Autophagy inhibition is emerging as a new paradigm for efficient
cancer therapy by overcoming multidrug resistance (MDR). Here, we developed an effective chemotherapeutic system for
oral squamous cell carcinoma (OSCC) based on polymeric nanomicelles for codelivery of the anticancer drug
doxorubicin (DOX) and the autophagy inhibitor
LY294002 (LY). The hydrophobic DOX was conjugated onto a hydrophilic and pH-responsive hyperbranched polyacylhydrazone (
HPAH), forming the DOX-conjugated
HPAH (
HPAH-DOX). Due to its amphiphilicity,
HPAH-DOX self-assembled into nanomicelles in an aqueous
solution and the autophagy inhibitor LY could be loaded into the
HPAH-DOX
micelles. The release of DOX and LY from the LY-loaded
HPAH-DOX
micelles was pH-dependent, whereas LY was released significantly faster than DOX at a mildly acidic condition. The in vitro evaluation demonstrated that the LY-loaded
HPAH-DOX
micelles could rapidly enter
cancer cells and then release LY and DOX in response to an intracellular acidic environment. Compared to the
HPAH-DOX
micelles and the physical mixture of
HPAH-DOX and LY, the LY-loaded
HPAH-DOX
micelles induced a higher proliferation inhibition of
tumor cells, illustrating a synergistic effect of LY and DOX. The preferentially released LY inhibited the autophagy of
tumor cells and made them more sensitive to the subsequent liberation of DOX. The polymeric codelivery system for programmable release of the
chemotherapy drug and the autophagy inhibitor provides a new platform for combination of traditional
chemotherapy and autophagy inhibition.