Development of a Vinyl Ether-Functionalized Polyphosphoesteras a Template for Multiple Postpolymerization Conjugation Chemistriesand Study of Core Degradable Polymeric Nanoparticles

摘要

A novel polyphosphoester (PPE) with vinyl ether side chain functionality was developed as a versatile template for postpolymerization modifications, and its degradability and biocompatibility were evaluated. An organocatalyzed ring-opening polymerization of ethylene glycol vinyl ether-pendant cyclic phosphotriester monomer allowed for construction of poly(ethylene glycol vinyl ether phosphotriester) (PEVEP). This vinyl ether-functionalized PPE scaffold was coupled with hydroxyl- or thiol-containing model small molecules via three different types of conjugation chemistries—thiol–ene “click” reaction, acetalization, or thio-acetalization reaction—to afford modified polymers that accommodated either stable thio–ether or hydrolytically labile acetal or thio–acetal linkages. Amphiphilic diblock copolymers of poly(ethylene glycol) and PEVEP formed well-defined micelles with a narrow and monomodal size distribution in water, as confirmed by dynamic light scattering (DLS), transmission electron microscopy, and atomic force microscopy. The stability of the micelles and the hydrolytic degradability ofthe backbone and side chains of the PEVEP block segment were assessedby DLS and nuclear magnetic resonance spectroscopy (¹Hand ³¹P), respectively, in aqueous buffer solutions atpH values of 5.0 and 7.4 and at temperatures of 25 and 37 °C.The hydrolytic degradation products of the PEVEP segments of the blockcopolymers were then identified by electrospray ionization, gas chromatography,and matrix-assisted laser desorption/ionization mass spectrometry.The parent micelles and their degradation products were found to benon-cytotoxic at concentrations up to 3 mg/mL, when evaluated withRAW 264.7 mouse macrophages and OVCAR-3 human ovarian adenocarcinomacells.