Preparation And Antitumor Effect Of Nanoformulations Based On [Pt₂S₂] Cluster And Mono-/Di-nuclear Pt Compounds

Platinum complexes are the main chemotherapeutic agents in the treatment of a variety of malignant tumors.They can be used independently or in combination with other drugs or treatment modalities.Cisplatin,carboplatin,and oxaliplatin are universally recognized platinum-based chemotherapeutic agents used in the clinic.However,the toxic and side effects of these drugs（such as renal toxicity,liver injury,neurotoxicity,etc.）and drug resistance to tumor cells have become serious clinical hurdles.In addition,the low solubility of platinum complexes and weak selectivity between tumor cells and normal cells greatly reduce their therapeutic efficacy.To overcome these issues,there are intense research efforts on the development of new platinum compounds or drug delivery methods with low toxicity and high activity.In this regard,this thesis focused on the synthesis and preparation of a new class of nanoformulations based on[Pt₂S₂]cluster and mono-/di-nuclear Pt compounds for cancer treatment.In Chapter 1,we review the common platinum-based chemotherapeutic agents in clinical practice and also introduce the new anticancer platinum complexes with different ligands and modes of action,as well as the latest progress in the improvement of platinum chemotherapy by advancing the delivery using nanotechnology.In Chapter 2,by using（1R,2R）-（-）-1,2-diamino cyclohexane（DACH）and triphenylphosphine（PPh₃）as ligands,we synthesize four amphiphilic coordination polymers based on the[Pt₂S₂]cluster core,namely[Pt₂（S-m PEG2k）₂（DACH）₂]（1）,[Pt₂（S-m PEG2k）₂（PPh₃）₄]（3）,and[Pt₂（S-m PEG2k-FA）₂（DACH）₂]（2）,[Pt₂（S-m PEG2k-FA）₂（PPh₃）₄]（4）with folate-targeting functions.The key advantages of these polymers are that they can self-assemble in aqueous solutions to form spherical nanoparticles in the range of 40-80 nm,and all components are connected through Pt without the need for further assembly with other drugs,thus simplifying the preparation process of nanomaterials.In vitro experiments show that nanoformulation 1,rather than folate-targeted 2,exhibits anticancer activity against murine colon cancer cell CT26.In addition,with oxaliplatin as a reference,nanoformulation 1 demonstrates a high uptake of tumor cells and reduced toxicity to the liver.Qualitative immunofluorescence experiments show that nanoformulations 1 with DACH ligand can induce the immunogenic cell death（ICD）process in colon cancer cell lines CT26 and Caco-2,and nanoformulation 2 also had ICD induction ability to Caco-2,whereas 3 and 4 with PPh₃as the ligand had no ICD induction effect.We thus identify nanoformulation 1 as a potential anticancer drug that can effectively treat colon cancer and induce the corresponding ICD process.In Chapter 3,we synthesize mononuclear complexes cis-PtCl₂（PPh₃）₂（5）,[Pt（PPh₃）₂（L-Cys）]·H₂O（7,L-Cys=L-cysteinate）,trans-PtCl₂（PPh₂Ph NMe₂）₂（8,PPh₂Ph NMe₂=4-（dimethylamine）triphenylphosphine）,trans-Pt I₂（PPh₂Ph NMe₂）₂（9）and dinuclear Pt cluster Pt₂（μ-S）₂（PPh₃）₄（6）.Further,we encapsulate complexes 5-8 with amphiphilic co-polymer Pluronic（?）F-127 to obtain the corresponding nanoformulations.Masking of these discrete molecular entities within the hydrophobic core of Pluronic（?）F-127 significantly boosts their solubility and stability,ensuring efficient cellular uptake.In vitro cytotoxicity experiments show that the cytotoxicity of these platinum nanoformulations against murine melanoma cell B16F10 is equivalent to that of cisplatin,with IC₅₀values in the range of 0.87-11.23μM.These results highlight the potential therapeutic value of Pt complexes featuring stable Pt-P bonds in nanocomposite formulations with biocompatible amphiphilic polymers.The implementation of this work has expanded the types of platinum anticancer complexes and provided new avenues toward platinum chemotherapeutic drugs or drug delivery methods with low toxicity and high activity.In the future,we will further study the antitumor activity of these nanoparticles in vivo with an eye on chemotherapy-immunotherapy synergy for combating cancer.