Tunable polymeric microparticles may serve as vehicles by which to transport small molecule anti-inflammatory therapeutics targeting alveolar macrophages. We apply a thiol-Michael addition reaction-based dispersion polymerization method to generate highly mono-disperse microparticles with tunable size variable by weight percent monomer in solution during synthesis as follows: 0.4% (0.8 +/- 0.2 um), 0.45% (0.9 +/- 0.2 um), 0.5% (1.4 +/- 0.3 um), 1% (1.9 +/- 0.2 um), 2.5% (2.9 +/- 0.4 um), 5% (4 +/- 0.5 um), 7.5% (5.2 +/- 0.9 um), 10% (7.4 +/- 1.6 um), 12.5% (10 +/- 5.4 um), and 15% (8.6 +/- 6.9 um). Furthermore, the customizable nature of the particles lends itself to developing the specificity required for targeted delivery. In this research, the monomers di(trimethylolpropane) tetraacrylate (DTPTA) and dipentaerythritol hexa-3-mercaptopropionate (DPHMP) were used to synthesize particles by a triethylamine-catalyzed dispersion reaction. Off-stoichiometry of the thiol:ene ratio was used to control the degree of crosslinking and allow further functionalization of the microparticles. Subsequently, free thiols were functionalized with iodoacetamide, N-(3-aminopropyl)methacrylamide hydrochloride, or n-methylmaleimide to yield amide, amine, or methyl functionality, respectively; likewise, free acrylates were reacted with 3-mercaptopropionic acid to yield carboxyl functionality. These particles were characterized by SEM, FTIR, zeta potential, Fluoraldehyde and Ellman’s assays, and fluorophore functionalization, which confirmed that intended chemical composition had been achieved.<br/>In parallel, a small molecule inhibitor, T61267923, of the MyD88-dependent inflammatory pathway was conjugated to PEG, as confirmed by transient monitoring of reactant functional group consumption, to enhance its water solubility. The synthesized treatment molecules were exposed to RAW 264.7 murine spleen macrophage-like cells with successive activation of the inflammatory pathway with TLR-2 agonist Pam3CSK4. To quantify the extent of inhibitor efficacy, alamarBlue viability assay, ELISA, and qPCR were performed; results indicate negligible reduction in viability with evidence of decreased IL-6 cytokine production following treatment. Further studies are underway to explore therapeutic microparticle conjugation and delivery mechanisms as well as characterize microparticle distribution to, uptake by, and degradation in macrophages for the purpose of targeting lung-specific conditions.

Tunable polymeric microparticle-facilitated delivery of anti-inflammatory therapeutics to the lungs

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