Prodrug Approach for Posterior Eye Drug Delivery: Synthesis of Novel Ganciclovir Prodrugs and in Vitro Screening with Cassette Dosing
| Autor: | Jukka Leppänen, Laura Hellinen, Kati-Sisko Vellonen, Lisa-Marie Jasper, Emma M. Heikkinen, Arto Urtti, Marika Ruponen, Jarkko Rautio, Seppo Auriola |
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| Rok vydání: | 2020 |
| Předmět: |
Drug
Ganciclovir Bioconversion Swine media_common.quotation_subject Pharmaceutical Science 02 engineering and technology Retinal Pigment Epithelium 030226 pharmacology & pharmacy Antiviral Agents 03 medical and health sciences Hydrolysis 0302 clinical medicine Drug Delivery Systems Tandem Mass Spectrometry Drug Discovery medicine Animals Prodrugs media_common Chromatography Chemistry Prodrug 021001 nanoscience & nanotechnology eye diseases In vitro Bioavailability Drug delivery Molecular Medicine sense organs 0210 nano-technology medicine.drug |
| Zdroj: | Molecular pharmaceutics. 17(6) |
| ISSN: | 1543-8392 |
| Popis: | Because of poor ocular drug bioavailability, intravitreal injections have become the gold standard for drug delivery to the posterior eye. The prodrug approach can be used for optimizing the biopharmaceutical properties of intravitreal drugs. The preclinical screening of prodrugs' properties, such as hydrolysis and bioconversion, should be conducted in a resource-efficient way for an extensive set of synthesized compounds with validated methods. Our objective was to explore cassette dosing in in vitro prodrug hydrolysis and bioconversion studies in buffer, vitreous, and retinal pigment epithelium (RPE) homogenate for rapid medium-throughput screening. Moreover, our aim was to correlate the prodrug structure with hydrolytic behavior. We synthesized 18 novel ganciclovir prodrugs and first studied their hydrolysis in aqueous buffer and porcine vitreous in vitro with cassette dosing for 35 h. A method for vitreous homogenate pH equilibration to a physiological level by using buffer and incubation under 5% carbon dioxide was validated. The hydrolysis of the prodrugs was evaluated in porcine RPE homogenate in vitro with cassette dosing, and five prodrugs were assayed individually to examine their bioconversion into ganciclovir in RPE after 2 h. Lastly, the prodrugs' binding to melanin was studied in vitro. The prodrugs showed a wide spectrum of hydrolysis rates, ranging from a few percentages to 100% in the vitreous and RPE; in general, hydrolysis in RPE was faster than in vitreous. Prodrugs with long carbon chains and disubstitution showed lability in the tissue homogenates, whereas prodrugs with branched carbon chains and aromatic groups were stable. All five prodrugs chosen for the bioconversion study in RPE were hydrolyzed into ganciclovir, and their hydrolytic behavior matched results from the cassette mix experiment, supporting the cassette mix approach for hydrolysis and bioconversion studies. None of the prodrugs bound highly to melanin ( |
| Databáze: | OpenAIRE |
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