Effect Of Hydrophilic Polymer Structure On Micelle’s Pharmacokinetics

Because of their good biocompatibility, high water-solubility and drug loading capacity, amphiphilic copolymers micelles have been extensively developed for drug delivery system. Hydrophilic polymers of micelles’ shell, such as polyethylene glycol (PEG), can reduce the recognition and clearance and then prolong the circulation time, through forming compact hydration layer to exclude protein’ adhesion. The composition and structure of hydrophilic polymer will affect hydration layer and its repulsive force to the protein, and may have a significant effect on drug-loaded micelles’ pharmacokinetics.In this article, we designed to synthesize three amphiphilic copolymers with same hydrophobic chains and various hydrophilic chains (phosphoester-contained brush-shaped copolymers PCL-POPPEG, brush-shaped copolymers PCL-pPEGMA, and linear PEG-PCL), to study the influences of hydrophilic polymer structure on micelles’ pharmacokinetics. Their structure, molecular weight and distribution were characterized in detail. Their critical micelle concentration were about 1 μg/mL. These amphiphilic copolymers micelles showed a similar drug loading capacity, and had the ability of slow-release and pH-response. These amphiphilic copolymers had little cytotoxicity, while free DOX and DOX-loaded micelles exhibited high cytotoxicity and good concentration-dependent properties. Furthermore, the intracellular distributions of these DOX-loaded micelles were observed by confocal laser scanning microscopy. Different with free DOX, these DOX-loaded micelles were not discovered in cell nucleus. These researches indicated that many amphiphilic copolymers’ properties, such as forming micelles, drug-loading, slow-release, cytotoxicity and intracellular distributions, were not close related to hydrophilic polymer structure.Cellular uptake of linear PEG-PCL micelles were much lower than that of other two brush-shaped copolymers micelles. Moreover, DOX/PEG-PCL micelles were cleared the most slowly among these DOX-loaded micelles. Because PCL-POPPEG was easy to degrade and be uptaken, DOX/PCL-POPPEG micelles were rapidly cleared. These results suggest that phosphoester-contained hydrophilic polymer have relatively poor stabilities and brush-shaped hydrophilic polymer structure could not improve copolymers micelles’ pharmacokinetics.