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第十一届全国化学生物学学术会议

作者： Tiantian Wu Jianbing Liu Baoquan Ding CAS Key Laboratory of Nanosystem and Hierarchical Fabrication CAS Center for Excellence in NanoscienceNational Center for Nanoscience and Technology

Cisplatin and related platinum analogs have been widely employed in the clinic as first-line chemo-drugs for the treatment of *** observed systemic toxicity and drug resistance induced by high doses of platinum drugs lead to the development of novel strategies to improve drug efficacy. DNA nanostructures,demonstrated excellent biocompatibility and high drug loading capability and were used to efficiently enrich therapeutic drugs in the tumor *** nanocarriers could be an ideal platform for targeted platinum drug ***,we report a facile and universal strategy to deliver platinum-based DNA intercalator(56 MESS) for targeted tumor therapy.A DNA tetrahedron is employed to load 56 MESS through intercalation with DNA *** targeted drug delivery,an anti-EGFR nanobody is conjugated with DNA and assembled on DNA *** nanosystem is used to realize higher drug accumulation in tumor region and block signal transduction of EGFR in the tumor cells with EGFR *** rationally designed DNA nanoplatform exhibits exceptional targetability and higher antitumor efficacy without observable systemic side-effects in *** report demonstrated the first example of combined cancer therapy based on platinum drug 56 MESS and EGFR blocking.

关键词： DNA nanotechnology Nanobody platinum drug drug delivery Cancer therapy

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Combining cisplatin and a STING agonist into one molecule for metalloimmunotherapy of cancer

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National Science Review 2024年第1期11卷 107-119页

作者： Shuren Zhang Dongfan Song Wenhao Yu Ji Li Xiaoyu Wang Yachao Li Zihan Zhao Qi Xue Jing Zhao Jie P.Li Zijian Guo State Key Laboratory of Coordination Chemistry School of Chemistry and Chemical EngineeringChemistry and Biomedicine Innovation Center (ChemBIC) Nanjing University Department of Urology Afflliated Drum Tower HospitalMedical SchoolNanjing University Nanchuang (Jiangsu)Institute of Chemistry and Health

Mounting evidence suggests that strategies combining DNA-damaging agents and stimulator of interferon genes(STING) agonists are promising cancer therapeutic regimens because they can amplify STING activation and remodel the immunosuppressive tumor microenvironment. However, a single molecular entity comprising both agents has not yet been developed. Herein, we designed two PtIV-MSA-2 conjugates(Ⅰand Ⅱ) containing the DNA-damaging chemotherapeutic drug cisplatin and the innate immuneactivating STING agonist MSA-2; these conjugates showed great potential as multispecific small-molecule drugs against pancreatic cancer. Mechanistic studies revealed that conjugate Ⅰ upregulated the expression of transcripts associated with innate immunity and metabolism in cancer cells, significantly differing from cisplatin and MSA-2. An analysis of the tumor microenvironment demonstrated that conjugate I could enhance the infiltration of natural killer(NK) cells into tumors and promote the activation of T cells, NK cells and dendritic cells in tumor tissues. These findings indicated that conjugate I, which was created by incorporating a Pt chemotherapeutic drug and STING agonist into one molecule, is a promising and potent anticancer drug candidate, opening new avenues for small-molecule-based cancer metalloimmunotherapy.

关键词： platinum drug STING agonist single-molecule multitarget metalloimmunology

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Antibody-platinum(IV)prodrugs conjugates for targeted treatment of cutaneous squamous cell carcinoma

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Journal of Pharmaceutical Analysis 2024年第3期14卷 389-400页

作者： Xiangye Yin Yingjie Zhuang Haiqin Song Yujian Xu Fan Zhang Jianxin Cui Lei Zhao Yingjie Yu Qixu Zhang Jun Ye Youbai Chen Yan Han Department of Plastic and Reconstructive Surgery The First Medical CenterChinese PLA General HospitalBeijing100853China Department of General Surgery Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghai200023China State Key Laboratory of Organic-Inorganic Composites Beijing Laboratory of Biomedical MaterialsBeijing University of Chemical TechnologyBeijing100029China Department of Plastic Surgery University of Texas MD Anderson Cancer CenterHoustonTX77030USA State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing100050China

Antibody-drug conjugates(ADCs)are a new type of targeting antibodies that conjugate with highly toxic anticancer drugs via chemical linkers to exert high specificity and efficient killing of tumor cells,thereby attracting considerable attention in precise oncology ***(Cet)is a typical antibody that offers the benefits of good targeting and safety for individuals with advanced and inoperable cutaneous squamous cell carcinoma(cSCC);however,its anti-tumor activity is limited to a single ***(CisPt)shows good curative effects;however,its adverse effects and non-tumor-targeting ability are major *** this study,we designed and developed a new ADC based on a new cytotoxic platinum(IV)prodrug(C8Pt(IV))and *** so-called antibody-platinum(IV)prodrugs conjugates,named Cet-C8Pt(IV),showed excellent tumor targeting in ***,it accurately delivered C8Pt(IV)into tumor cells to exert the combined anti-tumor effect of Cet and ***,metabolomic analysis showed that Cet-C8Pt(IV)promoted cellular apoptosis and increased DNA damage in cSCC cells by affecting the vitamin B6 metabolic pathway in tumor cells,thereby further enhancing the tumor-killing ability and providing a new strategy for clinical cancer treatment using antibody-platinum(IV)prodrugs conjugates.

关键词： Antibody drug conjugate Cutaneous squamous cell carcinoma DNA damage platinum drug Targeted therapy

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