Tuning small molecule release from polymer micelles: Varying HS release through cross linking in the micelle core.

Polymer micelles, used extensively as vehicles in the delivery of active pharmaceutical ingredients, represent a versatile polymer architecture in drug delivery systems. We hypothesized that degree of crosslinking in the hydrophobic core of amphiphilic block copolymer micelles could be used to tune the rate of release of the biological signaling gas (gasotransmitter) hydrogen sulfide (HS), a potential therapeutic. To test this hypothesis, we first synthesized amphiphilic block copolymers of the structure PEG--P(FBEA) (PEG = poly(ethylene glycol), FBEA = 2-(4-formylbenzoyloxy)ethyl acrylate). Using a modified arm-first approach, we then varied the crosslinking percentage in the core-forming block addition of a alkanediyl bis(hydroxylamine) crosslinking agent. We followed incorporation of the crosslinker by H NMR spectroscopy, monitoring the appearance of the oxime signal resulting from reaction of pendant aryl aldehydes on the block copolymer with hydroxylamines on the crosslinker, which revealed crosslinking percentages of 5, 10, and 15%. We then installed HS-releasing -aroylthiooxime (SATO) groups on the crosslinked polymers, yielding micelles with SATO units in their hydrophobic cores after self-assembly in water. HS release studies in water, using cysteine (Cys) as a trigger to induce HS release from the SATO groups in the micelle core, revealed increasing half-lives of HS release, from 117 ± 6 min to 210 ± 30 min, with increasing crosslinking density in the micelle core. This result was consistent with our hypothesis, and we speculate that core crosslinking limits the rate of Cys diffusion into the micelle core, decreasing the release rate. This method for tuning the release of covalently linked small molecules through modulation of micelle core crosslinking density may extend beyond HS to other drug delivery systems where precise control of release rate is needed.