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A promising class of PDT photosensitizers for triple negative breast cancer：the luminescent platinum (II) complex with BODIPY derivative Jia-Ming Lei†1, Zi-Han Wu†2, Shi-Jiao Cheng1, Fei-Fei Lu1, Mei-Chun Hu1* and Li Lin1* 1 Key Laboratory of Environmental Related Diseases and One Health, School of Basic Medical Sciences, Xianning Medical College, Hubei University of Science and Technology, Xianning, China 2 Xianning Traditional Chinese Medicine Hospital, Xianning, China *Correspondence: Mei-Chun Hu (Email: humeichun.530@163.com) Li Lin (Email: alison1012li@163.com) † These authors contributed equally to this work and share first authorship Breast cancer is the most common lethal malignant tumor in women and the second leading cause of cancer-related mortality worldwide [1], of which triple-negative breast cancer (TNBC) accounts for about 20% of breast cancer, which is prone to recurrence and metastasis, and has a high degree of malignancy and death rate [2]. Due to lack of HR and HER2 expression [3,4], endocrine therapy and anti-HER2 therapy for TNBC are usually proved ineffective [5]. Clinical studies have shown that photodynamic therapy (PDT) can prolong the survival time of cancer patients and improve the quality of life of patients. It has become one of the latest candidates for tumor treatment with broad prospects [6]. In our work recently reported in the paper entitled “Identification of a luminescent platinum (II) complex with BODIPY derivative as novel photodynamic therapy agent for triple negative breast cancer cells” in Journal of Inorganic Biochemistry, we designed a luminescent monofunctional platinum (II) complex with a BODIPY derivative, namely, I2BC-Pt, as a novel high PDT anti-triple-negative breast cancer (TNBC) agent. Under the irradiation of green light (520 nm), I2BC-Pt exhibited superior PDT effect against TNBC and impeded DNA repair by attenuating RAD51, FoxM1 and BRCA1/2 and induced p53-mediated apoptosis in TNBC cells. I2BC-Pt has good cellular selectivity and can be used as a promising photodynamic therapeutic agent, particularly suitable for triple-negative breast cancer. We examined the PDT anticancer activities of two novel monofunctional Pt (II) complexes BC-Pt, I2BC-Pt, and cisplatin toward six types of cancer lines, such as human TNBC cells (MDA-MB-468 and MDA-MB-231), human neuroblastoma cells (SH-SY5Y), human lung adenocarcinoma cells (HCC78), human pancreatic cancer cells (SW1990), human colorectal cancer cells (HCT116) and two types of normal cells including human immortal liver cells (THLE-3), human embryo kidney cells (SV40). In order to figure out the half of the maximum inhibitory concentrations (IC50) of each coordinator, we exposed the BC-Pt, I2BC-Pt and cisplatin for 48 h and derived the IC50 values. The green light (520 nm, 5 mW) had IC50 values of I2BC-Pt in the range of 0.11~0.71μM, much lower than BC-Pt and cisplatin which demonstrated good photodynamic efficacy. More interestingly, the human TNBC cells (MDA-MB-231) were sensitive to I2BC-Pt among all selected cancer cells, and showed satisfactory cytotoxicity with dark IC50 values of 6.1±0.5 μM and light IC50 values of 0.11±0.02 μM, which is the lowest. This indicates that I2BC-Pt exhibits optimal inhibitory efficacy against TNBC. Tumor localization of photosensitizers is an important factor in determining the efficacy of PDT. We performed confocal microscopic experiments using MDA-MB-231 cells as a model. The colocalization of Pt (II) complexes (BC-Pt, I2BC-Pt and cisplatin) with DAPI and MitoTracker Red proved that the Pearson's correlation coefficient between the green fluorescence of I2BC-Pt and the red fluorescence of MitoTracker was about 0.89 after 30 min of dark incubation with I2BC-Pt, implying that was I2BC-Pt mainly accumulated in the mitochondrion. and the cellular imaging data demonstrated that I2BC-Pt is a PDT agent that can be specifically localized within the mitochondria of cancer cells, with significant selectivity and safety. PDT can produce lethal cytotoxic effects, including induction of apoptosis, autophagy and cell necrosis. Since I2BC-Pt is mainly localized in mitochondria, we speculate that apoptosis may be the main mode of cell death. p53 protein dysfunction is closely related to mitochondria dysfunction and cell apoptosis. By protein immunoblotting hybridization experiments, the results showed that I2BC-Pt caused apoptosis and activated the p53-Bax-Bcl-2-caspase9 protein-caspase3-PARP1 pathway. To examine whether DNA repair is involved in the process of DNA damage, we investigated the level fluctuations of RAD51 and FoxM1 which are both crucial factors associated with DNA repair, in MDA-MB-231 cells treated by cisplatin, BC-Pt and I2BC-Pt . Under light irradiation, RAD51 and FoxM1 have synchronous reduction by I2BC-Pt compared to the control as well as cisplatin-treated groups. The results indicating that I2BC-Pt not only induced DNA damage severely but also hindered the repair of DNA. BRCA1 and BRCA2 are two genes that inhibit the occurrence of breast cancer containing TNBC, and play an important role in DNA damage repair. We further examined the expression of BRCA1 and BRCA2. Compared to control group, we found that the levels of these two genes decreased when MDA-MB-231 cells treated with I2BC-Pt under the light irradiation, demonstrating the genomic heterogeneity of MDA-MB-231 cells was significantly reduced with the expression of BRCA1 and BRCA2 protein expression levels declined. Thus, I2BC - Pt exhibit the highest phototoxic among the three Pt (II) complexes, as mentioned above. In conclusion, we have developed a series of monofunctional luminescent platinum compounds with BODIPY derivatives, which have a strong photodynamic responsiveness, high targeting as well as low toxic side effects, which are very promising new generation of photosensitizers, especially for triple-negative breast cancer, and it is worthy of further research and investigation. Funding This work was supported by the National Natural Science Foundation of China (No. 31900853)，the Science and Technology Research Project of Hubei Education Department (B2019161) Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. References [1] R.L. Siegel, K.D. Miller, H.E. Fuchs, A. Jemal, Cancer statistics, 2022, CA Cancer J. Clin. 72 (2022) 7–33. [2] LI Y, ZHANG H J, MERKHER Y, et al. Recent advances in therapeutic strategies for triple-negative breast cancer[J].J Hematol Oncol, 2022, 15(1): 1-30. [3] S.C. Houghton, S.E. Hankinson, Cancer progress and priorities: breast cancer, Cancer Epidemiol. Biomark. Prev. 30 (2021) 822–844. [4] L. Angus, M. Smid, S.M. Wilting, J. van Riet, A. Van Hoeck, L. Nguyen, S. NikZainal, T.G. Steenbruggen, V.C.G. Tjan-Heijnen, M. Labots, J. van Riel, H. J. Bloemendal, N. Steeghs, M.P. Lolkema, E.E. Voest, H.J.G. van de Werken, A. Jager, E. Cuppen, S. Sleijfer, J.W.M. Martens, The genomic landscape of metastatic breast cancer highlights changes in mutation and signature frequencies, Nat. Genet. 51 (2019) 1450–1458. [5] R.N. Pedersen, B.O. Esen, L. Mellemkjaer, P. Christiansen, B. Ejlertsen, T.L. Lash, M. Norgaard, D. Cronin-Fenton, The incidence of breast cancer recurrence 10-32 years after primary diagnosis, J. Natl. Cancer Inst. 114 (2022) 391–399. [6] BIKFALVI A, COSTA C A, AVRIL T, et al. Challenges in glioblastoma research: focus on the tumor microenvironment[J]. Trends Cancer,2023,9 (1) :9

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