Poly(PS-b-DMA) micelles for reactive oxygen species triggered drug release.
A new micelle drug carrier that consists of a diblock polymer of propylene sulfide (PS) and N,N-dimethylacrylamide (poly(PS₇₄-b-DMA₃₁₀)) has been synthesized and characterized for site-specific release of hydrophobic drugs to sites of inflammation. Propylene sulfide was first polymerized using a thioacyl group transfer (TAGT) method with the RAFT chain transfer agent (CTA) 4-cyano-4-(ethylsulfanylthiocarbonylsulfanyl) pentanoic acid (CEP), and the resultant poly(PS₇₄-CEP) macro-CTA was used to polymerize a second polymer block of DMA using reversible addition-fragmentation chain transfer (RAFT). The formation of the poly(PS₇₄-b-DMA₃₁₀) diblock polymer was confirmed by ¹H NMR spectra and gel permeation chromatography (GPC). Poly(PS₇₄-b-DMA₃₁₀) formed 100 nm micelles in aqueous media as confirmed by dynamic light scattering (DLS) and transmission electron microscopy (TEM). Micelles loaded with the model drugs Nile red and DiO were used to demonstrate the ROS-dependent drug release mechanism of these micelles following treatment with hydrogen peroxide (H₂O₂), 3-morpholinosydnonimine (SIN-1), and peroxynitrite. These oxidants were found to oxidize the micelle PPS core, making it more hydrophilic and triggering micelle disassembly and cargo release. Delivery of poly(PS₇₄-b-DMA₃₁₀) micelles dual-loaded with the Förster Resonance Energy Transfer (FRET) fluorophore pair DiI and DiO was used to prove that endogenous oxidants generated by lipopolysaccharide (LPS)-treated RAW 264.7 macrophages significantly increased release of nanocarrier contents relative to macrophages that were not activated. In vitro studies also demonstrated that the poly(PS₇₄-b-DMA₃₁₀) micelles were cytocompatible across a broad range of concentrations. These combined data suggest that the poly(PS₇₄-b-DMA₃₁₀) micelles synthesized using a combination of TAGT and RAFT have significant potential for site-specific drug delivery to tissues with high levels of oxidative stress.
Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA.
Mukesh K
MK
Gupta
Travis A
TA
Meyer
Christopher E
CE
Nelson
Craig L
CL
Duvall
D000180:Acrylic Resins / Q000008:administration & dosage / Q000737:chemistry*; D000818:Animals; D002232:Carbocyanines / Q000008:administration & dosage / Q000737:chemistry; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry*; D005456:Fluorescent Dyes / Q000008:administration & dosage / Q000737:chemistry; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008823:Micelles; D010078:Oxazines / Q000008:administration & dosage / Q000737:chemistry; D017382:Reactive Oxygen Species / Q000737:chemistry* / Q000378:metabolism; D013440:Sulfides / Q000008:administration & dosage / Q000737:chemistry*
C035005:3,3'-dihexadecylindocarbocyanine; D000180:Acrylic Resins; D002232:Carbocyanines; D004337:Drug Carriers; D005456:Fluorescent Dyes; D008823:Micelles; D010078:Oxazines; D017382:Reactive Oxygen Species; D013440:Sulfides; C578343:poly(propylene sulfide-block-N,N-dimethylacrylamide); C098044:3,3'-dioctadecyloxacarbocyanine; D007770:L-Lactate Dehydrogenase; C044808:nile red