Synthesis and Characterization of Ganciclovir Long Chain Lipid Prodrugs

Mitra, Ashim K.

doi:10.15406/aovs.2014.01.00007

AOVS

2014

DOI: 10.15406/aovs.2014.01.00007

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Synthesis and Characterization of Ganciclovir Long Chain Lipid Prodrugs

Ashim K. Mitra¹

Abstract: Ganciclovir (GCV) is indicated for the treatment of human cytomegalo virus (HCMV) retinitis in immunocompromised patients. Sub-optimal physicochemical properties prevent GCV from reaching therapeutic concentrations in back of the eye (retina) tissue after oral and intravenous administration. Chronic high dose administration results in systemic toxicity. Local intravitreal injections suffer from poor ocular bioavailability and require repeated administration which can cause retinal detachment, retinal/vitreal h… Show more

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Cited by 4 publications

References 30 publications

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Prodrug Approach for Posterior Eye Drug Delivery: Synthesis of Novel Ganciclovir Prodrugs and in Vitro Screening with Cassette Dosing

et al. 2020

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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 (<50% bound). In conclusion, cassette dosing proved useful for the rapid screening of prodrug hydrolysis and bioconversion properties. Analyzing several compounds simultaneously can complicate the analytics, and thus, choosing the compounds of the cassette mix should be done carefully to avoid mutual interference of the compounds with the results. The methodology and results of the work are applicable in ocular drug research and prodrug design.

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Prodrug Approach for Posterior Eye Drug Delivery: Synthesis of Novel Ganciclovir Prodrugs and in Vitro Screening with Cassette Dosing

et al. 2020

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Advances in the use of prodrugs for drug delivery to the eye

Taskar

Tatke

Majumdar

2016

Expert Opinion on Drug Delivery

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Ocular drug delivery is presented with many challenges, taking into account the distinctive structure of the eye. The prodrug approach has been, and is being, employed to overcome such barriers for some drug molecules, utilizing a chemical modification approach rather than a formulation-based approach. A prodrug strategy involves modification of the active moiety into various derivatives in a fashion that imparts some advantage, such as membrane permeability, site specificity, transporter targeting and improved aqueous solubility, over the parent compound. Areas covered: The following review is a comprehensive summary of various novel methodologies and strategies reported over the past few years in the area of ocular drug delivery. Some of the strategies discussed involve polymer and lipid conjugation with the drug moiety to impart hydrophilicity or lipophilicity, or to target nutrient transporters by conjugation with transporter-specific moieties and retrometabolic drug design. Expert opinion: The application of prodrug strategies provides an option for enhancing drug penetration into the ocular tissues, and overall ocular bioavailability, with minimum disruption of the ocular diffusion barriers. Although success of the prodrug strategy is contingent on various factors, such as the chemical structure of the parent molecule, aqueous solubility and solution stability, capacity of targeted transporters and bioreversion characteristics, this approach has been successfully utilized, commercially and therapeutically, in several cases.

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Protective Effects of Curcumin Ester Prodrug, Curcumin Diethyl Disuccinate against H2O2-Induced Oxidative Stress in Human Retinal Pigment Epithelial Cells: Potential Therapeutic Avenues for Age-Related Macular Degeneration

Muangnoi

Sharif

Bhuket

et al. 2019

IJMS

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Oxidative stress-induced damage to the retinal pigmented epithelium (RPE), a specialised post-mitotic monolayer that maintains retinal homeostasis, contributes to the development of age-related macular degeneration (AMD). Curcumin (Cur), a naturally occurring antioxidant, was previously shown to have the ability to protect RPE cells from oxidative stress. However, poor solubility and bioavailability makes Cur a poor therapeutic agent. As prodrug approaches can mitigate these limitations, we compared the protective properties of the Cur prodrug curcumin diethyl disuccinate (CurDD) against Cur in relation to oxidative stress induced in human ARPE-19 cells. Both CurDD and Cur significantly decreased H2O2-induced reactive oxygen species (ROS) production and protected RPE cells from oxidative stress-induced death. Both drugs exerted their protective effects through the modulation of p44/42 (ERK) and the involvement of downstream molecules Bax and Bcl-2. Additionally, the expression of antioxidant enzymes HO-1 and NQO1 was also enhanced in cells treated with CurDD and Cur. In all cases, CurDD was more effective than its parent drug against oxidative stress-induced damage to ARPE-19 cells. These findings highlight CurDD as a more potent drug compared to Cur against oxidative stress and indicate that its protective effects are exerted through modulation of key apoptotic and antioxidant molecular pathways.

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Synthesis and Characterization of Ganciclovir Long Chain Lipid Prodrugs

Cited by 4 publications

References 30 publications

Prodrug Approach for Posterior Eye Drug Delivery: Synthesis of Novel Ganciclovir Prodrugs and in Vitro Screening with Cassette Dosing

Prodrug Approach for Posterior Eye Drug Delivery: Synthesis of Novel Ganciclovir Prodrugs and in Vitro Screening with Cassette Dosing

Advances in the use of prodrugs for drug delivery to the eye

Protective Effects of Curcumin Ester Prodrug, Curcumin Diethyl Disuccinate against H2O2-Induced Oxidative Stress in Human Retinal Pigment Epithelial Cells: Potential Therapeutic Avenues for Age-Related Macular Degeneration

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