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Alejandra Nieto, Huiyuan Hou, Michael Sailor, William Freeman, Lingyun Cheng; Porous Silicon Microparticle Formulation as an Intravitreal Delivery System for Rapamycin. Invest. Ophthalmol. Vis. Sci. 2013;54(15):1085.
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Rapamycin (RAPA) is a potent immunosuppressant occasionally administered orally for refractory uveitis, however side effects are associated with systemic use. Intravitreal administration provides a means to deliver the drug to the target while limiting systemic adverse effects. Our study aimed at developing an intravitreally injectable rapamycin formulation based on nanostructured porous silicon particles and evaluating the effects of different surface chemistries on rapamycin delivery.
Porous silicon (pSi) was prepared by electrochemical etch of a silicon wafer. Microparticles were prepared by ultrasonic fracture. The pSi carrier prepared in this fashion had previously been shown to be non-toxic after intravitreal injection. Porous silicon surface was chemically modified following three different strategies. Commercial RAPA was loaded by infiltration from concentrated solutions into the nanopores, with diameters of ~13 nm. Rapamycin loaded pSi particles were added to a custom designed flow cell chamber, which duplicated the turnover rate of rabbit eye fluid. The effluent, HBSS (Hanks Balanced Salt Solution), was sampled and analyzed by HPLC-MS (High Performance Liquid Chromatography-Mass Spectrometry) to determine RAPA and model the drug release profile. Silicon degradation was simultaneously quantitated using ICP-OES (Inductively Coupled Plasma-Optical Emission Spectroscopy).
Surface chemistry had an influence in the rapamycin mass loading efficiency, being the order: 690 μg RAPA/mg pSi, 83 μg RAPA/mg pSi and 36 μg RAPA per mg pSi for the three different formulations. During a 14-day incubation in flow cell at 37°C, all formulations tested showed sustained and similar cumulative percent of RAPA released. Silicon concentration-time profile depended on surface chemistry following the order: 7 %, 4% and 0.5 % Si released for the three different formulations.
Commercial rapamycin can be loaded into nanoporous silicon. Results demonstrated the importance of surface chemistry of pSi on rapamycin loading and release, which can be used as a tool to tune drug loading efficiency and modulate matrix dissolution to control drug release rate and vitreous half-life of pSi-rapamycin delivery system. This represents a promising sustained and tunable intraocular RAPA delivery system for refractory chorioretinal diseases.
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