Bioresorbable Vesicles Formed through Spontaneous Self-Assembly of Amphiphilic Poly(ethylene oxide)-block-polycaprolactone

Abstract

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...

Polymersomes: A new multi-functional tool for cancer diagnosis and therapy

“…The ability to generate selfassembled, fully-bioresorbable vesicles comprised of an amphiphilic diblock copolymer consisting of two previously FDA-approved building blocks, poly(ethylene oxide) (PEO) and poly(caprolactone) (PCL), has been demonstrated by Ghoroghchian and coworkers [10]. Unlike polymersomes formed from the blending of "bio-inert" and hydrolysable block copolymers [26], these fully-bioresorbable PEO-b-PCL vesicles undergo acid catalyzed hydrolysis of their ester linkages and degrade without leaving any potentially toxic byproducts [10,29]. We have demonstrated the release of doxorubicin from these systems with timeconstants of 18-24 h, depending on pH; in vivo testing of these polymersomes for delivery is underway.…”

“…Delivery of doxorubicin in liposomes has been shown to extend the circulation time and alter the pharmacodynamics of doxorubicin in such a way as to decrease its toxicity while still maintaining its anticancer activity [38]. Using active loading methods originally developed for liposomes, doxorubicin can be efficiently loaded into the aqueous center [10,26,39] of polymer vesicles.…”

“…Ghoroghchian et al have successfully loaded doxorubicin into the hydrophilic reservoir of PEO-b-PCL polymersomes [10] by using an ammonium sulfate gradient [40][41][42]. Using doxorubicin, as a model system, the mechanism by which PEO-b-PCL based polymersomes release a physiologically relevant encapsulant was assessed under various conditions (pH 7.4 and pH 5.5 at 37 °C) [10].…”

“…1, is the large hydrophobic core of the polymersome membrane, which follows from the membrane-forming amphiphilic polymers being larger than conventional phospholipids [9]. Further, block copolymer chemistries can be tuned through polymer synthesis to yield polymersomes with diverse functionality [10]. A vast majority of vesicles made of synthetic copolymers have dense polyethylene oxide (PEO) outer shells, which affords them "stealth" like character that may lead to increased circulation times and in vivo biocompatibility [5].…”

“…In contrast, polymersomes can simultaneously encapsulate hydrophilic components in their aqueous interior and hydrophobic molecules within their thick lamellar membranes [10]. In addition, biologically active ligands, such as antibodies, can be readily conjugated to the exterior brush surface to target the vesicles or to provide a therapeutic response [19][20][21][22].…”