Optimization of rapamycin-loaded acetalated dextran microparticles for immunosuppression

Abstract

Immunosuppressive drugs can treat autoimmune disorders and limit rejection with organ transplants. However, delivering immunosuppressants like rapamycin systemically can have harmful side-effects. We aim to potentially reduce these toxic side-effects by encapsulating rapamycin in a polymeric microparticle to passively target phagocytes, the cells integral in immunosuppression. Acetalated dextran (Ac-DEX) is a recently described, biocompatible polymer which undergoes tunable burst degradation at the acidic conditions present in the phagosome (pH 5) but slower degradation at extracellular conditions (pH 7.4), thereby making it an ideal candidate for immune applications. Rapamycin-loaded microparticles were fabricated from Ac-DEX through a single emulsion (water/oil) technique. Optimized microparticles were determined by varying the chemical and physical parameters during particle synthesis. Microparticles synthesized from Ac-DEX with a molecular weight of 71k had higher encapsulation efficiency of rapamycin and slower overall degradation than microparticles synthesized from 10k Ac-DEX. To evaluate the ability of rapamycin-loaded Ac-DEX microparticles to reduce a pro-inflammatory response, they were incubated with lipopolysaccharide-stimulated RAW macrophages. RAW macrophages treated with rapamycin-loaded microparticles exhibited reduced nitric oxide production and favorable cell viability. Overall, we have shown optimization of immunosuppressive rapamycin-loaded microparticles using the novel polymer Ac-DEX. These particles will be advantageous for future applications in immune suppression therapies.