There is an important unmet need for a minimally invasive long acting, and monitorable drug delivery system for the treatment of posterior eye diseases. Due to the difficulty of crossing the blood-retinal barrier, intravitreal drug delivery has become the mainstay to treat posterior eye diseases. The current available medications require frequent intravitreal injection or invasive surgical intraocular implant. This application seeks to develop and evaluate a porous silicon (Psi) based intravitreal drug delivery system. Three candidate drugs: bevacizumab, daunorubicin, and dexamethasone, will be used as model drugs to investigate this novel and unique system. Bevacizumab represents large molecule such as protein;daunorubicin and dexamethasone represent small molecules which target two major components of chorioretinal diseases: unwanted proliferation and inflammation. We hypothesize that Psi particles are non-toxic and biodegradable after intravitreal injection, that their porosity can be used for hosting therapeutics, and that their optical property can be harnessed to report drug release from remote. Our preliminary data have shown that by modifying the surface chemistry of Psi via oxidation or hydrosilylation, the Psi particle's ability to remain in the vitreous can be extended from 1 week to 16 weeks without ocular toxicity. Our in vitro data demonstrated that the loading and removal of daunorubicin changed the spectrum of Psi particles which served as a barcode for drug monitoring and could be captured by a digital camera, allowing for non-invasive monitoring of drug release in the clinical setting. We also showed that covalent attachment of daunorubicin to either hydrosilylated or oxidized Psi particles extended the drug half-life from a few hours to 23 days (hydrosilylated) or even longer (oxidized). We have confirmed that released daunorubicin is fully functional through the cell culture and MTT assays. We will first optimize the Psi vitreous stability by oxidations, hydrosilylations, and electrochemical grafting of organohalides. Psi with a good vitreous stability will be optimized for loading of the candidate drugs using physical trapping, electrostatic adsorption, covalent attachment, or layer by layer approaches. We will evaluate non-invasive monitoring of drug release in vitro and in vivo approaches. The optimized drug loaded Psi particles and its non-invasive sensing ability will be further evaluated in animal eyes and animal models for its pharmacokinetics and efficacy. We will also evaluate the ability of this system to offer synergistic effect on macular degeneration CNV animal model by injection of a mixture of two types of Psi particles (each type loaded with one drug). It is expected that the proposed Psi based ocular drug delivery systems will alleviate the need for frequent intravitreal injections or intraocular surgery for drug device planting, significantly improving the quality of life of patients.
The goal of this project is to develop and evaluate a porous silicon based eye drug delivery system which is minimally invasive, slow releasing and long-lasting. The system could eliminate the need for frequent intravitreal injections or invasive intraocular implant surgeries for many of the refractory eye diseases such as macular degeneration, diabetic or trauma induced retinal scarring, and chronic uveitis.
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