Design And Synthesis Of Paradodecatungstate Antitumor Lead Compounds And Preparation Of Microparticle Drug Delivery System

Polyoxometalates（POMs）are metal-oxygen clusters consisting of high-valent pre-transition metals bonded by bridging of oxygen atoms.Currently,the discipline of polyacid medicinal chemistry is flourishing as the research on the pharmacological activity and structural modification of polyacids continues to intensify worldwide,the most notable of which is the research on polyacid antitumor drugs.Polyoxometalates antitumor compounds have the advantages of broad antitumor spectrum,high activity and low toxicity,and have potential applications as alternative molecules for antitumor drugs.However,the disadvantages are that the polyanions have a high negative charge which is not conducive to entry into the cells,they tend to interact electrostatically with proteins in the blood and cause toxic side effects,and the intracellular target specificity is weak.Designing and synthesizing new multi-acid antitumor compounds with strong antitumor effects and low toxicity and their drug delivery bodies is an effective strategy to solve the above problems.In this work,two paradodecatungstate-B compounds were prepared by conventional aqueous solution method;Solid Lipid Nanoparticles（SLNs）of paradodecatungstate were prepared using sodium stearate as a carrier;Characterization of paradodecatungstate compounds and particulate drug delivery systems by X-ray single crystal diffraction,infrared spectroscopy,UV-Vis spectroscopy,scanning transmission electron microscopy,transmission electron microscopy;The in vitro pharmacological activity of the compounds was investigated using the MTT method as follows:1.New paradodecatungstate compounds modified with sodium paradodecatungstate-B and transition metal zinc were synthesized by conventional aqueous solution method:Na₁₀（H₂O）₂₆[H₂W₁₂O₄₂](NaW₁₂)（H₃O）₆[Zn（H₂O）₆]₆{Zn₆(C₅H₁₁NO)₆（H₂O）₆[H₂W₁₂O₄₂]₃}·4H₂O(ZnW₁₂)X-ray single-crystal diffraction shows that NaW₁₂ consists of two types of metal oxygen clusters,paradodecatungstate-B anion[H₂W₁₂O₄₂]^10-and multinuclear sodium oxygen clusters.paradodecatungstate-B anion[H₂W₁₂O₄₂]^10-in ZnW₁₂ is connected into a two-dimensional structure through Zn octahedra,and the ligand cation[Zn（H₂O）₆]²⁺and crystalline water in the free state are present between the lattice.The in vitro anti-tumor assay of NaW₁₂ and ZnW₁₂ by MTT method showed that both compounds inhibited cervical cancer cells（He La）,liver cancer cells（Hep G2）and normal endothelial cells（EVC-304）,and the cell survival rate decreased with increasing concentration in a drug dose-dependent manner.The IC₅₀ of He La,Hep G2 and EVC-304 cells treated with different concentrations of NaW₁₂ were 160.5μmol/L,120.3μmol/L and 125.4μmol/L,respectively;the IC₅₀ of He La,Hep G2 and EVC-304 cells treated with different concentrations of ZnW₁₂ were 90.2μmol/L,0.46μmol/L and13.4μmol/L for He La,Hep G2 and EVC-304 cells,respectively;the antitumor activity of the paradodecatungstate-B compound modified with transition metal zinc was significantly enhanced compared with that of the parent acid NaW₁₂.The relationship between the paradodecatungstate-B compounds and ct-DNA was investigated by UV spectroscopy,and electrostatic or groove interactions were found between them;the compounds also interacted with bovine serum albumin（BSA）.2.NaW₁₂-SLNs,solid lipid nanoparticles of particulate drug delivery system,were prepared using sodium stearate as the carrier and NaW₁₂ as the main drug.The average particle size was about 110 nm.In vitro antitumor assays showed that NaW₁₂-SLNs could inhibit the proliferation of He La,Hep G2 and EVC-304 cells in a dose-dependent manner,with IC₅₀ values of 48.4μmol/L,3.42μmol/L and 62.7μmol/L for proliferation half-inhibition concentration,respectively.showed significantly enhanced antitumor pharmacological activity,lower toxicity to normal human cells and better selectivity for human hepatocellular carcinoma Hep G2 cells.This study demonstrates the potential of SLNs as polyoxometalate drug carriers and provides valuable basic research data for the application study of polyoxometalate drugs.