Vesicles prepared in water from a series of diblock copolymers -"polymersomes" -are physically characterized and compared to lipid vesicles. With increasing molecular weightM n , the hydrophobic core thickness d for the self-assembled bilayers of poly(ethylene oxide)-polybutadiene (PEO-PBD) increases up to ≃20 nm -considerably greater than any previously studied lipid system. The mechanical responses of these membranes, specifically, the area elastic modulus K a and maximal areal strain α c are measured by micromanipulation. As expected for interface-dominated elasticity, K a (≃100 pN/nm) is found to be independent ofM n , but lower than the usual values for zwitterionic lipid membranes. Experiments on polymersomes show α c increases in a nearly linear fashion withM n , approaching a limiting value predicted by mean-field ideas which is universal and about 10-fold above that typical of lipids. Nonlinear responses and memory effects generally emerge with increasingM n , indicating the onset of chain entanglements at higherM n . The effects ofM n thus suggest a compromise between stability and fluidity for biomembranes. More generally, the results highlight the interfacial limits of self-assemblies at the nanoscale.

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We investigated the micellar polymorphism of poly(ethylene oxide)(PEO)-based block copolymers to illustrate the possibility of a rational control of the aggregation structure through synthetic manipulation of the molecular characteristics. Boundaries for the micellar shape transitions from bilayers to cylinders to spheres with increasing PEO composition were determined with direct cryogenic transmission electron microscopic (cryo-TEM) imaging of the microstructures in the form of thin vitreous hydrated specimens. Analyses of cryo-TEM images lead to determination of the packing properties of the hydrophobic block in terms of the interfacial area per chain and the degree of chain stretching. Also, the micellar phases of the block copolymers are characterized by anomalous structural behaviors such as coexistence of different structures and formation of exotic compound structures, which are discussed in terms of metastability inherent in the system comprising polymeric materials.

We demonstrate that synthetic soft materials can extend the utility of natural vesicles, from predominantly hydrophilic reservoirs to functional colloidal carriers that facilitate the biomedical application of large aqueous-insoluble compounds. Near-infrared (NIR)-emissive polymersomes (50-nm-to 50-m-diameter polymer vesicles) were generated through cooperative self assembly of amphiphilic diblock copolymers and conjugated multi(porphyrin)-based NIR fluorophores (NIRFs). When compared with natural vesicles comprised of phospholipids, polymersomes were uniquely capable of incorporating and uniformly distributing numerous large hydrophobic NIRFs exclusively in their lamellar membranes. Within these sequestered compartments, long polymer chains regulate the mean fluorophore-fluorophore interspatial separation as well as the fluorophore-localized electronic environment. Porphyrin-based NIRFs manifest photophysical properties within the polymersomal matrix akin to those established for these high-emission dipole strength fluorophores in organic solvents, thereby yielding uniquely emissive vesicles. Furthermore, the total fluorescence emanating from the assemblies gives rise to a localized optical signal of sufficient intensity to penetrate through the dense tumor tissue of a live animal. Robust NIR-emissive polymersomes thus define a soft matter platform with exceptional potential to facilitate deep-tissue fluorescence-based imaging for in vivo diagnostic and drug-delivery applications.porphyrin ͉ vesicles ͉ nanoscale ͉ diblock copolymer S upramolecular self assembly has revolutionized soft materials research by enabling the efficient and high-throughput fabrication of complex multicomponent nanostructures (1-3). For decades, self-assembled vesicles comprised of phospholipids (liposomes) or small-molecule surfactants (4) have been used for sequestering high concentrations of hydrophilic compounds (5) and controlling their temporal release and distribution for maximal therapeutic efficacy (6). More recently, amphiphilic peptides and polymers have been shown to form very elaborate architectures (7-9) and serve as useful nanocontainers in aqueous solution (10). In particular, self-assembled materials are ideal for carrying promising imaging and therapeutic agents whose biomedical utility has hitherto been hampered by inadequate aqueous solubility (11). Here, we demonstrate the unique ability of synthetic amphiphiles to assemble into functional vesicles that membrane-disperse numerous large hydrophobic fluorophores and enable their specialized application for deeptissue fluorescence-based in vivo imaging.Although visible probes enable exquisite imaging of live animals by intravital microscopy (12), their utility is significantly limited at greater than submillimeter tissue depths as a result of extensive light scattering and optical absorption. Because light scattering diminishes with increasing wavelength, and hemoglobin electronic and water vibrational overtone absorptions approach their nadir over the near-infrared (N...

Carrier-mediated delivery of drugs into the cytosol is often limited by either release from the carrier or release from an internalizing endolysosome. Here, loading, delivery, and cytosolic uptake of drug mixtures from degradable polymersomes are shown to exploit both the thick membrane of these block copolymer vesicles and their aqueous lumen as well as pH-triggered release within endolysosomes. Our initial in vivo studies demonstrate growth arrest and shrinkage of rapidly growing tumors after a single intravenous injection of polymersomes composed of poly(ethylene glycol)-polyester. Vesicles are shown to break down into membrane-lytic micelles within hours at 37 degrees C and low pH, although storage at 4 degrees C allows retention of drug for over a month. It is then shown that cell entry of the polymersomes into endolysosomes is followed by copolymer-induced endolysosomal rupture with release of cytotoxic drugs. Above a critical poration concentration (CCPC) that is easily achieved within endolysosomes and that scales with copolymer proportions and molecular weight, the copolymer micelles are seen to disrupt lipid membranes and thereby enhance drug activity. Neutral polymersomes and related macrosurfactant assemblies can thus create novel pathways within cells for controlled release and delivery.

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We utilize a series of structurally homologous, multi-porphyrin-based, fluorophores (PBFs) in order to explore the capacity of polymer vesicles (polymersomes) to stably incorporate large hydrophobic molecules, non-covalently within their thick lamellar membranes. Through aqueous hydration of dry, uniform thin-films of amphiphilic polymer and PBF species deposited on Teflon, self-assembled polymersomes are readily generated incorporating the hydrophobic fluorophores in prescribed molar ratios within their membranes. The size-dependent spectral properties of the PBFs allow for ready optical verification (via steady-state absorption and emission spectroscopy) of the extent of vesicle membrane loading and enable delineation of intermembranous molecular interactions. The resultant effects of PBF membrane-loading on polymersome thermodynamic and mechanical stability are further assessed by cryogenic transmission electron microscopy (cryo-TEM) and micropipet aspiration, respectively. We demonstrate that polymersomes can be loaded at up to 10 mol/wt% concentrations, with hydrophobic molecules that possess sizes comparable to those of large pharmaceutical conjugates (e.g. ranging 1.4-5.4 nm in length and Mw = 0.7-5.4 kg mol 21 ), without significantly compromising the robust thermodynamic and mechanical stabilities of these synthetic vesicle assemblies. Due to membrane incorporation, hydrophobic encapsulants are effectively prevented from self-aggregation, able to be highly concentrated in aqueous solution, and successfully shielded from deleterious environmental interactions. Together, these studies present a generalized paradigm for the generation of complex multi-functional materials that combine both hydrophilic and hydrophobic agents, in mesoscopic dimensions, through cooperative self-assembly.