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Quercetin conjugated poly(β-amino esters) nanogels for the treatment of cellular oxidative stress.
Acta Biomater. 2015 Nov; 27:194-204.AB

Abstract

PβAE polymers have emerged as highly promising candidates for biomedical and drug delivery applications owing to their tunable, degradable and pH sensitive properties. These polymeric systems can serve as prodrug carriers for the delivery of bioactive compounds which suffer from poor aqueous solubility, low bioavailability and are biologically unstable, such as the antioxidant, quercetin. Using acrylate functionalized quercetin, it is possible to incorporate the polyphenol into the backbone of the polymer matrix, permitting slow release of the intact molecule which is perfectly timed with the polymer degradation. While formulating these quercetin conjugated PβAE matrix into nanocarriers would allow for multiple delivery routes (oral, intravenous, inhalation etc.), well known oil-water nano-emulsion formulation methods are not amenable to the crosslinked hydrolytically sensitive nanoparticle/nanogel. In this work, a single-phase reaction-precipitation method was developed to formulate quercetin conjugated PβAE nanogels (QNG) via reaction of acrylated quercetin (4-5 acrylate groups) with a secondary diamine under dilute conditions using acetonitrile as the reaction medium, resulting in a self-stabilized suspension. The proposed approach permits the post synthesis modification of the spherical nanogels with a PEGylated coating, enhancing their aqueous stability and stealth characteristics. Nanogel size was controlled by varying feed reactant concentrations, achieving drug loadings of 25-38wt%. Uniform release of quercetin over 45-48h was observed upon PβAE ester hydrolysis under physiological conditions with its retained antioxidant activity over the extended times.

STATEMENT OF SIGNIFICANCE

Here we present the first demonstration of using poly(beta amino ester) chemistry to form nanogels composed of a bioactive polyphenol for the control of cellular oxidative stress. Previous nanogel and nanoparticle approaches, which use a water phase, are not readily amenable to PBAE chemistry due to their hydrolytic sensitivity. Here we demonstrate a simple approach to control particle size, modify surface chemistry and achieve highly regulated controlled release of active antioxidants, which can protect cells against external oxidative stress signals. This work has importance in the area of controlling material biocompatibility through augmenting the antioxidant status of cells.

Authors+Show Affiliations

Department of Chemical and Materials Engineering, University of Kentucky, Lexington, KY 40506-0046, USA.Department of Chemical and Materials Engineering, University of Kentucky, Lexington, KY 40506-0046, USA.Department of Chemical and Materials Engineering, University of Kentucky, Lexington, KY 40506-0046, USA.Department of Chemical and Materials Engineering, University of Kentucky, Lexington, KY 40506-0046, USA. Electronic address: dziubla@engr.uky.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

26318804

Citation

Gupta, Prachi, et al. "Quercetin Conjugated Poly(β-amino Esters) Nanogels for the Treatment of Cellular Oxidative Stress." Acta Biomaterialia, vol. 27, 2015, pp. 194-204.
Gupta P, Authimoolam SP, Hilt JZ, et al. Quercetin conjugated poly(β-amino esters) nanogels for the treatment of cellular oxidative stress. Acta Biomater. 2015;27:194-204.
Gupta, P., Authimoolam, S. P., Hilt, J. Z., & Dziubla, T. D. (2015). Quercetin conjugated poly(β-amino esters) nanogels for the treatment of cellular oxidative stress. Acta Biomaterialia, 27, 194-204. https://doi.org/10.1016/j.actbio.2015.08.039
Gupta P, et al. Quercetin Conjugated Poly(β-amino Esters) Nanogels for the Treatment of Cellular Oxidative Stress. Acta Biomater. 2015;27:194-204. PubMed PMID: 26318804.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Quercetin conjugated poly(β-amino esters) nanogels for the treatment of cellular oxidative stress. AU - Gupta,Prachi, AU - Authimoolam,Sundar P, AU - Hilt,J Zach, AU - Dziubla,Thomas D, Y1 - 2015/08/28/ PY - 2015/04/07/received PY - 2015/08/15/revised PY - 2015/08/25/accepted PY - 2015/8/31/entrez PY - 2015/9/1/pubmed PY - 2016/8/5/medline KW - Antioxidants KW - Endothelial cells KW - Nanogels KW - Oxidative stress KW - Poly(β-amino esters) KW - Quercetin SP - 194 EP - 204 JF - Acta biomaterialia JO - Acta Biomater VL - 27 N2 - UNLABELLED: PβAE polymers have emerged as highly promising candidates for biomedical and drug delivery applications owing to their tunable, degradable and pH sensitive properties. These polymeric systems can serve as prodrug carriers for the delivery of bioactive compounds which suffer from poor aqueous solubility, low bioavailability and are biologically unstable, such as the antioxidant, quercetin. Using acrylate functionalized quercetin, it is possible to incorporate the polyphenol into the backbone of the polymer matrix, permitting slow release of the intact molecule which is perfectly timed with the polymer degradation. While formulating these quercetin conjugated PβAE matrix into nanocarriers would allow for multiple delivery routes (oral, intravenous, inhalation etc.), well known oil-water nano-emulsion formulation methods are not amenable to the crosslinked hydrolytically sensitive nanoparticle/nanogel. In this work, a single-phase reaction-precipitation method was developed to formulate quercetin conjugated PβAE nanogels (QNG) via reaction of acrylated quercetin (4-5 acrylate groups) with a secondary diamine under dilute conditions using acetonitrile as the reaction medium, resulting in a self-stabilized suspension. The proposed approach permits the post synthesis modification of the spherical nanogels with a PEGylated coating, enhancing their aqueous stability and stealth characteristics. Nanogel size was controlled by varying feed reactant concentrations, achieving drug loadings of 25-38wt%. Uniform release of quercetin over 45-48h was observed upon PβAE ester hydrolysis under physiological conditions with its retained antioxidant activity over the extended times. STATEMENT OF SIGNIFICANCE: Here we present the first demonstration of using poly(beta amino ester) chemistry to form nanogels composed of a bioactive polyphenol for the control of cellular oxidative stress. Previous nanogel and nanoparticle approaches, which use a water phase, are not readily amenable to PBAE chemistry due to their hydrolytic sensitivity. Here we demonstrate a simple approach to control particle size, modify surface chemistry and achieve highly regulated controlled release of active antioxidants, which can protect cells against external oxidative stress signals. This work has importance in the area of controlling material biocompatibility through augmenting the antioxidant status of cells. SN - 1878-7568 UR - https://www.unboundmedicine.com/medline/citation/26318804/Quercetin_conjugated_poly_β_amino_esters__nanogels_for_the_treatment_of_cellular_oxidative_stress_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1742-7061(15)30083-0 DB - PRIME DP - Unbound Medicine ER -