Folate-modified carboxymethyl chitosan-based drug delivery system for breast cancer specific combination therapy via regulating mitochondrial calcium concentration

Abstract

Although various drug delivery systems that regulated Ca2+ concentration has been developed for tumor therapy, their application still presented significant challenges due to the complex preparation and introduction of a large number of inorganic molecules that might cause serious toxic effects. To solve these problems, a folate-functionalized carboxymethyl chitosan (CMCS)/calcium phosphate hybrid nanoparticle (CF/CaP) with Ca2+ production was designed to treat breast cancer combined with the Ca2+ inhibitory effect of encapsulated curcumin (Cur). It was demonstrated that the optimal CF/CaP nanoparticles loaded with Cur (C@CF/CaP) were spherical nanoparticles, which exhibited a smaller size at about 179 nm than non-targeted nanoparticles with size at about 234 nm. C@CF/CaP had good biocompatibility, high stability and acid responsive drug release. Compared with the neutral environment, the cumulative release of Cur was >70 % after culture for 36 h at pH 5.0. Compared with non-targeted nanoparticles, C@CF/CaP could specifically target tumor tissues and then enter tumor cells through folate receptor-mediated endocytosis. C@CF/CaP could cause mitochondrial Ca2+ overload, trigger the mitochondrial apoptotic pathway, destroy the mitochondrial structure and finally have good anti-tumor efficiency. The results proved that Ca2+ nanomodulators based on CMCS might provide a potential organelle targeting strategy for cancer therapy.