Synthesis And Biological Properties Of The Nano Drug Carriers Based On Amphiphilic Polymer And Cyclodextrin Polyrotaxane

Drug delivery systems based on amphiphilic polymer have the diameter less than 1μm.The drug and other functional molecules can be dissolved,entrapped or attached to the nano-carriers through physical or chemical methods.Compared to free drug,drug-loaded nano-carriers can accumulate in tumors more easily,which leads to an improvement in anticancer efficacy.In a meanwhile,drug delivery systems can improve the biodistribution and metabolic status of the drugs to reduce the toxic side-effects.Despite the advantages,drug-loaded nano-carriers didn’t show satisfying result in clinic trial.Recently,more and more researches focused on developing new materials and investigating the effects of the physicochemical characteristics of nano-carriers on their circulation,biodistribution,cellular internalization.General physicochemical properties of polymer micelles including size,compositions,surface chemistry and stability are crucial factors influencing their fates in living systems and their overall drug-delivery properties.By studying these effects of polymer micelles on their biological properties,micelles with huge potential in the application of tumor treatment can be designed.a-Cyclodextrin polyrotaxane has been considered as an attractive nano-carrier because of its unique supramolecular structure and biocompatibility.α-cyclodextrin polyrotaxane is a kind of low-toxic inclusion complex self-assembled by a-cyclodextrin and PEG that can be used in drug delivery system.And there are abundant hydroxyl groups in a-cyclodextrin.The hydroxyl groups can be used to link to the drug or other functional molecules.This provides a-cyclodextrin polyrotaxane a huge potential as a nano-carrier.Zwitterionic materials are a kind of biocompatible materials that contain both cationic and anionic groups.They can resist nonspecific protein adsorption in blood serum,increase the stability of enzymes without losing the bioactivity and cause no immunological response in vivo in blood circulation.All these advantages make zwitterionic materials possible to be used in drug delivery systems.Herein,we studied of the size effect of protoporphyrin(PP)-poly(s-caprolactone)(PCL)-poly(ethylene glycol)(PEG)micelles on their in vivo behaviors.We also studied the synthesis of a-cyclodextrin polyrotaxane and its modification with zwitterionic polymer,drug loading and in vivo behaviors such as pharmacokinetics,biodistributions and diffusibility in tumor matrix etc.Details are as follows.(1)We prepared a series of doxorubicin(DOX)-loaded protoporphyrin(PP)-poly(ε-caprolactone)(PCL)-poly(ethylene glycol)(PEG)micelles with narrowly distributed sizes(40 nm,70 nm,100 nm,130 nm in diameter).The protoporphyrin moiety enhanced the stability of the micelles and provided luminous capability that can be used to study the cellular uptake of the micelles by fluorescent imaging.A typically sustained release profile is presented for each of the micelles at both pH 7.4 and 6.0.In vitro cytotoxicity tests show that all the DOX-loaded micelles have comparable cytotoxicity,which is lower than the cytotoxicity of free DOX at a dose larger than 0.5 μg/mL DOX equivalent.And the results of NIRF imaging,DOX biodistribution and antitumor experiments revealed that all micelles could improve the biodistribution and antitumor effects of DOX.(2)We synthesized a-CD polyrotaxane(PR)with PEG as axle and N-carbobenzyloxy-L-phenylalanine as end-capping groups.After the reaction of 2-bromoisobutyryl bromide with the hydroxyl groups in a-CD polyrotaxane,the copolymers PR-poly(2-Hydroxyethyl methacrylate)-poly(2-tert-butoxy-N-(2-(methacryloyloxy)ethyl)-N,N-dimethyl-2-oxoethanaminium)(PR-PHEMA-PCB-tBu)were synthesized by a two-step ATRP of 2-Hydroxyethyl methacrylate(HEMA)and 2-tert-butoxy-N-(2-(methacryloyloxy)ethyl)-N,N-dimethyl-2-oxoethanaminium(CB-tBu).After hydrolysis of tert-butoxy group(tBu),zwitterionic copolymers PR-poly(2-Hydroxyethyl methacrylate)-poly(N-(2-(methacryloyloxy)ethyl)-N,N-dimethyl-2-oxoethanaminium)(PR-PHEMA-PCB)was obtained.Then we characterized the PRs and copolymers with 1H NMR and GPC.(3)Water soluble paclitaxel(PTX)-loaded zwitterionic copolymers PR-PHEMA(PTX)-PCB were successfully prepared and their molecular size was determined to be about 3.5 nm by HR-TEM.In vitro cytotoxicity tests show that PR-PHEMA(PTX)-PCB has lower cytotoxicity than that of Taxol.The PR-PHEMA(PTX)-PCB could accumulate in tumor tissues rapidly and had good permeability in 3D cells and tumor tissues and thus showed better anticancer effect than Taxol.