There is a direct correlation between increase in the number of cancer stem cells CSCs and chemoresistance that impedes successful
chemotherapy. Synergistic
therapy by targeting both bulk
tumor cells and CSCs has shown promise in reversing chemoresistance and treating resistant
prostate cancer. Herein, we demonstrated the fabrication of a pH and
glutathione (GSH) sensitive nanocarrier for co-delivery of
docetaxel (DTX) and
rubone (RUB), a miR-34 activator for targeting CSCs, for the treatment of
taxane resistant (TXR)
prostate cancer. DTX loaded P-RUB (DTX/P-RUB)
micelles were prepared by encapsulating DTX into pH responsive diisopropylaminoethanol (DIPAE) and GSH responsive RUB
prodrug conjugated
polycarbonate based
micelles. The self-assembled DTX/P-RUB
micelles displayed good stability in vitro and could efficiently target to
tumors by enhanced permeability and retention (EPR) effect. After endocytosis by
tumor cells, the
micelles underwent expansion and disassembly due to the protonation of DIPAE and GSH induced cleavage of
disulfide bond in acidic endocytic vesicles, resulting in fast release of DTX and RUB. The released RUB then upregulated the intracellular miR-34a, which then affected the expression of
proteins involved in chemoresistance, thus sensitizing the
tumor cells towards DTX and further leading to significant inhibition of TXR
tumor progression. Thus, DTX/P-RUB
micelles have the potential to treat TXR
prostate cancer. By taking advantage of this dual responsive strategy, the successful delivery of many other hydrophobic drugs can be achieved for
cancer treatment.