HPPH

Photodynamic therapy (PDT) has attained extensive attention as a noninvasive tumor treatment modality. However, the hypoxia in solid tumors, skin phototoxicity of "always on" photosensitizers (PSs), and abundant supply of glutathione (GSH) in cancer cells severely hampered the clinical applications of PDT. Herein, a self-oxygenation nanoplatform (denoted as CZCH) with GSH depletion ability was encapsulated into the hyaluronic acid microneedle patch (MN-CZCH) to simultaneously improve the biosafety and therapeutic efficacy of PDT. The Cu²⁺-doped porous zeolitic imidazolate framework incorporated with catalase (CAT) is capable of efficiently loading PS 2-(1-hexyloxyethyl)-2-divinylpyropheophorbic-a (HPPH). The CZCH intermingled MN patch (MN-CZCH) could effectively penetrate the stratum corneum, topically transport HPPH to the target tumor site, achieve a long tumor retention time, and enhance the efficacy of PDT via the simultaneously synergistic effect of CAT-catalyzed self-supplying O₂ and Cu²⁺-mediated GSH depletion. Using traceable fluorescence (FL) imaging of the released HPPH from CZCH, the FL imaging-guided repeatable PDT can be achieved for enhanced antitumor efficacy. As a result, the MN-CZCH patch exhibited excellent therapeutic efficacy against melanoma with minimal toxicity, which has promising potential for cancer theranostics.

Pheophorbide-based photosensitizers have demonstrated tumor cell-specific retention. The lead compound 3-[1'-hexyloxyethyl]-2-devinylpyropheophorbide-a (HPPH) in a clinical trial for photodynamic therapy of head and neck cancer lesions indicated a complete response in 80% of patients. The question arises whether the partial response in 20% of patients is due to inefficient retention of photosensitizers by tumor cells and, if so, can the photosensitizer preference of individual cancer cases be identified prior to photodynamic therapy. This study determined the specificity of head and neck cancer cells and tumor tissues for the uptake and retention of diffusible pheophorbides differing in peripheral groups on the macrocycle that contribute to cellular binding. The relationship between photosensitizer level and light-mediated photoreaction was characterized to identify markers for predicting the effectiveness of photodynamic therapy in situ. The experimental models were stromal and epithelial cells isolated from head and neck tumor samples and integrated into monotypic tissue cultures, reconstituted three-dimensional co-cultures, and xenografts. Tumor cell-specific photosensitizer retention patterns were identified, and a procedure was developed to allow the diagnostic evaluation of HPPH binding by tumor cells in individual cancer cases. The findings of this study may assist in designing conditions for photosensitizer application and photodynamic therapy of head and neck cancer lesions optimized for each patient's case.