Integrating multi-modal therapies into one platform could show great promise in overcoming the drawbacks of conventional single-modal therapy and achieving improved therapeutic efficacy in cancer. In this study, we prepared pheophorbide a (Pheo a)/targeting ligand (epitope analog of oncoprotein E7, EAE7)-conjugated poly(γ-glutamic acid) (γ-PGA)/poly(lactide-co-glycolide)-block-poly(ethylene glycol) methyl ether (MPEG-PLGA)/hyaluronic acid (PPHE) polymeric nanoparticles via self-assembly and encapsulation method for the photodynamic therapy (PDT)/cold atmospheric plasma (CAP) combinatory treatment of human papillomavirus (HPV)-positive cervical cancer, thereby enhancing the therapeutic efficacy. The synthesized PPHE polymeric nanoparticles exhibited a quasi-spherical shape with an average diameter of 80.5 ± 17.6 nm in an aqueous solution. The results from the in vitro PDT efficacy assays demonstrated that PPHE has a superior PDT activity on CaSki cells due to the enhanced targeting ability. In addition, the PDT/CAP combinatory treatment more effectively inhibited the growth of cervical cancer cells by causing elevated intracellular reactive oxygen species generation and apoptotic cell death. Moreover, the three-dimensional cell culture model clearly confirmed the synergistic therapeutic efficacy of the PDT and the CAP combination therapy using PPHE on CaSki cells. Overall, these results indicate that the PDT/CAP combinatory treatment using PPHE is a highly effective new therapeutic modality for cervical cancer.

Photodynamic therapy (PDT) has been extensively explored as a promising alternative therapeutic approach for many malignant tumors. However, the PDT system generally involves unsatisfactory tumor specificity and nonspecific accumulation of photosensitizers around the target cancer cells, leading to phototoxic damage to adjacent healthy normal cells. In this study, we developed pheophorbide a (Pheo a)/human epidermal growth factor receptor 2 (HER2) targeting peptide (epitope form, HLTV, PEG2-LTVSPWY)-co-conjugated methoxy poly(ethylene glycol)-block-poly(L-lysine hydrochloride) (PEG-PLL)/hyaluronic acid (HA) (P3H2) polymeric micelles via a self-assembly method for HER2-targeted PDT treatment for breast cancer, thereby enhancing the PDT efficacy. The synthesized P3H2 polymeric micelles were spherical, with an average diameter of 125.7 ± 21.2 nm in an aqueous solution. The results of in vitro cytotoxicity assays demonstrated that the P3H2 polymeric micelles significantly improved PDT efficacy on the SK-BR-3 cells due to the enhanced targeting ability. In addition, PDT treatment using the P3H2 polymeric micelles effectively killed breast cancer cells by inducing higher intracellular reactive oxygen species generation and apoptotic cell death. In particular, the three-dimensional cell culture model proved the synergistic PDT efficacy using P3H2 polymeric micelles on the SK-BR-3 cells. Based on these results, the PDT treatment using P3H2 polymeric micelles can serve as a highly effective therapeutic modality for breast cancer.