Design,synthesis And Evaluation Of Nano-sized Hydroxycamptothecin Targeting Drug Delivery System For Inhibiting Tumor Metastasis

Cancer is currently the number one killer that threatens human life and health,and the non-surgical treatment of cancer mainly includes radiotherapy and chemotherapy.Chemotherapy drugs lack specific selection of tumor cells,it also produce the serious killing effect to the normal cells.Recently,targeted therapy for tumor has become the new favourite in clinical studies.In order to enhance the drug concentration in tumor site and specificly kill tumor cells and its neovascularization,we should find the delivery carrier which is specific to tumor cells and construct the targeted delivery system to deliver drug.E-selectin is only highly expressed on activated endothelial cells,and can specifically recognize some specific oligosaccharide structures on the surface of tumor cells.Through this recognition,tumor cells can adhere and migrate from endothelial cells.The E-selectin ligand peptide was applied to the drug delivery system,and the ligand-receptor-specific binding was used to inhibit the adhesion and migration of tumor cells.Polyethylene glycol(PEG)is a highly hydrophilic and well biocompatible polymer,it often used as a macromolecule carrier to couple with hydrophobic anticancer drugs or therapeutic proteins to form nano drugs for cancer treatment.Based on the specificity of tumor and the advantages of nano-carrier,we utilize the hydrophobic antitumor drug HCPT as the drug model,after five synthetic routes exploration and optimization,we ultimately determine the optimal route five,through this route,the ternary conjugates of polyethylene glycol,E-selectin peptide ligand and HCPT were successfully synthesized.Firstly,we synthesized the E-selectin polypeptide ligand by solid-phase synthesis.After that,the targeted nanoparticle drug delivery system which based on GSH responsed was synthesized through 8 steps.Its structure and purity were analyzed and identified by RP-HPLC,NMR,MALDI-TOF and other instruments.The inhibitory activity of the target compounds on tumor cells K562,HepG2 and HCT-116 was tested by MTT assay.The results showed that the anti-tumor activity was comparable to that of HCPT.Cell adhesion experiments showed it could inhibit the adhesion between THP-1 cells and vascular endothelial cells HUVEC,thus maybe could preventing the migration of tumor cells.The preliminary in vivo activity results showed that the conjugate had a comparable effect to HCPT at a dose of 6 mg/kg in the H22 hepatocarcinoma mouse model.The molecular weight of conjugate is about 10 times than HCPT,so its activity was about 10 times higher than HCPT.In addition,the maximal tolerance dose(MTD)of mice was measured by tail vein injection.The MTD of the conjugate was 300 mg/kg,which was 247.25 times of the clinical dose of HCPT.