Synthesis And Mechanism Study Of Thiosemicarbazone Cu,In And Pt Complexes For Overcoming Cisplatin Resistance

Cancer is one of the diseases with the highest mortality rate and is a serious threat to human life and health.Currently,chemotherapy is one of the most commonly used treatments,especially for patients with advanced tumor.Cisplatin is the most commonly used chemotherapeutic agent and is included within more than 50% of chemotherapy regimens.Nevertheless,the clinical application of cisplatin is limited by severe toxicities such as ototoxicity,nephrotoxicity and neurotoxicity,and drug resistance.Therefore,it is particularly urgent to develop novel metal-based drugs that can overcome cisplatin resistance and reduce its toxic side effects.On the one hand,thiosemicarbazone have good antitumor activity and are excellent metal chelators,and their metal complexes have excellent antitumor activity;on the other hand,unlike cisplatin,metal thiosemicarbazone complexes have more diverse mechanisms to inhibit tumor cell growth,which provides new ideas to overcome cisplatin resistance.However,there are still two major challenges in the development of metal drugs: 1)how to solve the delivery problem of metal complexes in vivo to avoid their structure being destroyed in blood circulation;2)how to improve the bioavailability of metal complexes,enhance the aggregation of drugs in tumor cells,and reduce their toxicity and side effects in vivo.In summary,in order to overcome cisplatin resistance,the following studies were carried out in this paper:1.Non-small cell lung cancer cells are prone to drug resistance and metastasis,which is an important reason for treatment failure.The development of a Cu(II)complex based on specific amino acid residues of human serum albumin(HSA)nanoparticles(NPs)acting on different cellular components in the tumor microenvironment(TME)to treat tumors is a promising therapeutic strategy.Thus,four Cu(II)complexes(C1-C4)were synthesized using o-vanillin thiosemicarbazone as ligand,and the Cu complex(C4)with optimal cytotoxicity was obtained by studying their structure-activity relationships.In addition,the HSA-C4 complex NPs delivery system(HSA-C4 NPs)was successfully constructed,and the binding mechanism of C4 and HSA was revealed by X-ray crystallography,two C4 molecules were bound to the IB and IIA subdomains of HSA,respectively.C4/HSA-C4 NPs effectively inhibited the growth and metastasis of cisplatin-resistant A549 cis R tumors in vivo,and HSA NPs enhanced the anticancer ability of C4.We further demonstrated the antitumor mechanism of C4/HSA-C4 NPs to overcome cisplatin resistance by multi-targeting tumor microenvironment components: killing cancer cells by acting on intracellular mt DNA and inducing apoptosis,resetting M2 macrophages to M1 phenotype,and inhibiting angiogenesis.2.In order to overcome the resistance of cancer cells to cisplatin and effectively inhibit tumor growth,a novel indium(In)complex based on liposome(Lip)was developed.Then,the In(III)complexes(C9)with sufficient cytotoxicity was obtained by optimizing five In(III)2-pyridinecarboxaldehyde thiosemicarbazone complexes(C5-C9).Subsequently,C9-loaded Lip(C9-Lip)delivery system was successfully constructed.Indeed,the results from in vitro and in vivo assays showed that C9/C9-Lip effectively suppressed the growth of cisplatin-resistant tumor cells MCF-7/DDP.Furthermore,Lip enhanced C9 accumulation in tumor cells and improved its antitumor activity.Although C9/C9-Lip acted weakly on DNA in cancer cells,they was able to attack two cellular components of the TME,namely,by inducing apoptosis and pro-death autophagy in tumor cells and by reprograming tumor-promoting M2 macrophages to the tumor-killing M1 type.3.Six Pt complexes(C10-C15)were synthesized using2-thiazolecarboxaldehyde thiosemicarbazone as ligand.Pt complexes showed strong cytotoxic activity against cisplatin-resistant lung cancer cells(A549cis R),with optimal activity of C15.C15 also effectively inhibited the growth of A549 cis R tumors xenografts.Further studies revealed that Pt complexes can target DNA,form DNA platination,and cause cell cycle arrest in S phase,thus hindering DNA synthesis.C15 induced apoptosis and lethal autophagy in A549 cis R cells.Furthermore,C15 reversed cisplatin-induced resistance by inhibiting P-gp expression and reducing GSH levels in A549 cis R cells,and the ERK pathway was also one of the C15-induced pathways to overcome cisplatin resistance.