Surface Engineering of Porous Silicon Microparticles for Intravitreal Sustained Delivery of Rapamycin

PURPOSE. To understand the relationship between rapamycin loading/release and surface chemistries of porous silicon (pSi) to optimize pSi-based intravitreal delivery system. METHODS. Three types of surface chemical modifications were studied: (1) pSi-COOH, containing 10-carbon aliphatic chains with terminal carboxyl groups grafted via hydrosilylation of undecylenic acid; (2) pSi-C12, containing 12-carbon aliphatic chains grafted via hydrosilylation of 1-dodecene; and (3) pSiO(2)-C8, prepared by mild oxidation of the pSi particles followed by grafting of 8-hydrocarbon chains to the resulting porous silica surface via a silanization. RESULTS. The efficiency of rapamycin loading follows the order (micrograms of drug/ milligrams of carrier): pSiO(2)-C8 (105 +/- 18) > pSi-COOH (68 +/- 8) > pSi-C12 (36 +/- 6). Powder X-ray diffraction data showed that loaded rapamycin was amorphous and dynamic drug-release study showed that the availability of the free drug was increased by 6-fold (compared with crystalline rapamycin) by using pSiO(2)-C8 formulation (P = 0.0039). Of the three formulations in this study, pSiO(2)-C8-RAP showed optimal performance in terms of simultaneous release of the active drug and carrier degradation, and drug-loading capacity. Released rapamycin was confirmed with the fingerprints of the mass spectrometry and biologically functional as the control of commercial crystalline rapamycin. Single intravitreal injections of 2.9 +/- 0.37 mg pSiO(2)-C8-RAP into rabbit eyes resulted in more than 8 weeks of residence in the vitreous while maintaining clear optical media and normal histology of the retina in comparison to the controls. CONCLUSIONS. Porous silicon-based rapamycin delivery system using the pSiO(2)-C8 formulation demonstrated good ocular compatibility and may provide sustained drug release for retina.