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.