Preparation Of Zwitterionic Amphiphilic Molecules Based Nanomedicines And Investigation Of Their Antitumor Properties

At present,chemotherapy is still the main means of clinical treatment of malignant tumors.However,the commonly used chemotherapeutic drugs have some disadvantages,such as poor water solubility,low selectivity,high toxic and side effects on normal tissues and easy removal of reticuloendothelial tissue,which increase the pain of cancer treatment for patients.Therefore,seeking an ideal nanodrug carrier is an important means to solve the above problems.In this paper,nanodrug delivery vehicles were prepared based on zwitterionic modified second-generation poly(propylene imine)dendrimers(G2 PPI)and the natural zwitterionic polypeptide daptomycin(Dap)to study the fabrication,characterization as well as in vitro and in vivo antitumor properties.The main text of this paper is as follows:(1)The small molecule anticancer drug doxorubicin(DOX)suffers from several drawbacks such as poor water solubility,low targeting,and great biological toxicity.In Chapter 2 of this paper,zwitterionic groups and targeting peptide c(RGDf C)were surface modified on G2 PPI to prepare nanodrug loaded micelles PPIMYRC-DOX by dialysis.It was experimentally demonstrated that PPIMYRC-DOX micelles had good stability in fibrinogen;in PBS buffer solution mimicking normal tissue and tumor microenvironment,there was no burst release phenomenon,and the released drug was p H responsive;in cell experiments,PPIMYRC-DOX micelles had enhanced cytotoxicity compared with free DOX;PPIMYRC has good biocompatibility;in vivo experiments demonstrated that PPIMYRC-DOX micelles had better tumor suppression effect.Its tumor volume of PPIMYRC-DOX micellesgroup was 7% of that of the saline group.(2)To further improve the drug loading capacity of micelles,and improve the water solubility of paclitaxel(PTX).In Chapter 3,amphiphilic prodrug molecules were prepared by surface modification of G2 PPI with hydrophilic zwitterionic groups and hydrophobic paclitaxel.Dialysis method was followed to prepare nanodrug loaded micelles PPIMPCDOX.The drug loading of doxorubicin in PPIPC-DOX micelles was calculated to be 6.7%,the drug loading of paclitaxel in PPIMPC-DOX micelles was 26.2%,and the total drug loading of PPIMPC-DOX was 32.9%,indicating that the micelles had a high drug loading capacity.It was experimentally demonstrated that PPIMPC-DOX micelles possessed good protein stability and p H responsiveness.PPIMPC-DOX had a better tumor suppressive effect in vivo experiments.(3)Traditional nano drug carriers have some disadvantages such as complicated molecular structure,instability of molecular weight,complicated synthetic steps and biodegradability.Chapter 4 of this paper used natural zwitterionic polypeptide Dap to prepare nanodrug loaded micelles Dap-DOX by dialysis method.Natural polypeptides have good biocompatibility and biodegradability.The experiments demonstrated that Dap-DOX micelles had good protein stability and enhanced cellular uptake ability.The Dap-DOX micelles were able to be enriched at the tumor site via the EPR effect as demonstrated by histofluorescence photographs over time.In vivo experiments,Dap-DOX micelles achieved good tumor inhibition effect,and the tumor volume of Dap-DOX micelles group was 10%of the tumor volume of saline group.