBD41, 42 and poly(propylene oxide) (PPO).43 Since these initial reports, there have been hundreds of papers that describe the formation of polymer vesicles and a number of excellent reviews.44–48 The remainder of this review will focus on recent advances and applications of block copolymer vesicles.

Perhaps not surprisingly, block copolymer vesicles (a.k.a. ‘polymersomes’) exhibit superior mechanical and physical properties compared to lipid-based vesicles (a.k.a. liposomes). The robust nature of polymeric vesicles was established in early studies, with micromanipulation verifying a ten-fold increase in critical areal strain before rupture compared to lipid vesicles.42, 49, 50 Higher copolymer molecular weights led to an increase in membrane thickness, which in turn led to vesicles with greater bending rigidities, kc.49, 50 Perhaps surprisingly, the membrane elasticity (Ka) of polymeric vesicles has been proven to be relatively independent of molecular weight, with similar Ka values being observed as those reported for phospholipid vesicles. This elasticity is dominated by the chemical nature of the membrane–solvent interface and hence is related to the surface tension, γ.49 Experimental studies of polymeric membrane structures have shed some light on their enhanced mechanical properties. Above the bulk entanglement molecular weight, copolymer chains within membranes undergo diffusion through reptation (which involves chain entanglement and release) as opposed to Rouse diffusion (i.e., lateral diffusion that is only inhibited by inter-chain friction).51 This interdigitation and chain entanglement within membranes (Figure 4) was confirmed for PEO-PBO diblock copolymer vesicles52 and explains both their robustness and increased bending rigidity. Compared to lipid analogues, the membrane permeability is also enhanced and this parameter depends on both molecular weight (hence wall thickness) and the relative polarity of the hydrophobic membrane. Both highly permeable and virtually impermeable membranes can be designed.42, 53–56 External constraints can also be exploited to tune membrane permeability, with the addition of protein channels57 and membrane plasticization58, 59 greatly increasing trans-membrane diffusion.

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Figure 4. Possible polymer vesicle membrane morphologies: a) interdigitated symmetric membrane from AB diblock copolymers, b) spatial segregation of a binary mixture of AB and BC diblock copolymers within the membrane (the enhanced curvature drives membrane asymmetry), and c) segregation of an ABC triblock copolymer within the membrane: the green chains are preferentially segregated to the outer face due to their relatively larger volume in comparison to the red chains.

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Biological membranes are much more complex and sophisticated than the simple vesicle structures reported here, since the former contain many types of proteins and cellular recognition elements. One of the defining characteristics of natural membranes is their inherent bilayer asymmetry: differing chemical entities are located at the inner and outer leaflets. Thus there have been a number of ‘bio-inspired’ experimental and theoretical studies to describe the formation of asymmetric membranes within polymer vesicles. For example, inter-polyelectrolyte complexes between polyacids and polybases appear to offer a versatile route for the preparation of asymmetric membranes through counter-ion complexation.60

Theoretical studies suggest that segregation of block copolymers across the bilayer should be favoured for bimodal copolymer mixtures of differing molecular weights in order to stabilize the interfacial curvature61, 62 (Figure 4). Subsequent experimental evidence for this segregation has been obtained using both AB diblock copolymer mixtures and ABC triblock copolymers.39, 63, 64 Meier and co-workers have also reported membrane asymmetry within PEO-PDMS triblock vesicles,65 utilizing the resulting chemically distinct faces to correctly orientate a trans-membrane protein.66 However, these copolymers are highly hydrophilic which normally favours micelle formation; vesicle formation was attributed to phase separation between the hydrophilic chains.65 Biocompatible asymmetric membranes have also been reported for PEO-PCL-PAA triblock copolymers. Again, these PAA-rich copolymers would normally be expected to form micelles in aqueous solution.67 Membrane asymmetry has also been induced in vesicles of an ABCA copolymer PEO-PS-PBD-PEO, using the high interfacial tension between PBD and water to locate the former chains towards the inner leaflet.68

Polymer vesicle formation is more complex than originally anticipated,45 with the many metastable phases present after aqueous dissolution of the copolymer amphiphile affecting the final vesicle morphology69, 70 (Figure 5). Several reliable methods for vesicle preparation have been developed. Well-defined nanometer-scale copolymer vesicles are usually generated from either a solvent switch or film rehydration followed by subsequent extrusion. Electroformation enables the generation of giant unilamellar vesicles by maintaining a constant, interfacial-concentration gradient, driving force.71 Recent developments in microfluidics have enabled the directed self-assembly of monodisperse vesicles from water/oil/water (w1/o/w2) double emulsions.72–74

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Figure 5. a) Isothermal phase diagram for bulk vesicle-forming PEO-PBO copolymers upon aqueous dilution.70 TEM images of b) hexagonally packed69 and c) dispersed vesicles,69 and d,e) interconnected vesicles70 (Reproduced with permission from ref.69, 70 © 2005 Nature Publishing Group and 2006 American Chemical Society, respectively)

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Surprisingly many ‘homopolymers’ can also undergo self-assembly into stable vesicles if they posses sufficient amphiphilic character. Vesicles can be generated from ‘polymeric surfactants’,75 amphiphilic ‘comb-like’ copolymers,76, 77 and somewhat surprisingly alternating copolymers synthesised by free-radical methods.78 Uzun and co-workers have reported the formation of ‘recognition-induced vesicles’ through the complementary complexation of modified PS, but these ‘homopolymers’ are believed to be gradient copolymers rather than pure homopolymers.79 Double-hydrophilic PEO-PAA block copolymers can self-assemble into vesicles, but only by rendering the PEO chains hydrophobic through α-cyclodextrin complexation.80

Reactive and Environmentally Responsive Membranes for Delivery Applications

The advantages offered by block copolymer vesicles are not just limited to their enhanced mechanical properties and tuneable permeability. In principle, they can be decorated with responsive and/or reactive groups through appropriate copolymer chemistry. For example, either membrane81–84 or coronal85 cross-linking of polymer vesicles can increase their rigidity and maintain their shape persistence in common solvents. Responsive membranes with environmental triggers for targeted delivery have also been developed and the technical challenges for this particular application continue to provide much of the current impetus for research.

Napoli et al.86 have reported the formation of oxidation-responsive vesicles, which destabilize on exposure to H2O2. Encapsulation of an enzyme (glucose oxidase) creates self-destructing vesicles through the internal conversion of β-D-glucose to glucolactone with H2O2 generation.87 Electroactive ferrocene moieties can be modified to form the hydrophilic corona, to create redox-active vesicles.88 The disulfide bond between the hydrophilic–hydrophobic junction of PEO-SS-PPS [poly(ethylene oxide)-disulfide-poly(propylene sulfide)] copolymer vesicles can be intracellularly cleaved for the controlled release of encapsulated dye.89 These redox-active vesicles may have possible applications for the selective delivery of actives to inflamed tissues. Cis/trans isomerization of an azobenzene-based diblock copolymer has been utilized to form vesicles that can be dissociated and reformed simply by irradiation with light.90 Thermo-sensitive vesicles have been developed using PNIPAM91 because of its relatively sharp phase transition at close to physiological temperatures (lower critical solution temperature (LCST) ≈ 32 °C). Using a cross-linkable hydrophilic coronal block allows vesicle stabilization below this LCST, which facilitates temperature-dependent membrane permeability.92, 93

Amine-based copolymers are known to exhibit pH-dependent aqueous solubility: they behave as weak cationic polyelectrolytes when protonated, whereas they are relatively hydrophobic in their neutral state. The pKa of such polymers typically indicates the hydrophilic/hydrophobic transition and this value depends on the precise nature of the monomer repeat units. For example, Förster and co-workers reported94 the pH-induced release of encapsulated dyes from P2VP-based copolymer vesicles at around pH 5. However, the relatively high Tg of the P2VP block may not be suitable for delivery applications as this membrane is prone to buckling, which makes such vesicles relatively ‘leaky’. In contrast, poly(tertiary amine methacrylates) generally have low Tg values and can be obtained by several convenient synthetic routes.95–97 Thus a number of studies have focused on preparing pH-responsive block copolymer vesicles based on these chains. For example, PDEA-based vesicles exhibit a pKa at around 7.3.98 The statistical incorporation of a hydrolytically cross-linkable monomer into such block copolymers allows more robust vesicles to be prepared with pH-tunable permeability.84 However, biological applications for such vesicles are somewhat limited. Bearing this in mind, diblock copolymer vesicles comprising pH-responsive PDPA (pKa ≈ 6.3) and the biomimetic hydrophilic polymer PMPC have been developed.99 The use of these highly biocompatible PMPC-PDPA copolymer vesicles as non-toxic synthetic vectors for the in vitro delivery of either DNA or dye molecules to living cells has been demonstrated.100, 101 DNA-loaded PMPC-PDPA vesicles undergo rapid endocytosis and the lower local pH within the endocytic organelle (pH 5–6) causes protonation of the hydrophobic PDPA chains, vesicle dissociation, and hence triggered release of the payload. High transfection efficiencies have been demonstrated using Human Dermal Fibroblast (HDF) cell lines for these delivery vehicles.101

Vesicles Based on Polypeptides, Polynucleotides, and Polysaccharides

Vesicles formed from the self-assembly of polypeptide copolymers, known as ‘peptosomes’, have been extensively studied by several research groups and both pH-tuneable membranes and reduced antigenicity have been reported.102, 103 Initially, polypeptide-based vesicles were formed by coupling PBD to hydrophilic poly(glutamic acid), to yield vesicles with peptide surface functionality.104, 105 Vesicles have also been developed from hybrid copolymers where the peptidic block forms the hydrophobic membrane and the coronal block is formed from a hydrophilic vinyl polymer chain.106 Oppositely charged ionic diblock copolymers based on poly(aspartate)-PEO formed semi-permeable vesicles that were christened ‘PICsomes’,107 which could reversibly bind oxygen using encapsulated myoglobin.108

More recently, so-called peptosomes have been developed from copolymers comprising both hydrophilic and hydrophobic polypeptide chains,102, 109 which can be used as intracellular cell delivery vehicles for both dyes103 and DNA.110, 111 Lecommandoux and co-workers reported the pH-responsive ‘schizophrenic’ nature of vesicles formed from poly(glutamic acid)–poly(lysine) copolypeptides, which offer a different surface chemistry depending on the solution pH.112 Biohybrid ‘giant-amphiphiles’ consisting of a synthetic polymer chain linked to a functional protein can form vesicles that retain the enzymatic activity of the protein.113, 114 Vesicles with biologically relevant coronal hydrophilic moieties have also been developed from both oligonucleotide dCMP sequences115 and polysaccharides.116–118

Biocompatible Copolymer Vesicles and the Delivery of Actives

It is clear that most biomedical applications of block copolymer vesicles require either zero or very low copolymer toxicity. A wide range of biocompatible polymers such as PEO, PLA, and PCL have been evaluated.119–124 PEO is hydrophilic and imparts in vivo protein resistance that facilitates longer circulation times, whereas both hydrophobic PLA and PCL are biologically inert and undergo slow hydrolytic cleavage of their main chain ester linkages under physiological conditions (pH 7.4, 37 °C). Perhaps surprisingly (in view of the relatively high Tg and crystalline nature of the hydrophobic chains), vesicles can be generated from film rehydration of both PEO-PLA and PEO-PCL.119, 124 However, these vesicles exhibit controlled release of active dyes and anti-cancer drugs over periods of up to two weeks.119, 122, 124 Drug efficacy and tumour cytotoxicity can be maximized when drugs with differing activities can be simultaneously delivered to the same cell or area of inflammation. Ahmed and co-workers120, 121 loaded PEO-PLA vesicles with two anti-cancer drugs: hydrophilic doxorubicin, which results in tumour apoptosis in the aqueous interior, and hydrophobic paclitaxel, which inhibits cell proliferation and also leads to cell apoptosis within the membrane. In vivo studies with solid tumours in a mouse model indicated a three-fold increase in tumour apoptosis after two days when treated with multiple drug-loaded vesicles when compared to injections of the free drugs.121 Pang et al. have also reported the successful in vivo rat brain delivery of peptide-loaded PEO-PCL vesicles, ameliorating the scopolamine-induced learning and memory impairments in rats.125 Therapeutic oxygen carriers based on PEO-PCL or PEO-PLA copolymer vesicles that are successfully loaded with either human or bovine haemoglobin that exhibits good oxygen binding and release, have been developed for potential applications as haemoglobin-based oxygen carriers for the treatment of ischemic tissues.126

Membrane Loading of Polymer Vesicles for Medical Uses

Hydrophobic moieties can be readily incorporated within polymer vesicle membranes. For example, membrane loading of highly conjugated, porphyrin-based near-infrared (NIR) supramolecular fluorophores has been reported.127–131In vivo cell tracking and tissue-imaging of dendritic cells to centimetre depths was achieved through Tat surface conjugation of such ‘NIR-polymersomes’.130 Vesicles with membrane-loaded hydrophobic magnetic nanoparticles have potential applications as contrast agents in magnetic resonance imaging (MRI) and for radio frequency-induced local heating of cancerous tissues.132, 133 The hydrophobic anti-cancer drug paclitaxel (TAX) loaded within PEO-PBD vesicle membranes exhibited long-term in vivo release, with reduced adverse patient toxicity and increased efficacy in MCF-7 breast cancer cell apoptosis.134

Vesicles as Nanoreactors and Synthetic-Based Copolymer Organelles

Copolymer vesicles are not just limited to being used as delivery agents, there are also numerous literature reports of the development of vesicular ‘nano-reactors’.135–137 Several pioneering reports based on PMOXA-PDMS-PMOXA triblock copolymer vesicles have demonstrated a wide variety of potential biological applications.137–140 Significant reduction in the cytotoxicity of anti-cancer drugs has been reported by encapsulating prodrugs within the vesicular interior, whereby the active (hence cytotoxic) compound is only generated when exposed to the specific conditions found within tumourous tissues.138 Functionalization of these vesicles with membrane channel proteins coupled with encapsulation of prodrug-activating enzymes also show some promise for cancer treatment.138 In related work, acid phosphotase, a pH-sensitive enzyme, has been encapsulated within vesicles that contain active channel membrane proteins.137 This enzyme proved to be catalytically active within the vesicle interior, converting a soluble non-fluorescent substrate into a non-soluble fluorescent substrate. These vesicles were only active at low pH with the incorporation of the protein channels, since this allowed diffusion of the soluble non-fluorescent substrate and proteins to the enzyme within the vesicle interior (Figure 6). These vesicles have also been evaluated as anti-oxidant nano-reactors, converting extra-vesicular superoxide radical (equation image), a toxic metabolic by-product, into harmless O2.140

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Figure 6. a) Schematic illustration of enzymatic nano-reactor in the processing of the external non-fluorescent substrate into an internalised fluorescent substrate.137 b) Fluorescent micrographs illustrating both the protein channel and pH-dependence on nano-reactor functionality.137 (Reproduced with permission from ref.137 © 2006 American Chemical Society)

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Choi and Montemagno135 described the use of protein-loaded polymer vesicles (so-called ‘proteopolymersomes’) for the biochemical synthesis of the cell fuel, adenosine triphosphate (ATP). Both bacteriorhodpsin and F0F1-ATP synthase were reconstituted within the copolymer vesicle membrane and demonstrated to work in tandem to successfully convert adenosine diphosphate (ADP) into ATP upon light emitting diode (LED) irradiation (5.04 W green LED, λ = 570 nm). PS-poly(L-isocyanoalanine(2-thiophen-3-yl-ethyl)amide) (PS-PIAT) copolymer vesicles have also been exploited as nano-reactors (Figure 7).136, 141 Multi-step cascade reactions have been reported using three enzymes: exterior candida antartica lipase B (CALB), membrane-bound horseradish peroxidase (HRP), and encapsulated glucose oxidase (GOX) (Figure 7).136 CALB was also encapsulated within both the membrane and inner volume of PS-PIAT vesicles in order to catalyze the ring-opening polymerization of lactones.141

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Figure 7. a) Schematic illustration of the three-enzyme multistep polymer vesicle nano-reactor system based on PS-PIAT copolymer vesicles.136 b) Schematic representation of the ‘proteopolymersome’ generation of the biological fuel ATP from ADP.135 (Reproduced with permission from ref.135 © 2007 Wiley-VCH and 2005 American Chemical Society respectively).

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Biotin-avidin conjugation has been utilized in order to study the cell adhesion (and hence cell targeting) of polymer vesicles. The excellent adhesive properties of biotin-functionalized vesicles to avidin beads were attributed to the surface availability of the biotin molecules, and vesicles with ‘pendent’ biotin units exhibited stronger adhesion.142–144 The same conjugation chemistry has been utilized for the cell-specific binding of PMOXA-PDMS-PMOXA copolymer vesicles to a macrophage scavenger target receptor, SRA1.139 Macrophages play an important role in many disease pathways, including infection, auto-immune disease, and cancer. They are also responsible for the uptake of polyanionic substances during endocytosis. Rapid macrophage uptake was only observed for vesicle surfaces functionalized with the SRA 1 specific binding ligand PolyG through the endocytotic pathway. This ligand binding/uptake specificity, coupled with minimal cytotoxicity, provides a promising approach for the cell-specific delivery of drugs, genes, and enzymes. The intra-cellular destination and longevity of these surface-chelated vesicles after cell endocytosis has also been deduced.145 Vesicles loaded with specific enzymes remain intact and functional within the cells for up to two days after cellular introduction, acting as synthetic organelles. Fluorescent studies confirmed that the hybrid vesicles were localized within the cell cytoplasm, where they were specifically trafficked to the endoplasmic reticulum and golgi apparatus, but never reach the mitochondria or nucleus. This elegant work illustrates the remarkable advances in the uses of polymer vesicles within the last decade and highlights possible future applications as therapeutic agents to replace either missing or non-functional enzymes for the treatment of genetic diseases.

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Block Copolymer Vesicles
  5. Conclusion
  6. Biographical Information
  7. Biographical Information
  8. Biographical Information

Over the past decade, vesicles formed from macromolecular polymeric amphiphiles have been widely studied and found to have many desirable properties in comparison to simple lipid-based vesicles formed from small molecule surfactants. The wide variety of literature reports has captured the imagination of both the academic and industrial communities, with a range of passive delivery devices already in development.

Many reports have included environmentally responsive and biologically active polymer vesicles, and highlight a diverse range of biomedical applications for the efficient and non-cytotoxic delivery of drugs, genes, and active agents. Biocompatible vesicles show promising applications for the in vivo delivery of anti-cancer drugs for tumour treatment121 and even in the treatment of degenerative brain conditions.125 Vesicles with responses to pH stimulus also exhibit applications for the rapid and non-cytotoxic cellular delivery of DNA sequences, which opens the possibilities for efficient gene-delivery for the treatment of specific genetic diseases.100, 101

The use of polymer vesicles as synthetic nano-reactors140 has also been reported with several biological connotations.137 Vesicles that can successfully convert ADP into the biochemical fuel ATP have been prepared,135 alongside multi-step cascade reactions that utilize vesicles with three different incorporated enzymes.136 Furthermore, the potential applications of polymer vesicles as synthetic intra-cellular organelles have been the basis for several striking reports, with possibilities for the treatment of genetic diseases caused by either enzyme inactivity or deficiency.145

If the rapid development of copolymer vesicles continues at the same rate as over the last ten years, then their future uses can only excite both the authors and their readers. The possible applications appear endless, with the generation of fully synthetic polymer-based cells seemingly not too far over the horizon. The ever broadening field of soft-nanotechnology is a current research theme here in Sheffield, using the polymer vesicle as a delivery agent attached to a molecular motor or biopolymer strip—to create a nanobot or ‘synthetic-sperm’.146 For now at least, the medical applications as non-toxic and targeted drug-delivery agents are being widely explored. This is especially the case for the treatment of degenerative diseases such as cancer, and if industrial and academic collaborations reach fruition, the move from the bench to the bedside may not be too far away.

Biographical Information

  1. Top of page
  2. Abstract
  3. Introduction
  4. Block Copolymer Vesicles
  5. Conclusion
  6. Biographical Information
  7. Biographical Information
  8. Biographical Information

Adam Blanazs graduated with a Masters degree in chemistry from the University of Sheffield in 2005, with a year of study based at the University of Queensland in Australia. He is currently a final year Ph.D. student based in the labs of both Professor Ryan and Professor Armes. His research interests include block copolymer synthesis and properties, colloidal particles, biocompatible materials, and amphiphilic self-assembly.

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Biographical Information

  1. Top of page
  2. Abstract
  3. Introduction
  4. Block Copolymer Vesicles
  5. Conclusion
  6. Biographical Information
  7. Biographical Information
  8. Biographical Information

Steven P. Armes is a synthetic polymer/colloid chemist whose research interests include controlled-structure water-soluble block copolymers, micellar and vesicular self-assembly of stimulus-responsive block copolymers, biocompatible block copolymers, colloidal nanocomposite particles, pH-responsive microgels, Pickering emulsifiers, branched copolymers, shell cross-linked micelles, surface polymerisation and conducting polymer particles. He was awarded the 2007 RSC Macro Group medal and is the recipient of a five-year Royal Society–Wolfson Research Merit Award.

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Biographical Information

  1. Top of page
  2. Abstract
  3. Introduction
  4. Block Copolymer Vesicles
  5. Conclusion
  6. Biographical Information
  7. Biographical Information
  8. Biographical Information

Tony Ryan has a B.Sc. and a Ph.D. in Polymer Science & Technology from the Victoria University of Manchester and a D.Sc. from UMIST. He is currently the Pro Vice Chancellor for the Faculty of Science at the University of Sheffield. He started his academic career with a lectureship in Polymer Science at UMIST and moved to a Chair in Sheffield where he has been the ICI Professor of Physical Chemistry and Director of the Polymer Centre at the University of Sheffield. His research covers the synthesis, structure, processing, and properties of polymers and he is widely engaged in public engagement in science. He presented the Royal Institution Christmas Lectures in 2002 and was made an Officer of the British Empire in 2006.

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