Polymersomes Spanning from Nano- to Microscales: Advanced

PERSPECTIVE pubs.acs.org/JPCL

Polymersomes Spanning from Nano- to Microscales: Advanced Vehicles for Controlled Drug Delivery and Robust Vesicles for Virus and Cell Mimicking Fenghua Meng and Zhiyuan Zhong* Biomedical Polymers Laboratory, and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, Department of Polymer Science and Engineering, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou, 215123, People's Republic of China ABSTRACT: Polymersomes provide a highly promising platform for mimicking biological membranes as well as for controlled delivery of various pharmaceuticals and biopharmaceuticals. The recent advancement has made it possible to prepare small to giant polymersomes spanning from nano- to microscales, stimuli-sensitive polymersomes that swell or collapse in response to an external or internal stimulus, chimaeric polymersomes that contain distinct interior environments separated from the outside by an asymmetric membrane, porous polymersomes with tailored permeability, biomimetic and targeting polymersomes that selectively deliver drugs, proteins, and/or imaging probes to the sites of action. In this Perspective, we will give a brief introduction to polymersomes, highlight recent design and preparation of several sophisticated polymersomes, and discuss future challenges.

P

olymersomes (also referred to as polymer vesicles) have attracted enormous interest since the early work of Eisenberg, Discher, Hammer, and co-workers.1,2 As liposomes, polymersomes have watery interiors that are separated from the outside aqueous environments by a thin hydrophobic membrane. While liposomes are made from small phospholipid molecules, polymersomes are microscopic assemblies of macromolecular amphiphiles. As a result of their significantly higher molecular weights, polymersomes usually have thicker membranes (in the range of 5
30 nm versus 3
5 nm for liposomes), superb colloidal stability, enhanced mechanical strength, and reduced chemical permeability as compared to liposomes. To achieve a prolonged circulation time in vivo, liposomes have to be modified with poly(ethylene glycol) (PEG), which are known as “stealth liposomes”. In contrast, most polymersomes are intrinsically stealthed in that they are typically made from amphiphilic copolymers consisting of nonfouling polymers such as PEG, dextran, and poly(acrylic acid) (PAA). The sizes of polymersomes, depending on their macromolecular parameters (structures, compositions, molecular weights, etc.) as well as fabrication methods (direct dissolution, phase inversion, film rehydration, etc.) span from nano- to micrometers, which renders them highly interesting for virus and cell mimicry. The presence of large watery interiors and robust hydrophobic walls makes polymersomes suitable for encapsulation and controlled delivery of both hydrophilic (e.g., proteins, siRNA, DNA, chelated Gd) and hydrophobic species (e.g., paclitaxel, doxorubicin, quantum dots). The drug release profiles can be elegantly controlled by manipulating polymersome degradability, membrane permeability, and stimuli-responsive properties.3,4 It should r 2011 American Chemical Society

further be noted that targeting polymersomes that selectively deliver payloads to the sites of action can be prepared by decorating polymersomes with a specific ligand such as an antibody, peptide, and folate. In this Perspective, we will first illustrate the formation of polymersomes and control of vesicle physicochemical properties. Then, we highlight the recent design and preparation of several sophisticated polymersomes including stimuli-sensitive polymersomes, chimaeric polymersomes, biomimetic polymersomes, spotted polymersomes, and tumortargeting polymersomes. Finally, future perspectives will be discussed.

Polymersomes have been prepared from macromolecular amphiphiles of vastly different architectures (diblock, triblock, graft, hyperbranched, etc.) and molecular weights (ranging from hundreds to tens of thousands of daltons).

Received: January 4, 2011 Accepted: June 1, 2011 Published: June 07, 2011 1533

dx.doi.org/10.1021/jz200007h | J. Phys. Chem. Lett. 2011, 2, 1533–1539

The Journal of Physical Chemistry Letters The formation of polymersomes is mainly dictated by the fraction of the hydrophilic block (fphil), the molecular weight, and the effective interaction parameter of the hydrophobic block with water (χ). For block copolymers with a high χ, vesicles are favored when fphil = 20
40%, which is the same as that for natural lipids. At higher fphil (>45%), cylindrical or spherical micelles are predominantly formed. Bates and co-workers found that the morphology diagram for poly(ethylene oxide)-b-polybutadiene (PEO-b-PB) block copolymers exhibits four basic structural motifs, that is, bilayers, Y-junctions, cylinders, and spheres, depending on block copolymer molecular weights and compositions, at 1 wt % concentration in water.5,6 However, at high polymer concentrations (26
50 wt %), a disordered network phase of densely interconnected cylinders was observed over a wide range of copolymer compositions.5,6 Battaglia and Ryan reported that evolution of vesicles from PEO-b-poly(butylene oxide) (PEO-b-PBO) diblock copolymers upon progressive dilution with water involves the following four phases: lamellae f interconnected sponge f hexagonally packed vesicles f isotropic vesicles.7 Interestingly, PEO-b-PBO diblock copolymers were shown to form unusual morphologies including neuron-like tubular membranes (myelin)8 and metastable multilamellar aggregates (lamellarsomes)9 at certain molecular weights and compositions. It should be noted that the block copolymer vesicles as micelles show extremely slow chain exchange dynamics (nonergodicity) and are able to retain their morphologies for a long time.10,11 Due to their higher molecular weight, polymersomes exhibit a much lower critical aggregation concentration (CAC) as compared to liposomes. Eisenberg and co-workers found that block copolymer vesicles are thermodynamically stabilized with short hydrophilic chains located preferentially at the watery core and long hydrophilic chains at the outer surface.12 The sizes of polymersomes span from nano- to microscales, depending on their macromolecular parameters (thermodynamics) as well as fabrication methods (kinetics). The preparation of polymersomes can be divided, depending on whether organic solvent is used, into two principal methods, phase inversion and solvent-free techniques. The phase inversion approach involves dissolving macroamphiphiles in a suitable organic solvent, exchanging with water, and removing organic solvent by dialysis or evaporation. This method usually yields nanosized polymersomes with narrow size distributions. It can be a challenge, nevertheless, to thoroughly remove the trace amount of organic solvent residing in the membrane. Jiang and coworkers studied the polymersome formation kinetics of amphiphilic ABA triblock copolymers by Monte Carlo simulation and found that the pathway of spontaneous polymersome formation depended greatly on the selective solvent addition rate.13 The solvent-free techniques include direct dissolution, film rehydration, electroformation, and templated formation. Electroformation usually leads to micrometer-sized polymersomes, while film rehydration with vigorous stirring, sonication, or extrusion produces nanometer-sized polymersomes. van Hest and coworkers recently reported that kinetic manipulation of the phase behavior of PEG-b-polystyrene (PEG-b-PS) copolymer led to controllable shape transformation of polymersomes (e.g., to polymersome stomatocytes) (Figure 1).14 Giant polymersomes are of particular interest for mimicking live cells. Zhou and Yan studied real-time membrane fission and fusion, that is, the cytomimetic process, of giant polymersomes (average diameters of 4.0
112.8 μm) based on hyperbranched

PERSPECTIVE

Figure 1. Shape transformation of polymersomes during dialysis of organic solvents (dark red spheres) against water (blue spheres) through a solvent-swollen bilayer membrane (paths 1
3). Shape change also results in prolate formation, depending on the architecture of the block copolymers (path 4). Direct quenching yields spherical polymersomes (path 5).14 Reprinted from ref 14.

poly(3-ethyl-3-oxetanemethanol) star-PEO copolymer triggered by addition of glucose using an optical microscope.15 Battaglia and co-workers reported that fusion of PEO-b-PBO giant polymersomes takes place upon addition of PEO, wherein the extent and kinetics of membrane fusion are controlled by PEO molecular weights.16 Very recently, Lecommandoux and co-workers reported temperature-induced vesicle fission and fusion of giant polymersomes (average diameters of ∼10 μm) based on poly(trimethylene carbonate)-b-poly(L-glutamic acid) (PTMC-bPGA) copolymer, in which vesicle budding and fission took place upon increasing the temperature to above the PTMC melting point while fusion events occurred upon decreasing the temperature.17 Howse and co-workers recently reported templated formation of giant polymersomes (diameters = 2.9
10.3 μm) with a controlled size and wall thickness by elegantly combining photolithography and dewetting (top-down control of vesicle diameters) with molecular self-assembly (bottom-up control of membrane thickness).18 Oana, Kishimura, and coworkers reported the spontaneous formation of giant unilamellar polymersomes from microdroplets of a pair of oppositely charged block copolymers (polyion complexes) by irradiation with a focused infrared laser using an optical tweezer.19 The sizes of resulting polymersomes were determined by the initial droplet size. The membrane thickness (d) of polymersomes is intimately dependent on the molecular weights of hydrophobic blocks (Mphobe). For instance, Discher and co-workers reported that the membrane thickness of PEO-b-PBD polymersomes increased from 9.6 to 21 nm when increasing Mphobe from 2.6 to 14.4 kDa, in which a scaling behavior of d ≈ Mphobe1/2 was established.20 A scaling exponent of 1/2 indicates that PBD chains are in an unperturbed random coiled state. The coarsegrained molecular dynamics (CG-MD) simulations confirmed a scaling exponent of 1/2 for a membrane thickness higher than 7 nm, though an exponent of 0.82 was observed for smaller hydrophobic blocks.21 Battaglia and Ryan reported a scaling exponent of 2/3 for di- and triblock copolymers of PEO and PBO, indicating a mixed and stretched conformation of the hydrophobic chain inside of the vesicle membrane (strong segregation).22 It appears that the membranes of low-molecular-weight polymer vesicles may exhibit a bilayer structure like that of liposomes, whereas 1534

dx.doi.org/10.1021/jz200007h |J. Phys. Chem. Lett. 2011, 2, 1533–1539

The Journal of Physical Chemistry Letters

PERSPECTIVE

substrates 6,8-difluoro-4-methylumbelliferyl octanoate (338 Da) and p-nitrophenyl acetate (181 Da).

The presence of large aqueous compartments as well as robust hydrophobic membranes makes polymersomes the most versatile carriers capable of delivering a myriad of species ranging from anticancer drugs (either hydrophilic or hydrophobic), proteins, siRNA, and DNA to diagnostic agents.

Figure 2. Schematic presentation of biodegradable chimaeric polymersomes based on asymmetric PEG-PCL-PDEA triblock copolymer.33 Reprinted from ref 33.

chains in membranes of high-molecular-weight polymer vesicles are likely interdigitated and entangled. The bending rigidity of polymersomes increased with increasing membrane thickness as a result of enhanced interdigitation. The membrane fluidity, on the other hand, usually decreased with increasing molecular weights and became more pronounced when hydrophobic chains were long enough to entangle. Helmerson and co-workers created robust long polymer nanotubes by directly pulling on the membrane of PEO-b-PBD polymersomes using either optical tweezers or a micropipet followed by chemical cross-linking.23 The aqueous core together with their remarkable stability makes these polymer nanotubes interesting candidates for applications in biotechnology including nanofluidics. The corona thickness of PEO-b-PBO polymersome was shown to scale with PEO molecular weights according to a fully stretched regime.24 The polymersome surface chemistry and topology can be tailored using block copolymers with complementary hydrophilic chains. For example, Battaglia and co-workers reported that the binary mixtures of poly(2-(methacryloyloxy)ethyl-phosphorylcholine)-b-poly(2- (diisopropylamino)ethyl methacrylate) (PMPC-b-PDPA) and PEG-b-PDPA copolymers produced hybrid polymersomes with specific PEG or PMPC domains within their exterior envelopes, which, along with polymersome size, played a significant role in cellular uptake.25 Discher and coworkers reported formation of spotted polymersomes from a mixture of charged block copolymer PAA-b-PBD and neutral block copolymer PEO-b-PBD in the presence of divalent cations such as calcium and copper that induced domain formation by selective binding with polyanionic amphiphiles.26 The permeability of polymersomes is governed by the membrane thickness according to Fick’s first law. The diffusion coefficients of polymersome membranes are one order lower as compared to those of liposomes (D ≈ 0.1 mm2 s
1 or less versus 1 mm2 s
1). The permeability of polymersomes can be fine-tuned by adjusting the hydrophobic block molecular weight and nature of the polymersome membrane or by incorporating degradable or stimuli-sensitive hydrophobic blocks into the vesicle membrane. Tsourkas and co-workers prepared porous polymersomes from a mixture of PEO-b-PBD and PEO-b-PCL that exhibit improved permeability to water flux and a large capacity to store chelated Gd within the aqueous lumen, giving rise to enhanced longitudinal relaxivity.27 van Hest and co-workers developed polymersomes with controllable permeability from PEG-b-PS (matrix-forming) and sugar-responsive PEG-b-poly(styrene boronic acid) (PEG-b-PSBA, pore-forming) block copolymers.28 In contrast to the nonporous controls, Candida antarctica Lipase B (CALB, model enzyme)-loaded porous polymersomes showed activity in the hydrolysis of the

Discher and co-workers reported that a single intravenous injection of DOX 3 HCl and PTX-loaded PEG-PCL polymersomes into nude mice bearing human breast carcinoma brought about growth arrest and shrinkage of rapidly growing tumors.29 Kokkoli and co-workers reported that PR_b-functionalized PEO-PBD polymersomes (PR_b is an effective R5β1 targeting peptide) efficiently delivered tumor necrosis factor-R (TNFR) to LNCaP human prostate cancer cells, resulting in dramatic enhancement of the cytotoxic potential of TNFR.30 Lecommandoux and co-workers reported that DOX-loaded poly(γ-benzylL-glutamate)-b-hyaluronan polymersomes, a self-targeting drug delivery cargo to CD44-overexpressing cells, suppressed growth of breast tumors on female Sprague
Dawley rats.31 Hammer, Therien, and co-workers showed that near-infrared (NIR)emissive polymersomes prepared by stably incorporating large multimeric porphyrin-based NIR fluorophores into the thick polymersome membrane were able to penetrate through the dense tumor tissue of a 9 L glioma-bearing rat.32 Chimaeric polymersomes that have distinct interior environments separated from the outside by an asymmetric membrane (analogous to the cellular membrane) have received recent interest. We have shown that biodegradable chimaeric polymersomes readily formed from asymmetric PEG-b-poly(ε-caprolactone)-b-poly(2-(diethylamino) ethyl methacrylate) (PEGPCL-PDEA, Mn PEG > Mn PDEA) triblock copolymers by film rehydration efficiently delivered and released exogenous proteins into cancer cells (Figure 2).33 The longer PEG block is preferentially oriented at the polymersome outlayer, thereby offering excellent biocompatibility and stability in the circulation, while the shorter cationic PDEA block is preferentially located inside of the polymersomes, which on one hand facilitates efficient encapsulation and stabilization of proteins and on the other hand may assist polymersomes in escaping from endosomes, resulting in efficient cytoplasmic delivery of proteins. Jin and co-workers reported fabrication of asymmetric polymersomes from PEG-b-PCL and dextran-b-PCL (DEX-b-PCL) by “phase-guided assembly”, in which DEX-b-PCL formed the inner leaflet around the dispersed dextran phase and PEG-b-PCL formed the outer leaflet with the PEG block facing the PEG continuous phase.34 Armes, Ryan, and co-workers reported formation of pH-sensitive asymmetric polymersomes from PEO-b-poly(2-(diisopropylamino) ethyl meth1535

dx.doi.org/10.1021/jz200007h |J. Phys. Chem. Lett. 2011, 2, 1533–1539

The Journal of Physical Chemistry Letters

PERSPECTIVE

Figure 3. (Left) Cartoon of asymmetric polymersomes based on PEG-b-PBD and UV-sensitive liquid-crystalline copolymer PEG-b-PMAzo. In the absence of UV light, the hydrophobic LC block of the PEG-b-PMAzo444 copolymer has a rod-like conformation. Under UV illumination, isomerization of the mesogenic groups induces a conformational change of the polymer backbone to a disordered, isotropic state. (Right) Morphologies of bursting asymmetric polymersomes under UV illumination. Bright-field images were taken by using a high-speed digital camera (scale bar, 5 μm).36 Reprinted from ref 36.

acrylate)-b-poly(2-(dimethylamino) ethyl methacrylate) (PEOb-PDPA-b-PDMA) triblock copolymers in aqueous solution.35 Nassoy, Li, and co-workers prepared asymmetric polymersomes from a mixture of PEG-b-PBD and UV-sensitive liquid-crystalline copolymer PEG-b-PMAzo, which, upon UV illumination, resulted in instantaneous bursting of polymersomes (Figure 3).36 Bai and Lodge recently reported preparation of robust PEO-bPB polymersomes with ionic liquid (1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl) imide) interiors dispersed in water.37

Stimuli-responsive polymersomes that swell or collapse in response to an external (temperature, light, ions, etc.) or internal stimuli (oxidation, reduction, pH, etc.) have generated widespread interest for programmed drug delivery. Hubbell and co-workers reported oxidation-responsive polymersomes based on PEG-b-poly(propylene sulphide) (PEG-b-PPS) that underwent rapid destabilization in the presence of H2O2 (oxidative agent) due to conversion of PPS hydrophobe into a hydrophile, poly(propylene sulphoxide), and ultimately poly(propylene Sulphone).38 The same authors have also designed reduction-responsive polymersomes based on PEG-SSPPS block copolymer containing an intervening disulfide bond, wherein cellular uptake and disruption of polymersomes leading to efficient cytoplasmic release of drugs were observed in cells following 10 min of incubation.39 There is a high concentration of glutathione tripeptides (reducing agent) in the cytosol and cell nucleus, which makes reduction-responsive nanovehicles highly promising for intracellular drug delivery.40 We devised robust dual-responsive polymersomes based on temperature-sensitive PEO-b-poly(acrylic acid)-b-poly(N-isopropylacrylamide) (PEOPAA-PNIPAM) triblock copolymer and cross-linking with cystamine via carbodiimide chemistry.41 The cross-linked polymersomes, while showing remarkable stability against dilution and a decrease of temperature, were otherwise rapidly dissociated into unimers under reductive conditions mimicking an intracellular environment, providing controlled release of FITC
dextran. Grubbs and co-workers reported that ABC triblock copolymers

Figure 4. Schematic illustration of the thermally induced size change of assemblies of copolymers containing a thermoresponsive block. Below the LCST, the central block (cyan) is hydrophilic; above the LCST, the central block (pink) becomes hydrophobic.43 Reprinted from ref 43.

with PEO as the A block, temperature-sensitive PNIPAM or poly(ethylene oxide-stat-butylene oxide) as the B block, and polyisoprene as the C block underwent reversible transitions from spherical micelles to polymersomes upon increasing temperatures to above their lower critical solution temperature (LCST) (Figure 4).42,43 Taking advantage of acidic endo/lysosomal compartments, pH-sensitive degradable polymersomes demonstrating pH-dependent release behavior of paclitaxel (PTX, hydrophobic) and doxorubicin hydrochloride (DOX 3 HCl, hydrophilic) were prepared from block copolymers composed of PEG and an acid-labile polycarbonate, poly(2,4,6-trimethoxybenzylidenepentaerythritol carbonate) (PTMBPEC).44 Dmochowski and co-workers prepared photoactive composite polymersomes by incorporating horse spleen ferritin (HSF) in the aqueous interior and bis[(porphinato)zinc] (PZn2) chromophore in the membrane of PEO-b-PBD block copolymer vesicles.45 The polymersomes were deformed and destructed on the minute time scale upon exposure to near-UV to near-IR light.

Polymersomes spanning from nano- to microscales provide an ideal technology platform for mimicking viruses and cells. 1536

dx.doi.org/10.1021/jz200007h |J. Phys. Chem. Lett. 2011, 2, 1533–1539

The Journal of Physical Chemistry Letters

PERSPECTIVE

Figure 5. Formation of biomimetic polymersomes from polysaccharide-b-polypeptide.49 Copyright Wiley-VCH Verlag GmbH & Co. KGaA. Reproduced with permission.

Choi and Montemagno reported ATP-producing cellular mimetic proteopolymersomes in which ATP has been generated by coupled reactions between bacteriorhodopsin, a lightdriven transmembrane proton pump, and F0F1-ATP synthase motor protein, reconstituted in polymersomes.46 These hybrid proteopolymersomes are interesting as artificial organelles for in vitro investigation of cellular metabolism as well as for synthesis of functional smart materials. Deming and co-workers prepared biomimetic pH-responsive polymersomes based on amphiphilic ethylene glycol-modified polyleucine-b-polylysine copolypeptide, in which vesicle size and structure were dictated, in a manner similar to viral capsids, essentially by the ordered conformations of polypeptides.47 In a following work, polyleucine-b-polyarginine copolypeptide was designed to form biomimetic polymersomes, in which polyarginine not only directed vesicle formation but also facilitated intracellular trafficking of polymersomes due to its mimicking of protein transduction domains (PTD).48 In an effort to mimic viral capsids, Lecommandoux and co-workers designed polysaccharide-b-polypeptide (simple glycolprotein analogue) copolymer vesicles (Figure 5).49 Interestingly, biomimetic polymersomes using hyaluronan as a hydrophilic stabilizing block were demonstrated to target cancer cells overexpressing CD44 glycoprotein receptors.50 Battaglia and co-workers reported that biomimetic pH-sensitive polymersomes based on PMPC-b-PDPA copolymers efficiently encapsulated and delivered DNA into cells.51 In conclusion, the past several years have witnessed significant progress in design, preparation, and applications of polymersomes. Despite at their infancy, polymersomes with enhanced stability and remarkable chemical versatility have emerged as an advanced alternative to widely applied liposomes in areas from virus and cell mimicry to controlled drug delivery. It remains a challenge, however, to produce polymersomes with precisely controlled physicochemical properties (including vesicle size, surface, shape, membrane thickness, permeability, etc.), which are of utmost importance to their practical applications. Notably, Percec and co-workers recently reported a modular synthesis strategy for vesicles with uniform sizes (termed as dendrimersomes) based on amphiphilic Janus dendrimers that allows systematic tuning of molecular structure and of selfassembled architecture.52 This may lead to eventual formation of advanced polymersomes that have not only monodisperse sizes but also specific biological functions. In accordance, much work should be focused on polymersome simulation, which may on one hand help understand the underlying self-assembly mechanism and on

the other hand assist design and controlled preparation of novel polymersomes.

In the future, vesicle-forming macroamphiphiles shall be designed on a molecular basis with programmed self-assembly as well as deassembly behaviors similar to those of the viral capsids (not simply relying on hydrophobic interactions). We envision that polymersomes will in particular play a pivotal role in targeted intracellular delivery of hydrophilic pharmaceuticals and biopharmaceuticals including anticancer drugs, proteins, peptides, and nucleic acids, as well as in combination cancer therapy and theranosis (combination of therapy and diagnosis), in which targeted delivery of two or more reagents (e.g., anticancer drugs, proteins, siRNA, DNA, quantum dots, etc.) using one single vehicle brings about synergistic treatment effects (e.g., for recurrent or resistant tumors). It should be noted, however, that the current polymersomes for drug delivery applications encounter several challenges, including cumbersome polymersome preparation procedures (e.g., often involving organic solvent), low drug loading content and loading efficiency, inferior in vivo specificity, and/or a noncontrolled drug release profile. In the future, efforts shall be directed to the development of novel multifunctional biocompatible polymersomes that are preferably formed directly in water (without assistance of organic solvent), have high drug loading levels, are stable in circulation, have programmed biodegradability in vivo, and preferentially accumulate and release drugs at the targeted sites in a controlled manner.

’ AUTHOR INFORMATION Corresponding Author

*Tel/Fax: þ86-512-65880098. E-mail: [email protected].

’ BIOGRAPHIES Fenghua Meng is a professor of the Soochow University Biomedical Polymers Laboratory. She received her Ph.D. under 1537

dx.doi.org/10.1021/jz200007h |J. Phys. Chem. Lett. 2011, 2, 1533–1539

The Journal of Physical Chemistry Letters the supervision of Prof. Dr. Jan Feijen from the University of Twente in 2003. Her research focuses on design and preparation of intelligent polymersomes and micelles that are responsive to one or multiple stimuli, intracellular protein delivery, combination cancer therapy, and theranosis. Zhiyuan Zhong is a professor and chair of the Soochow University Biomedical Polymers Laboratory and cochair of the Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application. He received his Ph.D. under the supervision of Prof. Dr. Jan Feijen from the University of Twente in 2002. He has served as an Editorial Advisory Board Member of Biomacromolecules (since 2011), the executive chair of the first Symposium on Innovative Polymers for Controlled Delivery (SIPCD 2010, Suzhou), and a coeditor of the Journal of Controlled Release SIPCD 2010 Special Issue. His research interests cover design and synthesis of novel biodegradable polymers, stimuli-responsive drug delivery systems, multifunctional polymer-based gene delivery systems, and injectable biohydrogels. For more information, please visit http://bmp.suda.edu.cn/.

’ ACKNOWLEDGMENT This work is financially supported by research grants from the National Natural Science Foundation of China (NSFC 50703028, 20974073, 50973078, and 20874070), the Scientific Research Foundation for the Returned Overseas Chinese Scholars (State Education Ministry), the Natural Science Foundation of the Jiangsu Higher Education Institutions of China (08KJB150016), a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions, and the Program of Innovative Research Team of Soochow University. ’ REFERENCES (1) Discher, B. M.; Won, Y. Y.; Ege, D. S.; Lee, J. C. M.; Bates, F. S.; Discher, D. E.; Hammer, D. A. Polymersomes: Tough Vesicles Made from Diblock Copolymers. Science 1999, 284, 1143–1146. (2) Discher, D. E.; Eisenberg, A. Polymer Vesicles. Science 2002, 297, 967–973. (3) LoPresti, C.; Lomas, H.; Massignani, M.; Smart, T.; Battaglia, G. Polymersomes: Nature Inspired Nanometer Sized Compartments. J. Mater. Chem. 2009, 19, 3576–3590. (4) Meng, F. H.; Zhong, Z. Y.; Feijen, J. Stimuli-Responsive Polymersomes for Programmed Drug Delivery. Biomacromolecules 2009, 10, 197–209. (5) Jain, S.; Dyrdahl, M. H. E.; Gong, X.; Scriven, L. E.; Bates, F. S. Lyotropic Phase Behavior of Poly(ethylene oxide)-poly(butadiene) Diblock Copolymers: Evolution of the Random Network Morphology. Macromolecules 2008, 41, 3305–3316. (6) Jain, S. M.; Gong, X. B.; Scriven, L. E.; Bates, F. S. Disordered Network State in Hydrated Block-Copolymer Surfactants. Phys. Rev. Lett. 2006, 96, 138304. (7) Battaglia, G.; Ryan, A. J. The Evolution of Vesicles from Bulk Lamellar Gels. Nat. Mater. 2005, 4, 869–876. (8) Battaglia, G.; Ryan, A. J. Neuron-Like Tubular Membranes Made of Diblock Copolymer Amphiphiles. Angew. Chem., Int. Ed. 2006, 45, 2052–2056. (9) Battaglia, G.; Tomas, S.; Ryan, A. J. Lamellarsomes: Metastable Polymeric Multilamellar Aggregates. Soft Matter 2007, 3, 470–475. (10) Jain, S.; Bates, F. S. Consequences of Nonergodicity in Aqueous Binary PEO-PB Micellar Dispersions. Macromolecules 2004, 37, 1511–1523. (11) Won, Y. Y.; Davis, H. T.; Bates, F. S. Molecular Exchange in PEO-PB Micelles in Water. Macromolecules 2003, 36, 953–955.

PERSPECTIVE

(12) Luo, L. B.; Eisenberg, A. Thermodynamic Stabilization Mechanism of Block Copolymer Vesicles. J. Am. Chem. Soc. 2001, 123, 1012–1013. (13) Han, Y. Y.; Yu, H. Z.; Du, H. B.; Jiang, W. Effect of Selective Solvent Addition Rate on the Pathways for Spontaneous Vesicle Formation of ABA Amphiphilic Triblock Copolymers. J. Am. Chem. Soc. 2010, 132, 1144–1150. (14) Kim, K. T.; Zhu, J. H.; Meeuwissen, S. A.; Cornelissen, J.; Pochan, D. J.; Nolte, R. J. M.; van Hest, J. C. M. Polymersome Stomatocytes: Controlled Shape Transformation in Polymer Vesicles. J. Am. Chem. Soc. 2010, 132, 12522–12524. (15) Zhou, Y. F.; Yan, D. Y. Real-Time Membrane Fission of Giant Polymer Vesicles. Angew. Chem., Int. Ed. 2005, 44, 3223–3226. (16) Smart, T. P.; Fernyhough, C.; Ryan, A. J.; Battaglia, G. Controlling Fusion and Aggregation in Polymersome Dispersions. Macromol. Rapid Commun. 2008, 29, 1855–1860. (17) Sanson, C.; Le Meins, J. F.; Schatz, C.; Soum, A.; Lecommandoux, S. Temperature Responsive Poly(trimethylene carbonate)-blockpoly(L-glutamic acid) Copolymer: Polymersomes Fusion and Fission. Soft Matter 2010, 6, 1722–1730. (18) Howse, J. R.; Jones, R. A. L.; Battaglia, G.; Ducker, R. E.; Leggett, G. J.; Ryan, A. J. Templated Formation of Giant Polymer Vesicles with Controlled Size Distributions. Nat. Mater. 2009, 8, 507–511. (19) Oana, H.; Kishimura, A.; Yonehara, K.; Yamasaki, Y.; Washizu, M.; Kataoka, K. Spontaneous Formation of Giant Unilamellar Vesicles from Microdroplets of a Polyion Complex by Thermally Induced Phase Separation. Angew. Chem., Int. Ed. 2009, 48, 4613–4616. (20) Bermudez, H.; Brannan, A. K.; Hammer, D. A.; Bates, F. S.; Discher, D. E. Molecular Weight Dependence of Polymersome Membrane Structure, Elasticity, and Stability. Macromolecules 2002, 35, 8203–8208. (21) Srinivas, G.; Discher, D. E.; Klein, M. L. Self-Assembly and Properties of Diblock Copolymers by Coarse-Grain Molecular Dynamics. Nat. Mater. 2004, 3, 638–644. (22) Battaglia, G.; Ryan, A. J. Bilayers and Interdigitation in Block Copolymer Vesicles. J. Am. Chem. Soc. 2005, 127, 8757–8764. (23) Reiner, J. E.; Wells, J. M.; Kishore, R. B.; Pfefferkorn, C.; Helmerson, K. Stable and Robust Polymer Nanotubes Stretched from Polymersomes. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 1173–1177. (24) Smart, T. P.; Mykhaylyk, O. O.; Ryan, A. J.; Battaglia, G. Polymersomes Hydrophilic Brush Scaling Relations. Soft Matter 2009, 5, 3607–3610. (25) Massignani, M.; LoPresti, C.; Blanazs, A.; Madsen, J.; Armes, S. P.; Lewis, A. L.; Battaglia, G. Controlling Cellular Uptake by Surface Chemistry, Size, and Surface Topology at the Nanoscale. Small 2009, 5, 2424–2432. (26) Christian, D. A.; Tian, A. W.; Ellenbroek, W. G.; Levental, I.; Rajagopal, K.; Janmey, P. A.; Liu, A. J.; Baumgart, T.; Discher, D. E. Spotted Vesicles, Striped Micelles and Janus Assemblies Induced by Ligand Binding. Nat. Mater. 2009, 8, 843–849. (27) Cheng, Z. L.; Thorek, D. L. J.; Tsourkas, A. Porous Polymersomes with Encapsulated Gd-Labeled Dendrimers as Highly Efficient Mri Contrast Agents. Adv. Funct. Mater. 2009, 19, 3753–3759. (28) Kim, K. T.; Cornelissen, J.; Nolte, R. J. M.; van Hest, J. C. M. A Polymersome Nanoreactor with Controllable Permeability Induced by Stimuli-Responsive Block Copolymers. Adv. Mater. 2009, 21, 2787–2791. (29) Ahmed, F.; Pakunlu, R. I.; Srinivas, G.; Brannan, A.; Bates, F.; Klein, M. L.; Minko, T.; Discher, D. E. Shrinkage of a Rapidly Growing Tumor by Drug-Loaded Polymersomes: pH-Triggered Release through Copolymer Degradation. Mol. Pharmaceutics 2006, 3, 340–350. (30) Demirgoz, D.; Pangburn, T. O.; Davis, K. P.; Lee, S.; Bates, F. S.; Kokkoli, E. Pr_b-Targeted Delivery of Tumor Necrosis FactorAlpha by Polymersomes for the Treatment of Prostate Cancer. Soft Matter 2009, 5, 2011–2019. (31) Upadhyay, K. K.; Bhatt, A. N.; Mishra, A. K.; Dwarakanath, B. S.; Jain, S.; Schatz, C.; Le Meins, J.-F.; Farooque, A.; Chandraiah, G.; Jain, A. K.; et al. The Intracellular Drug Delivery and Anti Tumor 1538

dx.doi.org/10.1021/jz200007h |J. Phys. Chem. Lett. 2011, 2, 1533–1539

The Journal of Physical Chemistry Letters Activity of Doxorubicin Loaded Poly(gamma-benzyl L-glutamate)b-hyaluronan Polymersomes. Biomaterials 2010, 31, 2882–92. (32) Ghoroghchian, P. P.; Frail, P. R.; Susumu, K.; Blessington, D.; Brannan, A. K.; Bates, F. S.; Chance, B.; Hammer, D. A.; Therien, M. J. Near-Infrared-Emissive Polymersomes: Self-Assembled Soft Matter for in Vivo Optical Imaging. Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 2922–2927. (33) Liu, G. J.; Ma, S. B.; Li, S. K.; Cheng, R.; Meng, F. H.; Liu, H. Y.; Zhong, Z. Y. The Highly Efficient Delivery of Exogenous Proteins into Cells Mediated by Biodegradable Chimaeric Polymersomes. Biomaterials 2010, 31, 7575–7585. (34) Zhang, Y. L.; Wu, F.; Yuan, W. E.; Jin, T. Polymersomes of Asymmetric Bilayer Membrane Formed by Phase-Guided Assembly. J. Controlled Release 2010, 147, 413–419. (35) Blanazs, A.; Massignani, M.; Battaglia, G.; Armes, S. P.; Ryan, A. J. Tailoring Macromolecular Expression at Polymersome Surfaces. Adv. Funct. Mater. 2009, 19, 2906–2914. (36) Mabrouk, E.; Cuvelier, D.; Brochard-Wyart, F.; Nassoy, P.; Li, M. H. Bursting of Sensitive Polymersomes Induced by Curling. Proc. Natl. Acad. Sci. U.S.A. 2009, 106, 7294–7298. (37) Bai, Z. F.; Lodge, T. P. Polymersomes with Ionic Liquid Interiors Dispersed in Water. J. Am. Chem. Soc. 2010, 132, 16265–16270. (38) Napoli, A.; Valentini, M.; Tirelli, N.; Muller, M.; Hubbell, J. A. Oxidation-Responsive Polymeric Vesicles. Nat. Mater. 2004, 3, 183–189. (39) Cerritelli, S.; Velluto, D.; Hubbell, J. A. PEG-SS-PPS: ReductionSensitive Disulfide Block Copolymer Vesicles for Intracellular Drug Delivery. Biomacromolecules 2007, 8, 1966–1972. (40) Meng, F. H.; Hennink, W. E.; Zhong, Z. Y. Reduction-Sensitive Polymers and Bioconjugates for Biomedical Applications. Biomaterials 2009, 30, 2180–98. (41) Xu, H. F.; Meng, F. H.; Zhong, Z. Y. Reversibly Crosslinked Temperature-Responsive Nano-Sized Polymersomes: Synthesis and Triggered Drug Release. J. Mater. Chem. 2009, 19, 4183–4190. (42) Sundararaman, A.; Stephan, T.; Grubbs, R. B. Reversible Restructuring of Aqueous Block Copolymer Assemblies through Stimulus-Induced Changes in Amphiphilicity. J. Am. Chem. Soc. 2008, 130, 12264–12265. (43) Cai, Y.; Aubrecht, K. B.; Grubbs, R. B. Thermally Induced Changes in Amphiphilicity Drive Reversible Restructuring of Assemblies of ABC Triblock Copolymers with Statistical Polyether Blocks. J. Am. Chem. Soc. 2011, 133, 1058–1065. (44) Chen, W.; Meng, F. H.; Cheng, R.; Zhong, Z. Y. pH-Sensitive Degradable Polymersomes for Triggered Release of Anticancer Drugs: A Comparative Study with Micelles. J. Controlled Release 2010, 142, 40–46. (45) Robbins, G. P.; Jimbo, M.; Swift, J.; Therien, M. J.; Hammer, D. A.; Dmochowski, I. J. Photoinitiated Destruction of Composite Porphyrin
Protein Polymersomes. J. Am. Chem. Soc. 2009, 131, 3872–3874. (46) Choi, H. J.; Montemagno, C. D. Artificial Organelle: ATP Synthesis from Cellular Mimetic Polymersomes. Nano Lett. 2005, 5, 2538–2542. (47) Bellomo, E. G.; Wyrsta, M. D.; Pakstis, L.; Pochan, D. J.; Deming, T. J. Stimuli-Responsive Polypeptide Vesicles by Conformation-Specific Assembly. Nat. Mater. 2004, 3, 244–248. (48) Holowka, E. P.; Sun, V. Z.; Kamei, D. T.; Deming, T. J. Polyarginine Segments in Block Copolypeptides Drive Both Vesicular Assembly and Intracellular Delivery. Nat. Mater. 2007, 6, 52–57. (49) Schatz, C.; Louguet, S.; Le Meins, J. F.; Lecommandoux, S. Polysaccharide-block-polypeptide Copolymer Vesicles: Towards Synthetic Viral Capsids. Angew. Chem., Int. Ed. 2009, 48, 2572–2575. (50) Upadhyay, K. K.; Le Meins, J. F.; Misra, A.; Voisin, P.; Bouchaud, V.; Ibarboure, E.; Schatz, C.; Lecommandoux, S. Biomimetic Doxorubicin Loaded Polymersomes from Hyaluronan-block-poly(gamma-benzyl glutamate) Copolymers. Biomacromolecules 2009, 10, 2802–2808. (51) Lomas, H.; Canton, I.; MacNeil, S.; Du, J.; Armes, S. P.; Ryan, A. J.; Lewis, A. L.; Battaglia, G. Biomimetic pH Sensitive Polymersomes

PERSPECTIVE

for Efficient DNA Encapsulation and Delivery. Adv. Mater. 2007, 19, 4238–4243. (52) Percec, V.; Wilson, D. A.; Leowanawat, P.; Wilson, C. J.; Hughes, A. D.; Kaucher, M. S.; Hammer, D. A.; Levine, D. H.; Kim, A. J.; Bates, F. S.; et al. Self-Assembly of Janus Dendrimers into Uniform Dendrimersomes and Other Complex Architectures. Science 2010, 328, 1009–1014.

1539

dx.doi.org/10.1021/jz200007h |J. Phys. Chem. Lett. 2011, 2, 1533–1539