Studies On Preparations And Drug Controlled Release Of PH And Reduction Dual-Sensitive Hyperbranched Nano Micelles

The chemical drug therapy is still the most direct and effective means for the treatment of cancer in the current situation. Many drugs have the ability to kill tumor cells, but they also have serious side effects on normal cells. It is still a challenge topic to deliver drugs to the tumor tissue safely and effectively, and enhance drug adsorption in tumor cells. This article has designed and synthesized pH and reduction dual-sensitive hyperbranched polymeric micelles for anti-cancer drugs-loading.This paper mainly includes the followings:The hyperbranched polymers were prepared via the nucleophilic ring-opening reaction of double ended epoxy groups of poly(ethylene glycol) diglycidyl ether(PEGDGE) and double ended amino groups of cystamine(Cys) in aqueous solution. The pH and reduction dual-sensitive nano micells with a core-shell structure were formed during dialysis against deionized water. The effect of reactant feed ratio on sizes and morphologies of polymeric nano micelles was studied, and the effects of the pH and glutathione on sizes of nano micelles were also explored. As a model drug, methotrexate(MTX) was loaded into the nano micelles for investigating controlled release in vitro. The cytotoxicity experiments were carried out on both blank micelles and drug-loaded micelles using methyl thiazolyl tetrazolium(MTT) assay. The results showed that the best nano micelle could be formed when the reactive functional groups molar ratio reached 1:2. The nano micelles had significant pH and reduction dual-sensitivities. The drug loading and encapsulation efficiency of micelles could reach 10.81% and 69.7% respectively. The in vitro release further revealed that the nano micelles had significant pH and reduction dual-sensitivities. The cell experiments showed that the nano micelles possessed perfect biocompatibility and excellent anti-tumor activity.The hyperbranched polymers were modified using three different anhydrides into three carboxyl functional pH-gradient sensitive hyperbranched polymers. The polymers could form micelles during dialysis against deionized water. The pH-gradient sensitivity, charge-reversal performance and the ability to anti-protein adsorption were studied by 1H-NMR, ζpotential and nano-sizer, DLS. The reduction-sensitivity and the relationship between the sensitivity and the concentration of glutathione(GSH) were explored systematically. Taking adriamycin(DOX) as a model drug, DOX was loaded into the nano micelles for investigating controlled release in vitro. The cytotoxicity experiments were carried out on both blank micelles and drug-loaded micelles using MTT assay. The results showed that these three carboxyl functional micelles had a pH-dependent charge-reversal capability and their reduction-sensitivity had a positive correlation with the concentration of GSH. They could also prevent protein adsorption. The in vitro release further revealed that the nano micelles had significant pH and reduction dual-sensitivities. The cell experiments showed that the nano micelles possessed perfect biocompatibility and excellent anti-tumor activity.The advantages of the two systems in this article are obvious: synthesis of polymer preparation process is simple and does not involve any organic solvent; the drug loading and encapsulation efficiency can be improved effectively by hyperbranched unique structure. The nano micelles are responsive to the tumor environment, enabling controlled release of anti-cancer drugs.