A polyampholyte core-shell microgel as an environmentally sensitive drug carrier

Abstract

In this study, we investigate a polyampholyte degradable core-shell (CS) microgel, with an anionic pH-sensitive core and a cationic pH- and temperature-sensitive shell, as a model system for drug delivery. The core was based on crosslinked poly(acrylic acid) and was synthesized through distillation precipitation polymerization. Then, the shell, based on cross-linked poly(poly(ethylene glycol) methyl ether methacrylate - N-(3-aminopropyl)methacrylamide), were built over the core via the seed polymerization. N,N′-bis(acryloyl)cystamine was used as the linker for cross-linking both core and shell to give the core-shell particles the ability to degrade in the presence of reducing agent. The swelling characteristics of the core-shell microgels were studied using dynamic light scattering (DLS). The core-shell particles exhibited sensitivity to pH due to the presence of carboxylic and amine groups in the core and shell, respectively. The degradation of the core-shell particles was examined using electron microscopy and DLS. In the presence of glutathione, which acts as a reducing agent for the -S-S- bridges, commonly found in cancer cells, the particles underwent complete degradation. Our findings also demonstrate that the presence of the positively charged shell still enables efficient uptake of a drug in the form of a cation (doxorubicin DOX) into the anionic core and the drug can be released through the cationic shell. The release of DOX from the carrier was studied under different pH conditions to mimic the environment found in cancer cells. The results showed that at pH 7.4, the carrier exhibited the lowest release of DOX. However, under conditions mimicking the acidic and reducing environment typically for tumor microenvironment (pH 5.0 and cGSH = 40 mM), the CS particles demonstrated the highest cumulative and sustained release of DOX. The results showed that the DOX-loaded particles exhibited increased cytotoxicity against MCF-7 cells, indicating enhanced anti-cancer activity. At the same time, these particles demonstrated reduced toxicity towards healthy MCF-10A cells, which suggests improved selectivity and reduced side effects. It is worth noting that the gel nanoparticles alone did not inhibit cell growth. Overall, these findings suggest that the DOX-loaded core-shell particles hold promise as a targeted drug delivery system, capable of preferentially releasing the drug in the acidic and reducing tumor microenvironment while minimizing toxicity towards healthy cells.