Abstract
In this study, we designed combination cancer therapeutic hyaluronan nanoparticles (NIR-responsive ROS-generating pheophorbide A and ROS-cleavable thioketal-linked SN38; PheoA-SN38-HC NPs). And the combined therapeutic effects of PheoA-SN38-HC NPs were investigated against HEY-T30 human ovarian cancer (OC) model which highly co-expresses cancer stem cell (CSC) markers and exhibits strong chemo-resistance. Clinical Proteomic Tumor Analysis Consortium (CPTAC) data showed that the expression of CSC markers (CD44, ALDH1A1, and CD117) rather than folic acid receptor is highly associated with poor clinical outcomes in OC patients. Western assay, migration and colony forming assay proved chemo-resistant HEY-T30 cells overexpress CSC markers and much more invasive than other cancer cells. Synthesized NPs were ~250 nm and spherical by DLS and TEM analysis. FACS and microscopic analysis revealed the active targeting property of PheoA-SN38-HC NPs in CD44+ HEY-T30 cells. Moreover, synergistic effects of the combination therapy of photodynamic ROS generation and ROS-triggered SN38 release were clearly demonstrated with in vitro HEY-T30 cells and an in vivo xenograft mouse model. In particular, the paracrine cytotoxic effect of SN38 released by ROS-trigger suggested that combination design could compensate for the clinical limitation of photodynamic therapy.
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