Design of folic acid conjugated chitosan nano-cur–bioenhancers to attenuate the hormone-refractory metastatic prostate carcinoma by augmenting oral bioavailability

Abstract

The objective of this study is to develop a folic acid (FA) functionalized co-delivery system for oral delivery of curcumin (CUR) with bioenhancers (B) (“trikatu”) to attenuate hormone refractory prostate cancer. The nano-cur–bioenhancer exhibited significantly elevated cytotoxicity in a prostate cancer cell line (PC3) compared to CUR. Further, mechanistic studies in PC3 cells revealed that nano-cur–bioenhancers induce apoptosis by mitochondrial membrane disruption and a ROS mediated pathway. Collaborative efforts of bioenhancers, mucoadhesive chitosan (CH) and active uptake through FA governed the success of the nanoparticles (NPs) as evidenced through the cell uptake experiments and Hoechst assay for P-glycoprotein functioning. Pharmacokinetic results confirmed nearly 7.7 fold increases in C_max of the nano-cur–bioenhancer CUR–B–CH-NPs as compared to a CUR solution and the AUC increased nearly 6 fold in CUR–B–CH-NPs than CUR. Thus, escalating drug uptake in prostate cancer PC3 and Caco-2 cell monolayers along with enhanced bioavailability substantiated effective oral delivery of nano-cur–bioenhancers. Thus, nano-cur–bioenhancers have remarkable potential as a multifunctional oral delivery system for management of hormone refractory prostate cancer.