Protein Nanogels with Temperature-Induced Reversible Structures and Redox Responsiveness

Abstract

There are many natural examples of smart structures that are able to change conformations and functionalities responding to the external stimuli. The responsiveness is directly related to their unique structures. In the design of new materials, it is crucial to endow these materials with the capabilities to change structures and functionalities under the external stimuli. In this research, virus-mimicking protein nanogels with temperature-induced reversible structures and redox responsiveness are synthesized by cross-linking a thermally responsive polymer poly(di(ethylene glycol) methyl ether methacrylate-co-2-(2-pyridyldisulfide) ethyl methacrylate) with reduced bovine serum albumin (BSA) molecules through thiol−disulfide exchange reaction. The lower critical solution temperature (LCST) and sizes of the nanogels can be controlled by controlling the reaction conditions. The nanogels are able to change their structures responding to the temperature change. Below the LCST, BSA molecules are embedded inside the nanogels and protected by the polymer chains. Above the LCST, polymer chains collapse forming the cores, and BSA moves to the shells to stabilize the nanogels. The disulfide-cross-linked nanogels are dissociated in the presence of glutathione. In vitro cytotoxicity assays and cell uptake assays demonstrate that the nanogels show low toxicity toward 3T3, 293T, and MCF-7 cells and can be internalized into the MCF-7 cells. The nanogels will find applications in protein delivery.

A Comprehensive Outlook of Synthetic Strategies and Applications of Redox‐Responsive Nanogels in Drug Delivery

“…A significant temperature difference exists between normal and tumor tissue that has been utilized as an additional stimulus for triggered drug release from redox‐responsive nanogels . Temperature‐ and redox‐responsive nanogels generally involve a redox‐responsive cross‐linker and temperature‐responsive polymer matrix.…”

“…A significant temperature difference exists between normal and tumor tissue that has been utilized as an additional stimulus for triggered drug release from redox-responsive nanogels. [64,65,204,205] Temperature-and redox-responsive nanogels generally involve a redox-responsive cross-linker and temperature-responsive polymer matrix. Some of the examples of temperature-responsive polymers are poly(N-isopropylacrylamide) (PNIPAAm), [206][207][208] poly (N,N′-diethyl acrylamide), [209,210] poly(N-(l)-(1-hydroxymethyl)propyl methacrylamide), [211][212][213] and poly(oligo(ethylene oxide)monomethyl ether methacrylate) (POEOMA).…”

Fabrication of Polymer–Protein Hybrids

“…By integrating multiple responsive features into one system, structural diversity and better control over the desired functionalities can be realized. We developed a type of smart protein–polymer biohybird nanogels with the capabilities to change structures and functionalities under the external stimuli . Virus‐like protein nanogels with temperature‐induced reversible structures and redox responsiveness were synthesized by cross‐linking a thermally responsive polymer with reduced BSA molecules through thiol–disulfide exchange reactions ( Figure a).…”

“…TEM images of nanogel prepared b) below and c) above the LCST. Reproduced with permission . Copyright 2016, American Chemical Society.…”

“…The hydrogels are able to respond reversibly to an environment stimulus, which causes a distinct change in properties. Various environment stimuli, including temperature, [201][202][203] pH, [204,205] enzyme, [206,207] redox potential, [208][209][210][211][212] and external additives [213,218] have been used to trigger the responses of the hydrogels.…”