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

Abstract

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.

pH/enzyme/light triple‐responsive vesicles from lysine‐based amphiphilic diblock copolymers

“…The newly generated ε‐NH 2 groups increase the hydrophilicity of the block copolymer and lead to swollen vesicles. On the other hand, the generated ε‐NH 2 groups can involve in several possible reactions, including single/double addition reactions with quinone methide intermediates, protonation, and intrachain and interchain amidation reactions 36–38 . Because the released ε‐NH 2 groups are within the hydrophobic vesicle membrane, the apparent pKa of these amines is effectively decreased, facilitating the occurrence of intra/inter‐chain amidation reactions 38,39 .…”

“…On the other hand, the generated ε-NH 2 groups can involve in several possible reactions, including single/double addition reactions with quinone methide intermediates, protonation, and intrachain and interchain amidation reactions. [36][37][38] Because the released ε-NH 2 groups are within the hydrophobic vesicle membrane, the apparent pKa of these amines is effectively decreased, facilitating the occurrence of intra/inter-chain amidation reactions. 38,39 The inter-chain amidations result in the crosslinked membrane and retain the vesicular nanostructure (Scheme 2).…”

Stimuli‐Responsive Nanoparticles for Controlled Drug Delivery in Synergistic Cancer Immunotherapy

“…[ 113 ] Therefore, enzyme‐mediated en‐srNPs for controlled drug delivery are cataloged by the effector biomolecule, such as proteases, lipases, hydrolases, oxidoreductases, and glycosidase. [ 114 ] For example, the core‐shell ICG/DOX@Gel‐CuS en‐srNP was consisted of CuS en‐srNP and gelatin (Gel) en‐srNP with loading DOX/ICG. [ 115 ] After accumulating ICG/DOX@Gel‐CuS en‐srNP, cancer overexpressing enzymes activated the disassembly of Gel and controlled delivery of ICG/DOX, which were visually imaged by the increasing fluorescent signal in the cancer field.…”

Enzyme-responsive strategy as a prospective cue to construct intelligent biomaterials for disease diagnosis and therapy

“…As the representative enzymes overexpressed in cancer cells, esterases have been considered as a biomarker for cancer diagnosis and treatment. 81 Esterases can catalyze the hydrolysis of ester bonds in the substrate. Thereby, Liu, Yu et al 82 prepared an enzyme-responsive supramolecular drug delivery system.…”