Biotransporting Self‐Assembled Nanofactories Using Polymer Vesicles with Molecular Permeability for Enzyme Prodrug Cancer Therapy

Abstract

As "biotransporting nanofactories", in vivo therapeutic biocatalyst nanoreactors would enable encapsulated enzymes to transform inert prodrugs or neutralize toxic compounds at target disease sites. This would offer outstanding potential for next-generation therapeutic platforms, such as enzyme prodrug therapy. Designing such advanced materials has, however, proven challenging. Here, it is shown that self-assembled nanofactories formulate with polymeric vesicles with an intrinsically permeable membrane. The vesicles, CAPsomes, are composed of carbohydrate-b-poly(propylene glycol) and show molecular-weight-depended permeability. This property enables CAPsomes to act as biocatalyst nanoreactors, protecting encapsulated enzymes from degradation while acting on low-molecular-weight substrates. In tumor bearing mice, combined treatment with enzyme-loaded CAPsomes and doxorubicin prodrug inhibit tumor growth in these mice without any observable toxicity. The results demonstrate, for the first time, in vivo therapeutic efficacy of CAPsomes as nanofactories for enzyme prodrug cancer therapy.

Adaptive Polymersome Nanoreactors

“…From an application perspective, a next step forward, following these advances, is the utility of polymersome nanoreactors as actual artificial organelles in vitro and finally in vivo. [41] For example, polymersome nanoreactors can treat certain diseases by in cellulo converting toxic substances into nontoxic ones. In some cases, the in situ conversion of nontoxic prodrugs into therapeutic agents by polymersome nanoreactors shows great promise to address challenging diseases such as cancer.…”

Biotransporting Biocatalytic Reactors toward Therapeutic Nanofactories

“…More recently, we developed intrinsic permeable polymer vesicles based on carbohydrate‐ b ‐poly(propylene glycol) ( Figure ) . The glycopolymer self‐assembles in aqueous solution into a unilamellar vesicle (referred to as CAPsome) of average diameter 100–150 nm.…”

“…A) Chemical structure of amphiphilic maltooligosaccharide‐ b ‐poly(propylene glycol) (PPG) with schematic diagram of self‐assembly of polymers to form permeable polymer vesicles and B) schematic diagram of coassembly of maltopentaose‐containing PPG and TAT‐modified PPG, and hydrolysis of doxorubicin prodrug by β‐galactosidase‐loaded TAT–CAPsomes in living cells. Reproduced with permission . Copyright 2017, Wiley‐VCH.…”

“…For example, we recently reported an enzyme prodrug activation system for cancer therapy, which is based on β‐galactosidase‐loaded polymer vesicles with inherent permeable membranes, as described in Section . The polymer vesicles (CAPsomes) showed molecular weight–dependent permeability, enabling enzyme encapsulation and permeation of low‐molecular‐weight substrates.…”

Regulating vesicle bilayer permeability and selectivity via stimuli-triggered polymersome-to-PICsome transition

“…Compared to liposomes selfassembled from small molecule lipids, polymersomes of amphiphilic block copolymers (BCPs) possess much improved microstructural stability. They have been increasingly utilized to fabricate delivery of nanovehicles [12][13][14] , nanoreactors [15][16][17][18] , and artificial organelles 3,19,20 . However, effective permeation of active agents through/from aqueous lumens is prohibited by the hydrophobicity of thick bilayer membranes 1,11 .…”