Overcoming drug resistance with functional mesoporous titanium dioxide nanoparticles combining targeting, drug delivery and photodynamic therapy.

The resistance of tumor cells is a major cause of chemotherapy failure in cancer patients. Photodynamic therapy (PDT) as a noninvasive treatment strategy with high specificity is a promising method for the treatment of cancer. In this study, a CD44 and N-cadherin dual targeting drug delivery system in combination with mesoporous titanium dioxide nanoparticle (MTN)-based PDT has been successfully constructed for overcoming drug resistance. Hyaluronic acid (HA) and ADH-1 (a cyclic pentapeptide) were grafted onto the surface of MTN to construct ADH-1-HA-MTN, and doxorubicin (DOX) was selected as a model drug. HA can both trap DOX in the wells of MTN and target CD44-overexpressing tumor cells. ADH-1 blocks the EMT process of tumor cells by selectively inhibiting the function of N-cadherin. Besides, a large number of reactive oxygen species (ROS) were generated by MTN under X-ray irradiation, which could provide a cancer cell killing effect. Cytotoxicity tests showed that ADH-1-HA-MTN/DOX was more toxic to tumor cells than its non-ADH-1 modified counterparts. Western blotting analysis showed that ADH-1-HA-MTN/DOX overcame the drug resistance of tumor cells by preventing the process of epithelial-mesenchymal transition. Taken together, ADH-1-HA-MTN may be a promising targeted drug delivery system to overcome the drug resistance of tumors.