title: Controlled curcumin release via conjugation into PBAE nanogels enhances mitochondrial protection against oxidative stress.
abstract: Mitochondria are considered to be the "power plants" of the cell, but can also initiate and execute cell death, stimulated by oxidative stress (OS). OS induced mitochondrial dysfunction is characterized by a loss in oxygen consumption and reduced ATP production. Curcumin, as a potential therapeutic, has been explored as a candidate for mitochondrial OS suppression, but rapid metabolism and aqueous insolubility has prevented it from being effective. Further, efficient delivery of curcumin via the incorporation into nanocarriers has again been limited due to low drug loading capacities and/or significant burst release, resulting in acute cytotoxicity. Hence, to increase the therapeutic potential and reduce the toxic effects of curcumin, curcumin conjugated poly(β-amino ester) nanogels (CNGs) were synthesized using Michael addition chemistry. This approach provided easy control over the nanogel size, with CNGs showing a uniform release of active curcumin over 48h with no burst release. This controlled release system significantly increased the safety limit for curcumin, with a ten fold increase in the cytotoxic threshold, as compared to free curcumin. Further, real-time mitochondrial response analysis with the Seahorse XF96 showed effective and prolonged suppression of H2O2 induced mitochondrial oxidative stress upon pre-treating endothelial cells with CNGs and this potential of nanogels was studied at different pre-treatment times prior to H2O2 exposure.
authors: Department of Chemical and Materials Engineering, F. Paul Anderson Tower, 512 Administration Drive, University of Kentucky, Lexington, KY 40506-0046, USA.
authors: Prachi
authors: P
authors: Gupta
authors: Department of Chemical and Materials Engineering, F. Paul Anderson Tower, 512 Administration Drive, University of Kentucky, Lexington, KY 40506-0046, USA.
authors: Carolyn T
authors: CT
authors: Jordan
authors: Redox Metabolism Shared Resource Facility, Markey Cancer Center, University of Kentucky, 1095 V.A. Drive, Health Sciences Research Building, Room 227, Lexington, KY 40536-0305, USA.
authors: Mihail I
authors: MI
authors: Mitov
authors: Redox Metabolism Shared Resource Facility, Markey Cancer Center, University of Kentucky, 1095 V.A. Drive, Health Sciences Research Building, Room 227, Lexington, KY 40536-0305, USA; Department of Chemistry, Chemistry-Physics Building, University of Kentucky, Lexington, KY 40506, USA.
authors: D Allan
authors: DA
authors: Butterfield
authors: Department of Chemical and Materials Engineering, F. Paul Anderson Tower, 512 Administration Drive, University of Kentucky, Lexington, KY 40506-0046, USA.
authors: J Zach
authors: JZ
authors: Hilt
authors: Department of Chemical and Materials Engineering, F. Paul Anderson Tower, 512 Administration Drive, University of Kentucky, Lexington, KY 40506-0046, USA. Electronic address: dziubla@engr.uky.edu.
authors: Thomas D
authors: TD
authors: Dziubla
mesh_terms: D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D003474:Curcumin / Q000008:administration & dosage* / Q000737:chemistry; D019610:Cytoprotection / Q000187:drug effects* / Q000502:physiology; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D000080385:Nanogels; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000737:chemistry; D011094:Polyethyleneimine / Q000008:administration & dosage* / Q000737:chemistry; D011108:Polymers / Q000008:administration & dosage* / Q000737:chemistry
chemical_list: D003692:Delayed-Action Preparations; D000080385:Nanogels; D011108:Polymers; C507253:poly(beta-amino ester); C413692:polyethylene glycol polyethyleneimine nanogel; D011092:Polyethylene Glycols; D011094:Polyethyleneimine; D003474:Curcumin
keywords: Curcumin release; Nanogels; Poly(β-amino esters); Seahorse bioscience XF96