Development of a Vinyl Ether-Functionalized Polyphosphoester as a Template for Multiple Postpolymerization Conjugation Chemistries and Study of Core Degradable Polymeric Nanoparticles

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 organo-catalyzed 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 of the backbone and side chains of the PEVEP block segment were assessed by DLS and nuclear magnetic resonance spectroscopy (1H and 31P), 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.

Development of Fully Degradable Phosphonium-Functionalized Amphiphilic Diblock Copolymers for Nucleic Acids Delivery

“…Despite the apparent similarity in behavior at both pH values, it should be noted that macroscopic precipitation was observed within 20 h upon incubation at pH = 7.4, whereas it took 5 d at pH = 5.0. The major effect exerted by the pH of the incubation medium over the kinetics of degradation of polyphosphoesters has been previously reported in the literature 34,37,39−43 and is discussed further below, in light of the DLS data. At lower temperature (4 °C) the polyphosphoester backbone was substantially more stable at both pH values and most of the degradation that occurred was imputable to the fact that the NMR experiments were run at room temperature, which led to a faster apparent degradation.…”

Facile method towards functionalization of partially fluorinated polyarylethers via sequential post-polymerization modification

“…In this case, P1 possesses primarily 1,2,2-hydrofluoroethane groups (more than ca. 95%) with only a small amount of CF = CF groups on the polymer backbone observed by 19 F NMR spectra of P1 (Fig. 1).…”

“…The successful conversion from polymer P3 to polymer P8 is easily visible in 19 F NMR spectrum. The diagnostic pattern of TFVEs is clearly shown in 19 (Fig. S8).…”

“…To ensure a successful PPM, the polymer backbone should tolerate the post-polymerization modification reaction conditions and modification reactions between reactive units in the side chains of polymer precursor and functional molecules should be very efficient and specific [18]. A number of recent and different chemistries have been employed for PPM, such as thiol-ene coupling reaction [19,20], Diels-Alder cycloaddition reaction [21,22], Michael addition reaction [23], active ester chemistry [24][25][26], and azide-alkyne click reaction [27]. Up to now, various kinds of functional polymers were prepared by PPM [28].…”

“…s, 6H) 19. F NMR (471 MHz, DMSO-d 6 ) δ − 84.92 (d, J = 145.2 Hz), − 85.67 (d, J = 143.1 Hz), − 141.2 (d, J = 57.5 Hz).…”