Development of a Vinyl Ether-Functionalized Polyphosphoester
as a Template for Multiple Postpolymerization Conjugation Chemistries
and Study of Core Degradable Polymeric Nanoparticles
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Abstract
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 chemistriesthiol–ene
“click” reaction, acetalization, or thio-acetalization
reactionto 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 of
the backbone and side chains of the PEVEP block segment were assessed
by DLS and nuclear magnetic resonance spectroscopy (<sup>1</sup>H
and <sup>31</sup>P), respectively, in aqueous buffer solutions at
pH 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 block
copolymers 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 be
non-cytotoxic at concentrations up to 3 mg/mL, when evaluated with
RAW 264.7 mouse macrophages and OVCAR-3 human ovarian adenocarcinoma
cells