Synthesis and evaluation of folate-mediated targeting and poly (beta-amino ester)-mediated pH-responsive delivery system of riccardin D based on the O-carboxymethylated chitosan micelles

This study aimed to combine the active targeting function of folate (FA) receptor-mediated endocytosis with the pH-responsive drug delivery of poly (ethylene glycol)-grafted-poly ( amino ester) copolymers (PEG-PAE) in cancer targeting therapy. Herein, O-carboxymethylated chitosan (OCMC) was grafted with hydrophobic deoxycholic acid (DOCA). Further, PEG-PAE and FA-conjugated DOCA modified OCMC were synthesized to develop the potential cancer-targeted carrier (PEG-PAE-DOMC-FA), for which the structure was investigated by H-1 NMR and FTIR. Then riccardin D (RD) was successfully loaded for tumor-targeted drug delivery. The particle size, zeta potential, encapsulating efficiencies, and loading content profiles of PEG-PAE-DOMC-FA/RD showed a strong dependence on the environmental pH values. The cumulative release of PEG-PAE-DOMC-FA/RD at pH 5.0 (90.63 %) was higher than pH 7.4 (51.12 %), which also indicated the pH sensitivity. Moreover, a lower IC50 and higher coumarin-6 uptake were found because of the folate-receptor-mediated endocytosis. In pharmacokinetic study, PEG-PAE-DOMC-FA/RD significantly improved the mean retention time (MRT) and AUC((0-infinity)) from 7.89 h and 36.1 mg/L center dot h of control group to 10.03 h and 123.8 mg/L center dot h. In the xenograft mice model, stronger antitumor efficacy and lower toxicity were confirmed. In conclusion, the multi-functional micelles could be considered as a promising vehicle for delivering hydrophobic drugs to tumors.

Automated summary

This study aimed to combine active targeting and pH-responsive drug delivery in cancer therapy using a potential cancer-targeted carrier. The carrier, PEG-PAE-DOMC-FA, showed pH sensitivity and folate-receptor-mediated endocytosis. It successfully loaded and delivered the hydrophobic drug, riccardin D, to tumors, exhibiting improved pharmacokinetics, antitumor efficacy, and reduced toxicity.