| The micelles of amphiphilic block copolymers have widely applied in insoluble drug delivery,because they have a hydrophobic core,which can encapsulate poorly water-soluble drugs and improve the pharmacokinetics and pharmacodynamics properties of the drug.In this study,amphiphilic solanesol derivatives(SPGS-2K,SPGS-5K and SPSGS-5K)were synthesized by esterification using solanesol as raw materials,for the delivery of coenzyme Q10 and small molecule anticancer drug DOX,to improve bioavailability and tumor targeting therapy of the drug.1?Pegylated Solanesol for Oral Delivery of Coenzyme Q10SPGS products with a molecular weight of 2000 and 5000 Da were obtained by using succinic acid to connect polyethylene glycol.CoQ10-SPGS micelles were prepared by the solvent evaporation method.The particle size,morphologies,drug loading content,dilution stability,light stability and oral administration of CoQ10-loaded micelles were investigated by dynamic light scattering,high resolution transmission electron microscopy,high performance liquid chromatography and differential scanning calorimetry and so on.The results showed that the size of CoQ10-loaded micelles was 180 nm with narrow size distributions.The micelles were spherical nucleus-shell state,and the drug loading was more than 39.0%.The coenzyme Q10 was good similarity with solanesol,The results demonstrated that the micelle solutions are diluted 1000-fold with water,they undergo very slight changes in sizes,which also indicate that they exhibit excellent thermodynamic stability.DSC and XRD data indicated that the encapsulation of a large amount of amorphous CoQ10 by SPGS micelles.MTT assay results reveal that both SPGS-2K and SPGS-5K blank micelles are nontoxic and biocompatible.In vivo experiments demonstrate that,as compared to that of the coarsesuspensions of CoQ10,there was three-fold enhancement of oral bioavailability for CoQ10-loaded SPGS micelles depending on varying molecular weight of SPGS.2?Preparation and drug loading properties of reduced sensitivity solanesol derivative micellesSolanesol was reacted with succinic anhydride and 3,3'-dithiodipropionic acid to obtain the mono-solanesol solanesyl succinate MSS and MDPA,respectively.Hydrophobic MSS and MDPA were covalently conjugated to the mPEG backbone by esterification reaction to afford SPGS and SPSGS.DOX-loaded micelles were prepared by dialysis method using DOX as model drug.The colloidal properties of DOX-loaded micelles were characterized by DLS,TEM and fluorescence spectrophotometer and so on.The results showed that particle size of DOX-loaded micelles was lower than 100 nm with narrow size distributions,The micelles exhibited spherical morphologies and the drug loading content was more than 4.0%.The release of DOX was significantly accelerated in the presence of 10 mM GSH.MTT assay results reveal that both SPGS-2K and SPGS-5K blank micelles exhibited severe cytotoxicity against tumor cells.The inhibitory effect of SPSGS-DOX on tumor cells was better than SPGS-DOX,and SPSGS-DOX could release DOX rapidly in tumor cytoplasm.The results showed that SPGS-DOX and SPSGS-DOX could remain the stability of the micelle structure and particle size when the solutions were 1000-fold diluted.The existence of polyethylene glycol hydration layer makes the micelle preparation have good resistance to protein adsorption,ability to maintain stability of particle size.Hemolysis assay showed that the blank micelles and drug-loaded micelles have a hemolysis rate of less than 5.0%,consistent with the requirements of intravenous direct injection.In vivo anti-tumor efficacy test of SPGS-DOX and SPSGS-DOX micelles were assessed on mice bearing H22 tumor xenografts.The results revealed that DOX-loaded micelles effectively inhibited tumor growth and significantly reduced the cardiotoxicity of DOX.The best antitumor efficiency was observed in the SSSP-DOX micelle-treated group.H&E and TUNEL results showed that SPSGS-DOX micelles induced maximal tumor cell necrosis and apoptosis. |
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