pH-Triggered Release of Macromolecules from Spray-Dried Polymethacrylate Microparticles

Purpose. pH-triggered microparticles release their therapeutic payloads at acidic pH (e.g., in the phagosome), making intracellular drug delivery more efficient. Here we modify lipid-based microparticles that are safe and efficacious in nerve and brain and are potentially inhalable, making them pH-triggerable by incorporating an acid-soluble polymethacrylate, Eudragit E100 (E100). Methods. Microparticles were produced by spray-drying and characterized by electron microscopy, Coulter counting, density measurement, and release kinetics of fluorescently labeled proteins. In addition, biocompatibility and cellular uptake were observed in rats. Results. Microparticles were spheroids 3 to 5 m in diameter with densities of 0.12 to 0.25 g/L. Microparticles with 20% (w/w) or more E100 demonstrated slow release of fluorescently labeled proteins at pH 7.4 but rapid release at pH 5. pH-triggerability was maintained for over 2 weeks in solution. Protein loadings of 0.2-20% (w/w) were pH-triggerable. Histologic examination of particles in rat connective tissue near nerve and muscle demonstrated biocompatibility aside from muscle edema in the cell layers adjacent to the particles and a localized inflammatory reaction with macrophages laden with microparticles. Conclusions. Microparticles containing E100 were pH-triggerable for many days and were taken up by macrophages, suggesting that they may be useful for intracellular drug delivery.