Complete preclinical platform for intravitreal chemotherapy drug discovery for retinoblastoma: Assessment of pharmacokinetics, toxicity and efficacy using a rabbit model
2021
Daniels, Anthony B. | Pierce, Janene M. | Chen, Sheau-chiann
Current melphalan-based intravitreal chemotherapy regimens for retinoblastoma vitreous seeds are effective, but cause significant ocular toxicity. We describe protocols for each step of a drug discovery pipeline for preclinical development of novel drugs to maximize efficacy and minimize toxicity. These protocols include: 1) determination of vitreous pharmacokinetics in vivo, 2) in vitro assessment of drug cytotoxicity against retinoblastoma based on empiric pharmacokinetics, 3) back-calculation of minimum injection dose to achieve therapeutic concentrations, 4) in vivo determination of maximum-tolerable intravitreal dose, using a multimodal, structural and functional toxicity-assessment platform, and 5) in vivo determination of drug efficacy using a rabbit orthotopic xenograft model of retinoblastoma vitreous seeds. We likewise describe our methodology for direct quantitation of vitreous seeds, and the statistical methodology for assessment of toxicity and efficacy in evaluating novel drugs, as well as for comparisons between drugs.•Multi-step pipeline for intravitreal chemotherapy drug discovery for retinoblastoma, using novel rabbit models.•Detailed protocols for determination of vitreous pharmacokinetics, calculation of optimal dose to inject to achieve therapeutic vitreous levels, determination of maximum tolerable dose using a novel complete toxicity-assessment platform, and in vivo efficacy against retinoblastoma using methodology to directly quantify vitreous tumor burden.•Associated statistical methodology is also presented.
اظهر المزيد [+] اقل [-]الكلمات المفتاحية الخاصة بالمكنز الزراعي (أجروفوك)
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