Esterase-Responsive Polypeptide Vesicles as Fast-Response and Sustained-Release Nanocompartments for Fibroblast-Exempt Drug Delivery

Enzyme-responsive polypeptide vesicles have attracted considerable attention for precision theranostics because of their biocompatibility, biodegradability, and unique secondary conformation transition triggered by the catalytic actions of enzymes. These promising potentials of polypeptide vesicles...

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Bibliographic Details
Published in:Biomacromolecules 2020-12, Vol.21 (12), p.5093-5103
Main Authors: Duan, Weihua, Ji, Sifan, Guan, Yu, Mu, Xueluer, Fang, Sha, Lu, Yingxi, Zhou, Xianfeng, Sun, Jing, Li, Zhibo
Format: Article
Language:English
Subjects:
Animals
Cell Line
Delayed-Action Preparations
Drug Carriers
Drug Delivery Systems
Esterases
Fibroblasts
Humans
Mice
Peptides
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Summary:Enzyme-responsive polypeptide vesicles have attracted considerable attention for precision theranostics because of their biocompatibility, biodegradability, and unique secondary conformation transition triggered by the catalytic actions of enzymes. These promising potentials of polypeptide vesicles could be limited in a drug delivery system by the very slow enzyme diffusion rate into vesicles that could reduce the efficacy of the drug. On the other hand, stimuli-responsive polymeric vesicles that respond to stimuli can undergo microstructure destruction for the burst release of drugs, which would penetrate through the membrane of dead cells and the tumor extracellular matrix, inducing acute toxicity to neighboring cells. Here, we designed amphiphilic PEG–polypeptide copolymers containing esterase-labile carbamate-caged primary amines. It was found that the diblock can self-assemble into vesicular structures. Esterase-triggered self-immolative decaging reactions could quickly release the primary amine moiety of monomers that can undergo an amidation reaction for transition of the bilayer of vesicles from hydrophobic to partially hydrophilic. This esterase-responsive process retains the nanostructure of vesicles but permeabilizes the vesicle membrane, which can afford the sustained release of encapsulating drugs. These esterase-responsive polypeptide vesicles mediate selective cytotoxicity in cancer cells with high esterase expression over normal fibroblasts with low esterase, enabling the potent anticancer chemotherapy with minimized side effects.
ISSN:1525-7797
1526-4602
DOI:10.1021/acs.biomac.0c01251