Tuning H₂S Release by Controlling Mobility in a Micelle Core

Abstract

Drug delivery from polymer micelles has been widely studied, but methods to precisely tune rates of drug release from micelles are limited. Here, the mobility of hydrophobic micelle cores was varied to tune the rate at which a covalently bound drug was released. This concept was applied to cysteine-triggered release of hydrogen sulfide (H 2 S), a signaling gas with therapeutic potential. In this system, thiol-triggered H 2 S donor molecules were covalently linked to the hydrophobic blocks of self-assembled polymer amphiphiles. Because release of H 2 S is triggered by cysteine, diffusion of cysteine into the hydrophobic micelle core was hypothesized to control the rate of release. We confirmed this hypothesis by carrying out release experiments from H 2 S-releasing micelles in varying compositions of EtOH/H 2 O. Higher EtOH concentrations caused the micelles to swell, facilitating diffusion in and out of their hydrophobic cores and leading to faster H 2 S release from the micelles. To achieve a similar effect without addition of organic solvent, we prepared micelles with varying core mobility via incorporation of a plasticizing co-monomer in the core-forming block. The glass transition temperature (T g ) of the core block could therefore be precisely varied by changing the amount of the plasticizing co-monomer in the polymer. In aqueous solution under identical conditions, the release rate of H 2 S varied over 20-fold (t ½ = 0.18 -4.2 h), with the lowest T g hydrophobic block resulting in the fastest H 2 S release. This method of modulating release kinetics from polymer micelles by tuning core mobility may be applicable to many types of physically encapsulated and covalently linked small molecules in a variety of drug delivery systems.

Supramolecular Tuning of H2S Release from Aromatic Peptide Amphiphile Gels: Effect of Core Unit Substituents

“…We recently saw similar effects in SATO-containing polymer micelles, which released H 2 S ~10-fold more slowly than analogous small SATO molecules. 38 In concentrated solution experiments (10 mg/mL), APAs 1-2 showed longer H 2 S peaking times (160-240 min) compared to APAs 4-5 (100-160 min), a trend that was consistent with the dilute solution release results. APAs 4 and 5 also had higher peaking concentrations, which tends to occur with faster-releasing H 2 S donors because more H 2 S builds up before it oxidizes and volatilizes.…”

“…Penetration of Cys into the hydrogels could be affected by many factors, including the rigidity of the supramolecular nanostructures and gel mesh size. 38,59 Overall, limited Cys penetration led to lower peaking concentrations (C max ) and much shorter peaking times for the gels than for the solutions. While the data appear to show much less overall release from the gels, the only difference between the two is the CaCl 2 gelating agent.…”

“…The methylene blue method is a widely employed colorimetric assay to detect H 2 S release. 22,36,38 Although it can lead to erroneous data in biological media, 39 we have found that it works well for measuring cumulative kinetics of H 2 S release in aqueous solution. 38 By converting N,N-dimethyl-p-phenylenediamine into methylene blue in the presence of trapped H 2 S, the absorbance at 750 nm indicates H 2 S concentration in solution.…”

“…22,36,38 Although it can lead to erroneous data in biological media, 39 we have found that it works well for measuring cumulative kinetics of H 2 S release in aqueous solution. 38 By converting N,N-dimethyl-p-phenylenediamine into methylene blue in the presence of trapped H 2 S, the absorbance at 750 nm indicates H 2 S concentration in solution. 39 In contrast to the methylene blue method, the H 2 S-sensitive electrode probe detects a wider concentration range of H 2 S and shows H 2 S release data in real-time.…”

“…The H 2 S release half-lives of dilute (0.1 mg/mL) APA solutions were determined by the methylene blue assay using previously reported conditions. 38 By fitting the cumulative release data to pseudo-first-order kinetics (Table S2), we found that half-lives of release ranged from 13 min (APA 5) to 31 min (APA 1). The data revealed a correlation between H 2 S release kinetics and Hammett σ values of the para-substituents ( Figure S4), with the Hammett plot showing a ρ value of 0.77, which is close to our previously reported ρ value of 1.05 for small molecule analogues of these APAs.…”