Nanoparticles (NPs) modified with targeting
ligands have often shown great potential in targeted
drug delivery for
tumor therapy. However, the clearance of NPs by the monocyte-phagocyte system (MPS) and the relatively low cellular uptake by
tumor cells have significantly limited the antitumor efficacy of a variety of nanomedicines. Tumor microenvironment-mediated multidrug resistance also reduces the antitumor efficacy of internalized nanomedicines. Herein, we developed an innovative nanomedicine for combined chemo-
photodynamic therapy of
melanoma through targeted
drug delivery and significantly improved the cellular uptake of the nanomedicine through the charge-reversal phenomenon. An amphiphilic
platinum (IV)-
polyethylenimine-
chlorin e6 (Pt(IV)-PEI-Ce6)
polymer was designed, prepared, and self-assembled into NPs (PPC) in an aqueous
solution, and these NPs were subsequently coated with
hyaluronic acid (HA) to afford PPC@HA. The surface-coated HA provided PPC with a negatively charged surface potential to reduce the clearance by the MPS during systemic circulation and enhanced the targeted delivery of PPC to CD44-overexpressing
melanoma cells. Upon accumulation in the
tumor site,
hyaluronidase overexpressed in the
tumor induced HA degradation to release the positively charged PPC, resulting in an increased internalization of PPC into
tumor cells. Bioactive Pt(II) was released in response to high
glutathione level in the
tumor cells for effective
tumor chemotherapy. Under 650 nm
laser irradiation, Ce6 produced
reactive oxygen species (ROS), thus driving
photodynamic therapy. Finally, PPC@HA exhibited combined photodynamic-chemotherapeutic antitumor efficacy against the
melanoma cells in mice. STATEMENT OF SIGNIFICANCE:
Tumors are one of the greatest threats to human health, and
chemotherapy has been one of the most common therapeutic modalities for treating
tumors; however, many challenges related to
chemotherapy remain, such as low delivery efficiency, side effects, and unsatisfactory therapeutic efficacy. Nanomedicines modified with targeting
ligands have often shown great potential in improving targeted
drug delivery for
tumor therapy; however, the clearance of nanomaterials by the monocyte-phagocyte system and the relatively low cellular uptake by
tumor cells have significantly limited the antitumor efficacy of a variety of nanomedicines. Herein, we developed a novel charge-reversal-based,
hyaluronic acid-coated, Pt(IV)
prodrug and
chlorin e6-based nanomedicine to improve systemic circulation and targeted accumulation of the nanomedicine in the
tumor tissue and to enhance its intracellular uptake. This nanomedicine may provide a potential new platform to improve the
drug content inside
tumor cells and to effectively inhibit
tumor growth through combined
chemotherapy and
photodynamic therapy.