Preparation Of Cholesterol-modified PH-Sensitive Polymers And Their Self-Assembled Micelle Controlled Drug Release

In recent years, much attention has been devoted to the nanoscopic pH-responsivemicelles self-assembled from amphiphilic copolymer which has been one of the mostprospective drug delivery systems (DDS). This specific polymers exhibited a series ofattractive properties, such as improved the bioavailability of poorly water soluble drugs,reduced the cytotoxicity and controlled release of the drugs depending on the different pH inthe body. In this study, two kinds of cholesteryl-modified pH-sensitive copolymers weredesigned and synthesized. And then the self-assembly, pH-sensitive and controlled releasebehaviors were studied.A novel amphiphilic pH-sensitive copolymer cholesteryl-conjugated poly(β-aminoesters)-g-poly(ethylene glycol) methyl ether)(PAE-g-MPEG-Chol) were synthesized using acombination of alcoholysis and michael addition polymerization. The successful synthesis ofthe graft copolymer was confirmed by proton nuclear magnetic resonance (1H NMR) and gelpermeation chromatography (GPC). Dynamic light scattering (DLS) showed that thepolymeric micelles had a size of120nm at physiological pH and were responsive to pH. Aspherical morphology was observed for the micelles using transmission electron microscopy(TEM).A novel amphiphilic pH-sensitive copolymer brush poly(2-Hydroxyethylmethacrylate-co-2-(diethylamino)ethyl methacrylate)-b-poly(poly-(ethylene glycol) methylether monomethacrylate)(P(HEMA-co-DEA)-b-PPEGMA) block copolymer weresynthesized by a continuous activators regenerated by electron transfer atom transfer radicalpolymerization (ARGET ATRP). These polymers were modified by cholesteryl chloroformateto improve the hydrophobicity of the micelle core. GPC and1H NMR characterization resultsindicated that the well-defined products with specific content ratio were acquired. The criticalmicelle concentration (CMC) of Chol-P(HEMA-co-DEA)-b-PPEGMA in aqueous solutionwas extremely low (6.92mg/L) using florescence spectroscopy. The diameter of theself-assembled micelles was120-180nm by DLS.Doxorubicin (DOX) was used as a model drug and encapsulated into the copolymersself-assembled micelles. Both PAE-g-MPEG-Chol and Chol-P(HEMA-co-DEA)-b-PPEGMA micelles have pH sensitivity as drug carriers. The DOX release rate was significantlyaccelerated by decreasing pH from7.4to6.0, due to the swelling of micelles at lower pHconditions caused by the protonation of tertiary amine groups in PAE and PDEA. All theresults indicate that the pH-sensitive PAE-g-MPEG-Chol andChol-P(HEMA-co-DEA)-b-PPEGMA micelles may be a potential hydrophobic drugs deliverycarrier for cancer targeting therapy with sustained release. The work would promote theapplication of the stimuli-responsive micelles in the drug delivery system (DDS).