Developing Anticancer Metal (Au,Pt)thiosemicarbazone Compounds Based On Endogenous Protein

Currently,chemotherapy is still the main method to treat cancer,but it is difficult to eradicate all cancer cells by use the single target chemotherapy drug because the cancer is a complex and changeable disease.Because of their unique redox properties and various coordination modes,metal complexes have become abroad-spectrum anticancer drug,which not only has the advantages of exact curative effect,but also has a variety of anti-tumor mechanisms.However,the innovative development of metal anticancer drugs still face the following great challenges:1)how to protect metal complex in blood circulation;2)how to improve the bioavailability of metal complexin vivo and effectively accumulate in tumor tissues;3)How to improve the drug properties of metal complex,especially the therapeutic effect,targeting ability and decreasing its side effects in vivo.Natural endogenous proteins(such as human serum albumin and ferritin)are inherent proteins in human body,which are non-toxic,non immunogenic and highly biocompatible.SPARC protein and Transferrin receptor 1(Tf R1)are highly expressed on the surface of tumor cells,which can specifically bind to albumin or ferritin,respectively.These two proteins can be used as transporters to target tumor cells for drug delivery,which is expected to solve the problems of high toxicity,low bioavailability and poor targeting of metal complexes.To sum up,the following aspects were studied:1)the apoferritin(AFt)-Au complex nano platform was constructed,and AFt-Au complex NPs combined the advantages of thedual mode of action(dual-MOA)Au complex that kills glioma cells by inducing lethal autophagy and apoptosis with the ability of AFt to penetrate the BBB;2)The human serum albumin(HSA)-Au complex nano platform was constructed,and its anticancer effect,mechanism of inducing immune response and apoptosis in vivo/in vitro were studied and discussed;3)The drug delivery system of HSA-platinum(Pt)complex was constructed,and its anti-tumor angiogenesis and tumor effects in vitro and in vivo were evaluated.The specific research results are divided into the following parts:1.A series of glioma sensitive thiosemicarbazone gold complexes were designed and synthesized.Their structures were characterized by ~1H NMR,HRMS and single crystal diffraction,and analyzed theirstructure-activity relationships,obtaining an Au agent(C6)with remarkable cytotoxicity inglioma.In vivo experiments conducted in Luc-U87MG model mice showed that AFt-C6 NPs can inhibit the rate of tumor growth by 69.2%,which is 3.0times greater than the tumor inhibitory rate of free C6(IRT=22.8%).Moreover,we confirmedthat C6 kills gliomacells by inducing lethal autophagy and apoptosis.Importantly,our results revealed that the successfully constructed AFt-C6 NPs can effectively cross the BBB,inhibit glioma growth,and selectively accumulate in tumors.2.To effectively targeting treatgastric cancer,we innovatively proposed to develop a metal agent to integrate immunotherapyand chemotherapy by dual-targetingto cellular components in the tumor microenvironment(TME)based on the specific residue of human serum albumin(HSA)nanoparticles(NPs).We synthesized a series of Au(III)?-N-heterocyclic thiosemicarbazones compounds and obtained an Au agent(C11)with remarkable cytotoxicity to gastric cancer cells;moreover,we successfully constructed a novel HSA-C11complex NPs delivery system.Importantly,in vivoresults showed that C11/HSA-C11NPs effectively inhibited gastric tumor growth,as the inhibition rate of the HSA-C11 NPs(75.3%)was1.5-fold higher than that of C11 alone(51.1%),and the HSA-C11NPs enhanced therapeutic efficiency,bioavailability,and targeting ability compared with C11 alone.Furthermore,in vitro/vivo results revealed that C11/HSA-C11NPs could integrate chemotherapy and immunotherapy by polarizing the tumor-associated macrophages and inducing apoptosis of gastric cancer cells.3.To develop the next generation novel anticancer platinum(Pt)agent for overcoming the deficiencies of Pt drugs and synergistically treating cancer in all round,we proposed to rationally design a Pt agent based on tumor micro-environment,not DNA,and then constructed a human serum albumin(HSA)-Pt agent complex delivery system to improve its pharmaceutical properties.Herein,we designed and synthesized a Pt agent(C13)with remarkable cytotoxicity based on the structure-activity relationships of?-N-heterocyclic thiosemicarbazones in vitro.In vivo results showed that C13 inhibited tumor growth by inhibiting tumor angiogenesis and inducing ferroptosis.Importantly,we successfully constructed a novel HSA-C13 complex delivery system,which effectively protected the integrity of C13 in blood circulation and prolongedits retention time of C13,and improved its targeting ability,reducingits side effects in vivo.