Synthesis Of Hyaluronic Acid-Based Amphiphilic Polymers And Its Applications In Antitumor Drug Delivery

Hyaluronic acid(HA) has been widely used in biomedical, pharmaceutical and cosmetical industries due to its excellent rehology properties, biocompatibility as well as biodegrability. Recent studies found that many tumor cell overexpressing CD44 on their suface which can serve as receptor for HA, thus many groups worldwide are working on developing target anticancer drug delivery system based on HA-CD44 specific interaction. In this research, hydrophobic octadecylamine(OA) was grafted to the hydrophilic HA to prepare hyaluronic acid-octodecane(HOA) amphiphilic polymers for targeted delivering Doxorubicin(DOX) to CD44 overexpressing tumor cells. DOX-load HOA polymeric micelles and HOA modified DOX-lipidosomes(DOX/LP/HOA) were prepared and their pharmaceutical and cytotoxic properties were tested.HOA was synthesized by forming amide bond between the carboxylic group of HA and the primary amino group of OA, catalyzed by EDC/NHS. The chemical sturcture of HOA was characterized by 1H-NMR. DOX/HOA polymeric micelles were prepared by classical ultrasonic method. The size of DOX/HOA micelles, the encapsulation efficiency and drugloading was measured to be(176.1±2.16) nm,(95.8±0.68)% and(15.9±1.12)%, repectively. The in vitro drug releasing profile showed that DOX/HOA had a sustained releasing behavior as only about 40% of loaded DOX cumulatively released in 72 h. Cytotoxicity of the polymeric micelles against human breast cancer MCF-7 cells, which overexpressing CD44 receptors, was tested by MTT method. DOX/HOA micelles showed higher cytotoxicity to MCF-7 cells than free DOX, suggesting more DOX internized into cancer cells through CD44 mediated endocytosis.DOX/LP/HOA was prepared through film dispersion method. The yield HA modified DOX loaded liposomes showed a regular orbicular structure, and its average particle size, electric potential and encapsulation efficiency were measured as(50.17±0.60) nm,(-7.61±0.43) mV, and(98.85±0.40)%, respectively. In vitro release behavior of DOX/LP/HOA was tested by dynamic dialysis method, which showed a typical sustained drug releasing profile. Cytotoxicity assay in vitro showed that DOX/LP/HOA and had significant higher cytotoxicity to MCF-7 cells than DOX/LP liposomes, suggesting HA modification increased the cellular uptake of liposomes through CD44 receptor. While no obvious cytotoxicity difference on COS7 cells was observed between DOX/LP/HOA and DOX/LP liposomes. Taken together, HA modified liposomes could selectivley recognize CD44 expressing tumor cells and transport more anticancer drug into the cell, thus showed a increased cytotoxicity.