Construction And Evaluation Of Pt(Ⅳ)-HDAC Inhibitors Upconversion Nanoparticles(UCNPs)

Cisplatin is a classic anti-tumor drug.It has been the first-line anti-tumor drug in clinical practice.However,the drug resistance was greatly limited the application of platinum drugs.At present,there are three main Strategies for the development of novel platinum-based therapies:1)development of novel Pt（II）compounds;2)Pt（Ⅳ）prodrug strategy;and 3)Pt-based nano drug delivery system.Herein,to overcome the drawbacks of conventional platinum-based drugs,histone deacetylase inhibitor phenylbutyric acid（Ph B）and lipophilic long chains have been introduced into the design of Pt（Ⅳ）compounds,and an up-conversion nanoparticle（UCNPs）delivery system has been established to improve the tumor targeting properties of the Pt（Ⅳ）drugs.Objective:To introduce histone deacetylase（HDACs）inhibitor phenylbutyric acid and lipophilic long chains into the design of tetravalent platinum prodrugs to improve the antitumor activity by enhancing the ability of drug uptake and DNA damage.We designed and constructed an up-conversion nanoparticle delivery system modified with polyethylene glycol（PEG）to enhance the targeting properties of HDACi-Pt（Ⅳ）prodrugs.Under near-infrared radiation,Pt（Ⅳ）-HDACi-loaded UCNPs can convert NIR light into UV/vis region emission light,thereby releasing Pt（Ⅳ）prodrugs.Methods:Firstly,Pt（Ⅳ）-HDACi compounds 3a-c were synthesized.The cytotoxicity of the compounds was measured using the MTT method,the DNA cross-linking method was determined using agarose gel electrophoresis,and the uptake of platinum in whole cells and DNA was measured using ICP-MS.The effects of tumor cell cycle and apoptosis,immunofluorescence and Western blot were used to investigate the effects of compounds on the expression of related proteins,and the mechanism of action was explored in depth.In addition,we also designed and synthesized the up-conversion nanomaterial Na Gd F₄:Yb/Tm@Na Gd F₄.Results:（1）The synthesized compounds have good activity in tumor cells,especially compound 3a.The IC₅₀value of 3a in the selected cancer cell lines ranges from as low as 14n M（MCF-7）to 24n M（A549）,which is 863times and 375 times higher than cisplatin,respectively.In addition,3a showed the most significant toxicity(IC₅₀=12 n M)in cisplatin-resistant A549cis R cells,which increased by 2062 compared with cisplatin.Times,showing superior antitumor activity.In addition,our synthetic compounds3a-c have significantly increased uptake in cells compared to cisplatin.In addition to the increased uptake,we also found that the cross-linking method different from cisplatin-interchain cross-linking is also our compound.An important reason for having such excellent characteristics.（2）We successfully constructed a drug-loading system consisting of up-conversion nanomaterials,PEG,Pt（Ⅳ）compound 3c,and curcumin（Cur）.It has also produced good antitumor activity.Conclusions:（1）Introducing histidine deacetylase（HDACs）inhibitor phenylbutyric acid and lipophilic long chain into the design of tetravalent platinum prodrug,and three lipophilic tetravalent platinum prodrugs 3a-c were synthesized.（2）Our synthesized compounds 3a-c generate DNA damage by interacting with DNA in a completely different way than cisplatin.At the same time,the introduction of phenylbutyric acid inhibits DNA repair,enhances DNA damage,and effectively kills tumor cells.（3）The up-conversion nano system we constructed enables the drug to obtain good water dispersion,enhances the drug’s targeting,reduces the toxic and side effects of the drug on the human body.