Synthesis of Architecture-Controlled Poly(ethylene oxide)s as Biocompatible Materials

Abstract

Poly(ethylene oxide)s are well known biocompatible, non-toxic, anti-fouling materials in biomedical fields and have been used for applications such as drug delivery, gene therapy, imaging modality and surface modification of carriers. Molecular weight, molecular weight distribution and primary architecture of poly(ethylene oxide) can be precisely controlled employing anionic polymerization of ethylene oxide in a high-vacuum system. 4-arm, 6-arm, 8-arm star-shaped poly(ethylene oxide)s were synthesized using pentaerythritol, sorbitol and 4-arm star-shaped poly(ethylene) oxide precursor as initiators. All polymerizations were carried out in DMSO based on 30 mole% activation of hydroxyl groups in initiators to minimize the side reaction of DMSO activation by DPMK catalyst, known as dimsyl anion formation. Dendritic poly(ethylene oxide)s were prepared in the same condition. Linear, star-shaped, dendritic poly(ethylene oxide)s were synthesized and surface modification at focal point as well as at each peripheral end was successfully controlled. All the polymers were characterized using 1H NMR, GPC and UV spectrometer. Anionic polymerization of poly(ethylene oxide)s produced the polymers with very narrow molecular weight distribution, which is an important requirement for a biomaterial applicable to drug and cell delivery system in vivo. For delivery of anticancer drugs on tumor site, nanostructures were used for efficiency in delivery and minimized side effects. Block copolymers consisting of 5 K poly(ethylene oxide), functionalized middle block and 2 K poly(caprolactone) were synthesized. Cysteine residues with thiol pendent group were introduced as a functionalized block between two polymers for enhanced stability during blood stream and selective degradation at a targeted site. Doxorubicin was used as anticancer drug and drug loaded nanoparticles displayed the size of 221 nm. Doxorubicin-loading amount and efficiency was around 8.7 and 26.0 %, respectively. Release profile of doxorubicin was monitored under two different conditions with the presence as well as absence of DTT and selective drug release at intracellular condition was observed. 8-arm star-shaped and dendritic poly(ethylene oxide)s were obtained without any noticeable side reactions. Molecular weight was 80 K with narrow molecular weight distribution of 1.03 and functionalized end groups were utilized for islet surface modification as well as double layer coating with unfractionated heparin (UFH). Two catechol groups in average were conjugated at the peripheral ends of 8-arm star poly(ethylene oxide)s and reacted with either thiol or amine groups on the cell surface in mild condition. Cell coverage and viability were optically visualized by FITC dyes which were additionally conjugated at the unreacted ends of the polymers. Modification of cell surface with double layers of poly(ethylene oxide)s and ultra fractionated heparin did not significantly affect the viability and biological functions of islets in vitro and in vivo. Dendritic poly(ethylene oxide)s were applied for islet modification with the similar method as star-shaped poly(ethylene oxide)s. Dendritic poly(ethylene oxide)s were activated by NHS at the focal point for the conjugation with amine groups on the islet surface. In vivo immunoprotection effects were investigated and dendritic poly(ethylene oxide)-modified islets showed high coverage effect and viability compared to unmodified islets.