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

Lim YH, Heo GS, Rezenom YH, Pollack S, Raymond JE, Elsabahy M, Wooley KL - Macromolecules (2014)

Bottom Line: 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 ((1)H and (31)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.

View Article: PubMed Central - PubMed

Affiliation: Departments of Chemistry, Chemical Engineering, and Materials Science and Engineering, Laboratory for Synthetic-Biologic Interactions, Texas A&M University, P.O. Box 30012, 3255 TAMU, College Station, Texas 77842-3012, United States.

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 ((1)H and (31)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.

No MeSH data available.


Related in: MedlinePlus

1H (300 MHz, CD2Cl2, ppm) and 31P (121 MHz, CD2Cl2, ppm, inset) NMRspectra of (a) 2, (b) 3, (c) 4, and (d) 5.
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fig1: 1H (300 MHz, CD2Cl2, ppm) and 31P (121 MHz, CD2Cl2, ppm, inset) NMRspectra of (a) 2, (b) 3, (c) 4, and (d) 5.

Mentions: The same molar ratio used for the kineticstudy was applied for a scaled-up production of 2. Thepurification of 2 by precipitation in diethyl ether wasinsufficient to remove the residual starting materials and benzoicacid completely. Silica gel column chromatography was also attempted,but instability of the PPE backbone was problematic. Dialysis (MWCO6–8 kDa) of the reaction mixture against organic solvents,switching from MeOH to DCM, was the most assured purification methodamong those tested. Dialysis in basic aqueous solutions (e.g., carbonatebuffer at pH 7–8) was also feasible, but the complete removalof water was challenging, which is imperative for the following postpolymerizationmodification reactions. Being consistent with the kinetic study, quenchingthe polymerization at a predetermined time (9 min), targeting at 50%conversion, yielded the predicted molecular weight and PDI. The degreeof polymerization (DPn) calculated based on 31P NMR spectroscopy-determined monomer conversion was in agreementwith that calculated from chain-end analysis by 1H NMRspectroscopy, i.e., by comparisons of the integrals of proton resonancesof the benzyl group (7.43–7.34 or 5.08 ppm, labeled as a orb, respectively, in Figure 1a) of the initiatedchain end to those of the distinct double bonds (6.49 or 4.06 ppm,labeled as f or g2, respectively, in Figure 1a) or β protons on the substituents to the phosphorusatom (3.94–3.86 ppm, labeled as e in Figure 1a) of 2, which was indicative of retention ofthe vinyl groups (Figure 1a). In addition,one distinct 31P resonance confirmed the stability of thedegradable PPE backbone during ROP of 1 and the work-upprocess of 2. GPC analysis of 2 showed amonomodal peak with PDI of 1.05.


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

Lim YH, Heo GS, Rezenom YH, Pollack S, Raymond JE, Elsabahy M, Wooley KL - Macromolecules (2014)

1H (300 MHz, CD2Cl2, ppm) and 31P (121 MHz, CD2Cl2, ppm, inset) NMRspectra of (a) 2, (b) 3, (c) 4, and (d) 5.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4296319&req=5

fig1: 1H (300 MHz, CD2Cl2, ppm) and 31P (121 MHz, CD2Cl2, ppm, inset) NMRspectra of (a) 2, (b) 3, (c) 4, and (d) 5.
Mentions: The same molar ratio used for the kineticstudy was applied for a scaled-up production of 2. Thepurification of 2 by precipitation in diethyl ether wasinsufficient to remove the residual starting materials and benzoicacid completely. Silica gel column chromatography was also attempted,but instability of the PPE backbone was problematic. Dialysis (MWCO6–8 kDa) of the reaction mixture against organic solvents,switching from MeOH to DCM, was the most assured purification methodamong those tested. Dialysis in basic aqueous solutions (e.g., carbonatebuffer at pH 7–8) was also feasible, but the complete removalof water was challenging, which is imperative for the following postpolymerizationmodification reactions. Being consistent with the kinetic study, quenchingthe polymerization at a predetermined time (9 min), targeting at 50%conversion, yielded the predicted molecular weight and PDI. The degreeof polymerization (DPn) calculated based on 31P NMR spectroscopy-determined monomer conversion was in agreementwith that calculated from chain-end analysis by 1H NMRspectroscopy, i.e., by comparisons of the integrals of proton resonancesof the benzyl group (7.43–7.34 or 5.08 ppm, labeled as a orb, respectively, in Figure 1a) of the initiatedchain end to those of the distinct double bonds (6.49 or 4.06 ppm,labeled as f or g2, respectively, in Figure 1a) or β protons on the substituents to the phosphorusatom (3.94–3.86 ppm, labeled as e in Figure 1a) of 2, which was indicative of retention ofthe vinyl groups (Figure 1a). In addition,one distinct 31P resonance confirmed the stability of thedegradable PPE backbone during ROP of 1 and the work-upprocess of 2. GPC analysis of 2 showed amonomodal peak with PDI of 1.05.

Bottom Line: 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 ((1)H and (31)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.

View Article: PubMed Central - PubMed

Affiliation: Departments of Chemistry, Chemical Engineering, and Materials Science and Engineering, Laboratory for Synthetic-Biologic Interactions, Texas A&M University, P.O. Box 30012, 3255 TAMU, College Station, Texas 77842-3012, United States.

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 ((1)H and (31)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.

No MeSH data available.


Related in: MedlinePlus