Poly(PS-b-DMA) micelles for reactive oxygen species triggered drug release

Abstract

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.

Lipophilic siRNA targets albumin in situ and promotes bioavailability, tumor penetration, and carrier-free gene silencing

“…Oligonucleotide-L 2 characterization. Critical micelle concentration (CMC) of oligo-L 2 was assessed fluorescently using Nile red, as described previously (65,66). Briefly, different dilutions were prepared from a 1 mg/mL stock solution to obtain micelle samples ranging in concentration from 0.0001 to 1 mg/mL Then, 10 μL of a 1 mg/mL Nile red stock solution in methanol was added to 1 mL of each sample and incubated overnight in the dark at room temperature.…”

Reactive Oxygen Species-Activated Nanomaterials as Theranostic Agents

“…For aqueous stability, hydrophilic ends are generally added, making up micelle forming A-B-A block copolymer. Some variations of PPS-based materials include, diblock PEG-b-PPS, PPS-b-poly dimethyl acrylamide, small PPS-PEG (20, 45, 100 nm) and polymers conjugated to model antigen [72,73]. …”

Exploiting Oxidative Microenvironments in the Body as Triggers for Drug Delivery Systems

“…On oxidation, thioether moieties are converted into sulfones and sulfoxides that create highly hydrophilic molecules due to the strong dipole between oxygen and sulfur. At the molecular level, the increase in polarity and water affinity (solvation) leads to morphological disruption (76,139) (Fig. 5a, b) or swelling and solubilization (3,149) (Fig.…”

“…Studies in activated macrophages and neutrophils have demonstrated that several systems, including a boronic estermodified polymeric particle (45), a polymer-based hydrogel cross-linked with proline oligomers (202), and micelles composed of a poly(propylene sulfide) (PPS) core (76), respond to biological levels of H 2 O 2 . The first of these studies was especially well controlled, as it compared responsiveness of the designed ROS-sensitive polymer with that of poly(lactic-co-glycolic) acid (PLGA) and a control polymer lacking ROS-reactive groups; neither control releases cargo in response to activated neutrophils (45).…”

“…This finding may lead to the polymer's use in targeting drugs to tissues that are characterized by a high level of neutrophils (e.g., inflammatory diseases such as SIRS and COPD). Though the PPS micelle study only demonstrated a 10% difference between release induced by activated and nonactivated macrophages, their release assay was creative: a reduction in fluorescence resonance energy transfer between co-encapsulated dyes (76). Systems such as this that were demonstrated to respond to activated macrophages could prove useful for targeting drugs to sites which are rich in these cells, such as vulnerable atherosclerotic plaques.…”