Nanosized Formulation Of Amphiphilic Solanesol Deriveritvs For Cancer Thearpy

In the process of nanocarriers transporting poorly soluble drugs,micelles have attracted much attention due to their good performance and application.However,the introduction of a large number of inert materials in the micellar system will cause problems such as toxic accumulation and biological metabolism.In this study,the pharmacologically active solanesols was used as raw material to synthesize solanesol derivative and construct drugs nano-carrier system for anti-tumor research.1.Study on synthesis of solanesol derivatives and properties of its micelles?1?Three solanesol derivatives including SOL-Br?Solanesyl Bromide?,STS?Solanesyl Thiosalicylate?and MSS?Monosolanesol Solanesyl Succinate?were synthesized based on solanesol by esterification,bromination and introduction of thioether bonds,and blank micelles were prepared.CMC?Critical Micelle Concentration?determination,storage,dilution stability and hemolysis rate of four blank micelles were examined by laser particle size analyzer,fluorophotometer,microplate reader,etc.It was found that the modified solanesol derivatives had higher performance than the solanesol,but the SOL-Br,STS,MSS micelles had problems such as failure of drug loading.The hemolysis rate was higher than 5%at STS and MSS micelle concentrations of 10-30?g/mL,but the control group of FTS?Farnesyl thiosalicylic acid?similar to the STS structure met medical standards.?2?Investigate and compare the toxicity of solanesol and its derivatives to cancer cells HepG-2,MCF-7and L02 by MTT assay.It was found that the toxicity of STS,MSS,SOL-Br and SOL micelles decreased in turn.Moreover,the toxicity of STS micelles was significantly higher than that of the control group of FTS?IC50 values is 0.021 mg/mL and 0.117 mg/mL in 48 hours towards HepG2 respectively?,indicating that the prepared solanesol derivatives showed a significant increase in antitumor activity compared with the raw materials.2.Anti-tumor study of drug-loaded system formed by solanesol derivatives and PEG₆₀₀₀-DiHZ?1?PEG₆₀₀₀-DiCHO and PEG₆₀₀₀-DiHZ are obtained by modifying PEG with terminal aldehyde group and hydrazone bond,which are used as a hydrophilic segment to form self-assembly system with solanesol and its derivatives.Firstly,only PEG₆₀₀₀-DiHZ can be used to form drug-loaded self-assembly system with the solanesol derivatives STS,MSS and SOL-Br.With the highest drug loading as the evaluation standard,when the molar ratio was 2:1,the drug loading of the model drug doxorubicin was 3.55%,3.46%and2.91%,respectively.?2?According to the molar ratio of PEG₆₀₀₀-DiHZ to solanesol derivatives STS,MSS and SOL-Br of2:1,blank and drug-loaded self-assembly system were obtained.The stability and hemolysis rate were investigated,which not only solved the problems of hemolysis and durg loading failure of solanesol derivatives,but also demonstrated that the self-assembly system have the potential for further intravenous administration.?3?In the simulated vitro release experiment of drug carrying self-assembly system in vitro,the release amounts of the three drug-loading self-assembly system reached 75-80%after 60 h at pH 5.0.?4?Cytotoxicity of blank and drug-loaded self-assembly system was investigated in vitro,the order of results for the inhibition of cancer cells was found to be Free DOX>STS:PEG₆₀₀₀-DiHZ-DOX>MSS:PEG₆₀₀₀-DiHZ-DOX>SOL-Br:PEG₆₀₀₀-DiHZ-DOX.In addition,the blank self-assembly systems still maintained the cytotoxicity of the derivatives of solanesol in the previous chapter,and the order of cell inhibition was STS:PEG₆₀₀₀-DiHZ>MSS:PEG₆₀₀₀-DiHZ>SOL-Br:PEG₆₀₀₀-DiHZ.?5?Using H22 tumor-bearing mice as a model to evaluate the pharmacodynamics of blank and drug-loaded self-assembly system.The order of antitumor effect was found to be:STS:PEG₆₀₀₀-DiHZ-DOX>MSS:PEG₆₀₀₀-DiHZ-DOX>SOL-Br:PEG₆₀₀₀-DiHZ-DOX>Free DOX>STS:PEG₆₀₀₀-DiHZ>MSS:PEG₆₀₀₀-DiHZ>SOL-Br:PEG₆₀₀₀-DiHZ;The combined anti-tumor effect of solanesol derivatives and drugs was also verified by H&E and TUNEL results,which shows the good application prospect of the pharmacophore-active self-assembly system in nanomedicine.