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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: 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 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.

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

Self-assemblyresults of micelle 7 in water. (a) DLSresults of 7: Dh(intensity) = 49 ± 7 nm, Dh(volume) = 46 ±7 nm, and Dh(number) = 44 ± 6 nm(PDI = 0.114). (b) TEM image of 7: Dav = 39 ± 5 nm, after counting more than 150 nanoparticles.AFM height image (c) and three-dimensional image (d) of 7: Dav = 40 ± 7 nm, after countingmore than 100 nanoparticles.
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fig3: Self-assemblyresults of micelle 7 in water. (a) DLSresults of 7: Dh(intensity) = 49 ± 7 nm, Dh(volume) = 46 ±7 nm, and Dh(number) = 44 ± 6 nm(PDI = 0.114). (b) TEM image of 7: Dav = 39 ± 5 nm, after counting more than 150 nanoparticles.AFM height image (c) and three-dimensional image (d) of 7: Dav = 40 ± 7 nm, after countingmore than 100 nanoparticles.

Mentions: The self-assembly behavior of the amphiphilicdiblock copolymer,mPEG44-b-PEVEP336, was studied by direct dissolution in nanopure water. A high concentrationof 6 could be dispersed in nanopure water or buffer (>15mg/mL) without a significant turbidity or precipitation, which allowedfor analyses to be performed across a broad range of concentrationsand also serves as a promising criterion for its use as a drug deliverycarrier. The morphology and surface charge of the resulting micellarnanoparticles, 7, were characterized by dynamic lightscattering (DLS), transmission electron microscopy (TEM), atomic forcemicroscopy (AFM), and ζ-potential measurements (Figure 3 and Figure S4). DLSand ζ-potential analyses indicated narrow and monomodal sizedistributions (PDI = 0.114) with almost neutral charges and a negligibledifference at pH 5.0 and 7.4, −4.52 and −7.64 mV, respectively.The number-averaged hydrodynamic diameter of 7 by DLSwas ca. 44 ± 6 nm. The TEM images also revealed uniform nanoparticleswith an average diameter of 39 ± 5 nm. Although the hydrodynamicand dry-state diameters measured by DLS and TEM, respectively, werein agreement, AFM indicated significant deformation of the micellesupon deposition and drying on the mica substrate. The ca. 3 nm heightand 40 ± 7 nm diameter indicate flattening of the micelles, whichis predicted to occur based upon the fluid shell and core components,each being composed of a highly viscous polymer, PEG (Tg = −17 °C) and PEVEP (Tg = −39 °C, Table 1 and Figure S9). The AFM data are useful qualitatively;however, further quantitative analysis is complicated by the presenceof substantial amounts of polymer debris and agglomerations of 7 across the substrate (Figure 3c,d),which are also indicators of the fluidity of the micellar assemblies.


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)

Self-assemblyresults of micelle 7 in water. (a) DLSresults of 7: Dh(intensity) = 49 ± 7 nm, Dh(volume) = 46 ±7 nm, and Dh(number) = 44 ± 6 nm(PDI = 0.114). (b) TEM image of 7: Dav = 39 ± 5 nm, after counting more than 150 nanoparticles.AFM height image (c) and three-dimensional image (d) of 7: Dav = 40 ± 7 nm, after countingmore than 100 nanoparticles.
© Copyright Policy
Related In: Results  -  Collection

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

fig3: Self-assemblyresults of micelle 7 in water. (a) DLSresults of 7: Dh(intensity) = 49 ± 7 nm, Dh(volume) = 46 ±7 nm, and Dh(number) = 44 ± 6 nm(PDI = 0.114). (b) TEM image of 7: Dav = 39 ± 5 nm, after counting more than 150 nanoparticles.AFM height image (c) and three-dimensional image (d) of 7: Dav = 40 ± 7 nm, after countingmore than 100 nanoparticles.
Mentions: The self-assembly behavior of the amphiphilicdiblock copolymer,mPEG44-b-PEVEP336, was studied by direct dissolution in nanopure water. A high concentrationof 6 could be dispersed in nanopure water or buffer (>15mg/mL) without a significant turbidity or precipitation, which allowedfor analyses to be performed across a broad range of concentrationsand also serves as a promising criterion for its use as a drug deliverycarrier. The morphology and surface charge of the resulting micellarnanoparticles, 7, were characterized by dynamic lightscattering (DLS), transmission electron microscopy (TEM), atomic forcemicroscopy (AFM), and ζ-potential measurements (Figure 3 and Figure S4). DLSand ζ-potential analyses indicated narrow and monomodal sizedistributions (PDI = 0.114) with almost neutral charges and a negligibledifference at pH 5.0 and 7.4, −4.52 and −7.64 mV, respectively.The number-averaged hydrodynamic diameter of 7 by DLSwas ca. 44 ± 6 nm. The TEM images also revealed uniform nanoparticleswith an average diameter of 39 ± 5 nm. Although the hydrodynamicand dry-state diameters measured by DLS and TEM, respectively, werein agreement, AFM indicated significant deformation of the micellesupon deposition and drying on the mica substrate. The ca. 3 nm heightand 40 ± 7 nm diameter indicate flattening of the micelles, whichis predicted to occur based upon the fluid shell and core components,each being composed of a highly viscous polymer, PEG (Tg = −17 °C) and PEVEP (Tg = −39 °C, Table 1 and Figure S9). The AFM data are useful qualitatively;however, further quantitative analysis is complicated by the presenceof substantial amounts of polymer debris and agglomerations of 7 across the substrate (Figure 3c,d),which are also indicators of the fluidity of the micellar assemblies.

Bottom Line: 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 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.

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