Hierarchical assembly of dual-responsive biomineralized polydopamine-calcium phosphate nanocomposites for enhancing chemo-photothermal therapy by autophagy inhibition.

The induction of autophagy in cancer cells would occur in response to several therapy strategies, including chemotherapy and photothermal therapy (PTT). Hence, combined autophagy inhibition has been regarded as a prevailing strategy to enhance treatment sensitivity in cancers. Herein, dual pH/thermal responsive biomineralized nanocomposites (PCNPs) were rationally designed and prepared based on the hierarchical assembly of calcium phosphate (CaP) and polydopamine (PDA). The first step in the self-assembly process involves the incorporation of hydrophobic chemotherapeutic docetaxel (DTX) into the CaP nanoparticles. Next, PDA was utilized as the coating to hierarchically self-assemble onto the surface of CaP through a simple self-polymerization of dopamine. Third, the autophagy inhibitor chloroquine (CQ) was absorbed onto the surface of PDA via non-covalent interactions, forming PCNPs/DC. CQ was the only FDA approved autophagy inhibitor in clinical trials that could inhibit autophagosome fusion and degradation. The resulting PCNPs/DC could exhibit dual pH/thermal responsive properties due to the acid-sensitive CaP core and the photothermal effect of the PDA coating. Effective inhibition of autophagy in cancer cells could be realized by blocking the lysosome and weakening the degradation of autolysosomes by PCNPs/DC. Interestingly, complementary autophagy inhibition could therefore sensitize the effects of chemo-photothermal therapy both in vitro and in vivo with negligible toxicity. Therefore, these hierarchically assembled biomineralized nanocomposites would be used as a prevailing strategy to sensitize chemo-photothermal therapy by complementary autophagy inhibition.