Cu-Cy Nps@ZIF-8@HA-Mediated Photodynamic Therapy for Cutaneous Squamous Cell Carcinoma

Na Li,1,* Xiao Wan,1,2,* Xiaoyang Hou,3 Jingxi Zhang,3 Congcong Zhang,3 Yao Sun,3 Fengdi Wang,3 Shujing Kong,3 Chunsheng Yang,4 Guan Jiang3 1The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221006, People’s Republic of China; 2Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, People’s Republic of China; 3Department of Dermatology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221006, People’s Republic of China; 4Department of Dermatology, the Affiliated Huai’an Hospital of Xuzhou Medical University, The Second People’s Hospital of Huai’an, Huai’an, Jiangsu, 223002, People’s Republic of China*These authors contributed equally to this workCorrespondence: Guan Jiang, Email [email protected] Chunsheng Yang, Email [email protected]: The complex tumor microenvironment poses an important challenge for the effective treatment of tumors, so it is important to develop efficient multimodal nanomaterials for tumor therapy. This study introduces a novel nanomaterial, Cu-Cy Nps@ZIF-8@HA (CNZH), based on zeolitic imidazolate framework-8 (ZIF-8) backbone. CNZH offers the combined merits of facile synthesis, environmental benignity, and effective therapeutic performance against cutaneous squamous cell carcinoma(cSCC).Patients and Methods: The photosensitizer Cu-cy Nps (Cu-Cy Nanoparticles) was initially synthesized and subsequently encapsulated within a zeolitic imidazolate framework-8 framework to construct Cu-cy Nps@ZIF-8 (CNZ), which was further surface-modified with hyaluronic acid(HA) to yield the final nanocomposite CNZH. In vitro evaluations demonstrated excellent biocompatibility, as evidenced by hemolysis assays and CCK-8 cytotoxicity tests. Transmission electron microscopy (TEM) confirmed efficient cellular uptake by A-431 cells, while Western blot analysis validated its tumor-targeting specificity. Functional characterization revealed CNZH’s remarkable capacity for reactive oxygen species(ROS) generation, GSH depletion, and singlet oxygen (1O2) production. For in vivo assessment, an A-431 xenograft mouse model was established, with subsequent tumor tissue analyses including TUNEL apoptosis assay, ROS staining, and immunohistochemical examination, collectively demonstrating the nanocomposite’s significant therapeutic efficacy and precise tumor-targeting capability.Results: This study successfully designed and fabricated a novel ZIF-8-based nanomaterial, CNZH, which exhibits POD, CAT, and GSH-Px enzymatic activities along with the capability to generate 1O2. In vitro, the apoptosis rate of A-431 cells treated with LCNZH (CNZH+UV) was 77.1% (predominantly early apoptosis),the survival rate of A-431 cells treated with 200 μg/mL CNZH for 24h was 32%, which was significantly lower than that of the CNZ group (65%, P< 0.05). In vivo, the tumor volume of the LCNZH group was significantly smaller than that of the PBS and CNZ groups after 12 days of treatment. PBS control, no-light groups Both in vitro and in vivo experimental results demonstrated that CNZH can effectively target tumor cells, synergistically exert outstanding anti-cancer effects through combined CDT/PDT therapy, while maintaining excellent biosafety.Conclusion: CNZH is expected to be a highly efficient nanomaterial for the synergistic treatment of cutaneous squamous cell carcinoma, thereby opening up a new avenue for the application of nanomaterials in the treatment of this malignancy. Keywords: nanomaterials, synergistic therapy, chemodynamic therapy, CDT, photodynamic therapy, PDT, cutaneous squamous cell carcinoma, cSCC