Self-assembled nanostructures obtained from natural and synthetic amphiphiles serve as mimics of biological membranes and enable the delivery of drugs, proteins, genes, and imaging agents. Yet the precise molecular arrangements demanded by these functions are difficult to achieve. Libraries of amphiphilic Janus dendrimers, prepared by facile coupling of tailored hydrophilic and hydrophobic branched segments, have been screened by cryogenic transmission electron microscopy, revealing a rich palette of morphologies in water, including vesicles, denoted dendrimersomes, cubosomes, disks, tubular vesicles, and helical ribbons. Dendrimersomes marry the stability and mechanical strength obtainable from polymersomes with the biological function of stabilized phospholipid liposomes, plus superior uniformity of size, ease of formation, and chemical functionalization. This modular synthesis strategy provides access to systematic tuning of molecular structure and of self-assembled architecture.

Liposomes (nontoxic/nonantigenic vesicles derived from phospholipids) have long been utilized in numerous biotechnology and pharmaceutical applications to improve therapeutic indices and enhance cellular uptake.1 Their structural stability, however, is dependent upon many intrinsic and environmental parameters that often serve to compromise their efficacy.2 Polymersomes (polymer vesicles formed from a wide variety of fully synthetic amphiphiles) 3 -5 have similar utility to their lipid counterparts but possess several advantageous properties including vastly superior stability6 and diverse functionality afforded by tuning material chemistries through polymer synthesis. Recently, there has been considerable interest in the development of degradable polymersomes suitable for in vivo drug delivery. Here, we present the generation of self-assembled vesicles comprised entirely of an amphiphilic diblock copolymer of poly(ethylene oxide) (PEO) and polycaprolactone (PCL), two previously FDAapproved polymers. Unlike degradable polymersomes formed from blending bioinert and hydrolyzable components,7 , 8 PEO-b-PCL-based vesicles promise to be fully bioresorbable, 9 leaving no potentially toxic byproducts upon their degradation. Moreover, unlike published reports of other degradable (peptide-, polyester-, or polyanhydride-based) polymersomes, 10-12 these bioresorbable vesicles are formed through spontaneous self-assembly of their pure component amphiphile.Poly(ethylene oxide) was chosen as the hydrophilic block as it imparts to the vesicle's surface biocompatibility and prolonged blood circulation times.13 -15 Polycaprolactone constitutes the vesicles' hydrophobic membrane portion. PCL is degraded by hydrolysis of its ester linkages in physiological conditions (such as in the human body) and has therefore received a great deal of attention for use as an implantable biomaterial in drug delivery devices, bioresorbable sutures, adhesion barriers, and scaffolds for injury repair via tissue engineering. 16 -19 Compared to other biodegradable aliphatic polyesters, PCL has several advantageous properties, including (1) high permeability to small drug molecules, (2) NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript neutral pH environment upon degradation, (3) facility in forming blends with other polymers, and (4) suitability for long-term delivery afforded by slow erosion kinetics as compared to polylactide (PLA), polyglycolide (PGA), and polylactic-co-glycolic acid (PLGA). 17 Utilization of PCL as the hydrophobic block in our formulations promises that the resultant polymersomes should have safe and complete in vivo degradation.Amphiphilic poly(ethylene oxide)-b-polycaprolactone was generated via ring-opening polymerization of cyclic ∊-caprolactone (CL) in the presence of stannous(II) octoate (SnOct) and monocyano-or monomethoxypoly(ethylene oxide) (PEO, 0.75K, 1.1K, 1.5K, 2K, 5K, 5.5K, 5.8K; Polymer Source, Dorval, Canada). 20 The reactions yielded PEO-b-PCL copolymers with varying PCL block size (betwe...

Nanoparticles are being developed as delivery vehicles for therapeutic pharmaceuticals and contrast imaging agents. Polymersomes (mesoscopic polymer vesicles) possess a number of attractive biomaterial properties that make them ideal for these applications. Synthetic control over block copolymer chemistry enables tunable design of polymersome material properties. The polymersome architecture, with its large hydrophilic reservoir and its thick hydrophobic lamellar membrane, provides significant storage capacity for both water soluble and insoluble substances (such as drugs and imaging probes). Further, the brush-like architecture of the polymersome outer shell can potentially increase biocompatibility and blood circulation times. A further recent advance is the development of multi-functional polymersomes that carry pharmaceuticals and imaging agents simultaneously. The ability to conjugate biologically active ligands to the brush surface provides a further means for targeted therapy and imaging. Hence, polymersomes hold enormous potential as nanostructured biomaterials for future in vivo drug delivery and diagnostic imaging applications.

The ability to add synthetic channels to polymersome (polymer vesicle) membranes could lead to novel membrane composites with unique selectivity and permeability. Proton transport through two different synthetic pores, self‐assembled from either a dendritic dipeptide, (6Nf‐3,4‐3,5)12G2‐CH2‐Boc‐L‐Tyr‐L‐Ala‐OMe, or a dendritic ester, (R)‐4Bp‐3,4‐dm8G1‐COOMe, incorporated into polymersome membranes are studied. Polymersomes provide an excellent platform for studying such transport processes due to their robustness and mechanical and chemical stability compared to liposomes. It is found that the incorporated dendritic dipeptide and dendritic ester assemble into stable helical pores in the poly(ethylene oxide)‐polybutadiene (PEO‐PBD) polymersomes but not in the poly(2‐methyloxazoline)‐poly(dimethylsiloxane)‐poly(2‐methyl oxazoline) (PMOX‐PDMS‐PMOX) polymersomes. The incorporation is confirmed by circular dichroism (CD), changes in purely synthetic mechanical strength (e.g., areal expansion modulus) as assessed by micropipette aspiration, and cryo‐TEM. In addition to the structural analyses, a transport measurement shows the incorporated dendritic helical pores allow facile transport of protons across the polymersome membranes after up to one month of storage. This integration of synthetic porous channels with polymersome substrates could provide a valuable tool for studying active transport processes in a composite membrane. These composites will ultimately expand the family of biologically inspired porous‐membrane mimics.

Biodegradable polymersomes are promising vehicles for a range of applications. Their stabilization would improve many properties, including the retention and controlled release of polymersome contents, yet this has not been previously accomplished. Here, we present the first example of stabilizing fully biodegradable polymersomes through acrylation of the hydrophobic terminal end of polymersome-forming poly(caprolactone-b-ethylene glycol). Exposure of the resulting polymersomes loaded with a hydrophobic photoinitiator to ultraviolet light polymerized the acrylates, without affecting polymersome morphology or cell cytotoxicity. These stabilized polymersomes were more resistant to surfactant disruption and degradation. As an example of stabilized polymersome utility, the unintended release of doxorubicin (DOX) due to leakage from polymersomes decreased with membrane stabilization and slower sustained release was observed. Finally, DOX-loaded polymersomes retained their cytotoxicity following stabilization.