Cystine proportion regulates fate of polypeptide nanogel as nanocarrier for chemotherapeutics

The physicochemical characteristics of nanoparticles are closely related to their drug delivery performances in vitro and in vivo . A well-designed nanocarrier can prolong the drug half-life in the blood circulation, upregulate the drug accumulation at the target site, and enhance the treatment efficacy. To elucidate the impact of physicochemical properties on the fate of nanogel as a nanocarrier of chemotherapeutics, three methoxy poly(ethylene glycol)-poly( L -phenylalanine- co-L -cystine) (mPEG-P(LP- co -LC)) nanogels with different L -cystine proportions were developed, namely mPEG-P(LP 10 - co -LC 5 ) (NG 10-5 ), mPEG-P(LP 10 - co -LC 10 ) (NG 10-10 ), and mPEG-P(LP 10 - co -LC 15 ) (NG 10–15 ). The three nanogels shared similar surface charge and reduction-responsive behavior, but they had distinct diameters and different drug release profiles. Among them, NG 10-5 , which has the smallest diameter, was preferentially internalized by tumor cells in vitro and showed rapid migration to the tumor site in vivo . Using doxorubicin (DOX) as a model chemotherapeutic agent, NG 10-5 /DOX had the most prolonged blood circulation period and highest tumor accumulation after intravenous administration. NG 10-5 /DOX also had the most potent antitumor effect of all three drug-loaded nanogels. Accordingly, adjusting physicochemical characteristics by changing the amino acid composition might improve the therapeutic efficacies of nanogels and enhance their potential for clinical application.