Limits...
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

Study of the micelle stability by using DLS.Changes in the hydrodynamicdiameter of micelles at pH 5.0 (a) or pH 7.4 (b) and at a temperatureof 25 °C (black line) or 37 °C (red line) over a periodof time. (c) Changes in the relative intensity of micelles in differentenvironments, pH and temperature, over a period of time. The averagevalues and their standard deviations, from three measurements, areshown.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4296319&req=5

fig6: Study of the micelle stability by using DLS.Changes in the hydrodynamicdiameter of micelles at pH 5.0 (a) or pH 7.4 (b) and at a temperatureof 25 °C (black line) or 37 °C (red line) over a periodof time. (c) Changes in the relative intensity of micelles in differentenvironments, pH and temperature, over a period of time. The averagevalues and their standard deviations, from three measurements, areshown.

Mentions: It was hypothesizedthat hydrolysis of the PPE backbone would decrease the proportionof the hydrophobic:hydrophilic block segment ratio and that hydrolysisof the side chain vinyl ether groups would increase the hydrophilicityof the PPE backbone; thereby, each would weaken the micelle assemblies.In order to demonstrate the effects of pH-dependent hydrolytic degradationof the polymer on the behavior and stability of the micelles, 7, aqueous buffer solutions containing 6 at pH5.0 and 7.4 were incubated at 25 and 37 °C, and their degradationprofiles were assessed by measuring the changes in hydrodynamic diameterand the intensity of light, scattered by micelles, when measured byDLS over a period of time (Figure 6). Overall,as predicted from the NMR degradation studies, the micelle assembliesin pH 5.0 aqueous solutions, at both 25 and 37 °C, became unstablewithin 1 day, and the nanoparticles were undetectable within 7 and2 days, respectively. The swelling behavior of the micelles upon hydrolysisof PEVEP segment was accounted for by the diffusion of water intothe core region (Figure 6a). Interestingly,the unstable and dissociated micelles did not cause the formationof visible precipitates, and thus, the micelle solutions remainedclear during monitoring. Also, in agreement with the lack of backboneor side chain hydrolysis observed by NMR spectroscopy, the nanoparticlesizes in pH 7.4 aqueous solutions at 25 °C remained consistentover 39 days (Figure 6b). Surprisingly, whenthe samples were incubated at pH 7.4 and 37 °C, large aggregatesformed after 20 days, which persisted until day 43 when particleswere no longer detectable. The lack of changes in the NMR data overthe same period of time and conditions suggests that transesterificationreactions may be a possible chemical change that produced subsequentmorphological changes. In accordance with these observations, theintensity of light, scattered by the nanoparticles, as measured byDLS, was also dependent on the pH of water and temperature (Figure 6c). In the case of nanoparticles in pH 5.0 aqueoussolutions, both at 25 and 37 °C, the signal intensities becameweaker rapidly, reaching below 20% as compared to the initial intensity,and finally were undetectable within a week. The signal intensityof light scattered by micelles in pH 7.4 aqueous solution at 37 °Cdecreased gradually over a period of month. Meanwhile, there was nosignificant change in the signal intensity for the micelles in pH7.4 aqueous solution at 25 °C throughout the monitoring period.Taken together, the acidity of solutions was the primary determinantof the micelle stability.


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)

Study of the micelle stability by using DLS.Changes in the hydrodynamicdiameter of micelles at pH 5.0 (a) or pH 7.4 (b) and at a temperatureof 25 °C (black line) or 37 °C (red line) over a periodof time. (c) Changes in the relative intensity of micelles in differentenvironments, pH and temperature, over a period of time. The averagevalues and their standard deviations, from three measurements, areshown.
© Copyright Policy
Related In: Results  -  Collection

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

fig6: Study of the micelle stability by using DLS.Changes in the hydrodynamicdiameter of micelles at pH 5.0 (a) or pH 7.4 (b) and at a temperatureof 25 °C (black line) or 37 °C (red line) over a periodof time. (c) Changes in the relative intensity of micelles in differentenvironments, pH and temperature, over a period of time. The averagevalues and their standard deviations, from three measurements, areshown.
Mentions: It was hypothesizedthat hydrolysis of the PPE backbone would decrease the proportionof the hydrophobic:hydrophilic block segment ratio and that hydrolysisof the side chain vinyl ether groups would increase the hydrophilicityof the PPE backbone; thereby, each would weaken the micelle assemblies.In order to demonstrate the effects of pH-dependent hydrolytic degradationof the polymer on the behavior and stability of the micelles, 7, aqueous buffer solutions containing 6 at pH5.0 and 7.4 were incubated at 25 and 37 °C, and their degradationprofiles were assessed by measuring the changes in hydrodynamic diameterand the intensity of light, scattered by micelles, when measured byDLS over a period of time (Figure 6). Overall,as predicted from the NMR degradation studies, the micelle assembliesin pH 5.0 aqueous solutions, at both 25 and 37 °C, became unstablewithin 1 day, and the nanoparticles were undetectable within 7 and2 days, respectively. The swelling behavior of the micelles upon hydrolysisof PEVEP segment was accounted for by the diffusion of water intothe core region (Figure 6a). Interestingly,the unstable and dissociated micelles did not cause the formationof visible precipitates, and thus, the micelle solutions remainedclear during monitoring. Also, in agreement with the lack of backboneor side chain hydrolysis observed by NMR spectroscopy, the nanoparticlesizes in pH 7.4 aqueous solutions at 25 °C remained consistentover 39 days (Figure 6b). Surprisingly, whenthe samples were incubated at pH 7.4 and 37 °C, large aggregatesformed after 20 days, which persisted until day 43 when particleswere no longer detectable. The lack of changes in the NMR data overthe same period of time and conditions suggests that transesterificationreactions may be a possible chemical change that produced subsequentmorphological changes. In accordance with these observations, theintensity of light, scattered by the nanoparticles, as measured byDLS, was also dependent on the pH of water and temperature (Figure 6c). In the case of nanoparticles in pH 5.0 aqueoussolutions, both at 25 and 37 °C, the signal intensities becameweaker rapidly, reaching below 20% as compared to the initial intensity,and finally were undetectable within a week. The signal intensityof light scattered by micelles in pH 7.4 aqueous solution at 37 °Cdecreased gradually over a period of month. Meanwhile, there was nosignificant change in the signal intensity for the micelles in pH7.4 aqueous solution at 25 °C throughout the monitoring period.Taken together, the acidity of solutions was the primary determinantof the micelle stability.

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