title: Cell protective, ABC triblock polymer-based thermoresponsive hydrogels with ROS-triggered degradation and drug release.
abstract: A combination of anionic and RAFT polymerization was used to synthesize an ABC triblock polymer poly[(propylenesulfide)-block-(N,N-dimethylacrylamide)-block-(N-isopropylacrylamide)] (PPS-b-PDMA-b-PNIPAAM) that forms physically cross-linked hydrogels when transitioned from ambient to physiologic temperature and that incorporates mechanisms for reactive oxygen species (ROS) triggered degradation and drug release. At ambient temperature (25 °C), PPS-b-PDMA-b-PNIPAAM assembled into 66 ± 32 nm micelles comprising a hydrophobic PPS core and PNIPAAM on the outer corona. Upon heating to physiologic temperature (37 °C), which exceeds the lower critical solution temperature (LCST) of PNIPAAM, micelle solutions (at ≥2.5 wt %) sharply transitioned into stable, hydrated gels. Temperature-dependent rheology indicated that the equilibrium storage moduli (G') of hydrogels at 2.5, 5.0, and 7.5 wt % were 20, 380, and 850 Pa, respectively. The PPS-b-PDMA-b-PNIPAAM micelles were preloaded with the model drug Nile red, and the resulting hydrogels demonstrated ROS-dependent drug release. Likewise, exposure to the peroxynitrite generator SIN-1 degraded the mechanical properties of the hydrogels. The hydrogels were cytocompatible in vitro and were demonstrated to have utility for cell encapsulation and delivery. These hydrogels also possessed inherent cell-protective properties and reduced ROS-mediated cellular death in vitro. Subcutaneously injected PPS-b-PDMA-b-PNIPAAM polymer solutions formed stable hydrogels that sustained local release of the model drug Nile red for 14 days in vivo. These collective data demonstrate the potential use of PPS-b-PDMA-b-PNIPAAM as an injectable, cyto-protective hydrogel that overcomes conventional PNIPAAM hydrogel limitations such as syneresis, lack of degradability, and lack of inherent drug loading and environmentally responsive release mechanisms.
authors.affiliation: Biomedical Engineering, Vanderbilt University , Nashville, Tennessee 37235, United States.
authors.forename: Mukesh K
authors.initials: MK
authors.lastname: Gupta
authors.forename: John R
authors.initials: JR
authors.lastname: Martin
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Werfel
authors.forename: Tianwei
authors.initials: T
authors.lastname: Shen
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Page
authors.forename: Craig L
authors.initials: CL
authors.lastname: Duvall
mesh_terms: D000178:Acrylamides / Q000737:chemistry; D000180:Acrylic Resins / Q000737:chemistry; D000818:Animals; D001672:Biocompatible Materials / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D004337:Drug Carriers / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D065546:Drug Liberation; D020100:Hydrogels / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D008823:Micelles; D008958:Models, Molecular; D008968:Molecular Conformation; D041681:NIH 3T3 Cells; D010078:Oxazines / Q000737:chemistry; D011108:Polymers / Q000737:chemistry*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012212:Rheology; D013440:Sulfides / Q000737:chemistry; D013696:Temperature
chemical_list: D000178:Acrylamides; D000180:Acrylic Resins; D001672:Biocompatible Materials; D004337:Drug Carriers; D020100:Hydrogels; D008823:Micelles; D010078:Oxazines; D011108:Polymers; D017382:Reactive Oxygen Species; D013440:Sulfides; C429790:poly(N,N-dimethylacrylamide); C522256:poly(propylene sulfide); C052970:poly-N-isopropylacrylamide; C044808:nile red