Synthesis, metabolism and cellular permeability of enzymatically stable dipeptide prodrugs of acyclovir

Talluri, Ravi S.; Samanta, Samiran; Gaudana, Ripal; Mitra, Ashim K.

doi:10.1016/j.ijpharm.2008.05.024

Cited by 48 publications

(44 citation statements)

References 21 publications

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“…The yield, mass, and NMR spectra for LV-LV-ACV, LV-DV-ACV, DV-LV-ACV, and DV-DV-ACV has already been published from our laboratory by Talluri et al 15 Bioreversion of all the prodrugs (LV-LV-ACV, LV-DV-ACV, DV-LV-ACV, and DV-DV-ACV) was studied in rPCECs and ocular tissue homogenates. Dipeptide prodrugs with D-valine moiety at the terminal position exhibited more stability and were less susceptible to enzymatic degradation.…”

Section: Resultsmentioning

confidence: 99%

“…An enhanced mass spectrum (EMS) mode was used for the conformation of intermediates and final compounds. 15 …”

Section: Synthesismentioning

confidence: 99%

“…15 The HPLC system comprised of a Rainin Dynamax Pump SD-200, HP 1100 series fluorescence detector set at an excitation wavelength of 285 nm and an emission wavelength 360 nm. Alcott auto sampler Model 718 AL and a C18 Luna column 4.6 · 250 mm (Phenomenex) were utilized.…”

Section: Analytical Proceduresmentioning

confidence: 99%

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Ocular Sustained Release Nanoparticles Containing Stereoisomeric Dipeptide Prodrugs of Acyclovir

Jwala

Boddu

Shah

et al. 2011

Journal of Ocular Pharmacology and Therapeutics

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Purpose: The objective of this study was to develop and characterize polymeric nanoparticles of appropriate stereoisomeric dipeptide prodrugs of acyclovir (L-valine-L-valine-ACV, L-valine-D-valine-ACV, D-valine-Lvaline-ACV, and D-valine-D-valine-ACV) for the treatment of ocular herpes keratitis. Methods: Stereoisomeric dipeptide prodrugs of acyclovir (ACV) were screened for bioreversion in various ocular tissues, cell proliferation, and uptake across the rabbit primary corneal epithelial cell line. Docking studies were carried out to examine the affinity of prodrugs to the peptide transporter protein. Prodrugs with optimum characteristics were selected for the preparation of nanoparticles using various grades of poly (lactic-co-glycolic acid) (PLGA). Nanoparticles were characterized for the entrapment efficiency, surface morphology, size distribution, and in vitro release. Further, the effect of thermosensitive gels on the release of prodrugs from nanoparticles was also studied. Results: L-valine-L-valine-ACV and L-valine-D-valine-ACV were considered to be optimum in terms of enzymatic stability, uptake, and cytotoxicity. Docking results indicated that L-valine in the terminal position increases the affinity of the prodrugs to the peptide transporter protein. Entrapment efficiency values of Lvaline-L-valine-ACV and L-valine-D-valine-ACV were found to be optimal with PLGA 75:25 and PLGA 65:35 polymers, respectively. In vitro release of prodrugs from nanoparticles exhibited a biphasic release behavior with initial burst phase followed by sustained release. Dispersion of nanoparticles in thermosensitive gels completely eliminated the burst release phase. Conclusion: Novel nanoparticulate systems of dipeptide prodrugs of ACV suspended in thermosensitive gels may provide sustained delivery after topical administration.

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Section: Resultsmentioning

confidence: 99%

“…An enhanced mass spectrum (EMS) mode was used for the conformation of intermediates and final compounds. 15 …”

Section: Synthesismentioning

confidence: 99%

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Ocular Sustained Release Nanoparticles Containing Stereoisomeric Dipeptide Prodrugs of Acyclovir

Jwala

Boddu

Shah

et al. 2011

Journal of Ocular Pharmacology and Therapeutics

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“…exhibited different affinities to the peptide transporter, permeabilities and bioreversion rates in Caco-2 and rPCEC cell lines, as well as intestine, liver and ocular tissues (Talluri et al, 2008;Jwala et al, 2011). It was revealed that incorporation of one D-Val in a dipeptide diminished, but does not negate its affinity towards peptide transporters but significantly improve enzymatic stability of stereoisomeric dipeptide prodrugs to a large extent depending on the position of D-amino acid in a dipeptide conjugate (Tamura et al, 1996;Friedrichsen et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Uptake and bioconversion of stereoisomeric dipeptide prodrugs of ganciclovir by nanoparticulate carriers in corneal epithelial cells

et al. 2015

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Purpose: The objective of this study is to investigate cellular uptake of prodrug-loaded nanoparticle (NP). Another objective is to study bioconversion of stereoisomeric dipeptidePoly( D,L -lactic-co-glycolic acid) (PLGA) NP encapsulating prodrugs of GCV were formulated under a double emulsion method. Fluorescein isothiocyanate isomer-PLGA conjugates were synthesized to fabricate biocompatible fluorescent PLGA NP. Intracellular uptake of FITC-labeled NP was visualized by a fluorescent microscope in HCEC cells. Results: Fluorescent PLGA NP and non-fluorescent NP display similar hydrodynamic diameter in the range of 115-145 nm with a narrow particle size distribution and zeta potentials around À13 mV. Both NP types showed identical intracellular accumulation in HCEC cells. Maximum uptake (around 60%) was noted at 3 h for NP. Cellular uptake and intracellular accumulation of prodrugs are significantly different among three stereoisomeric dipeptide prodrugs. The microscopic images show that NPs are avidly internalized by HCEC cells and distributed throughout the cytoplasm instead of being localized on the cell surface. Following cellular uptake, prodrugs released from NP gradually bioreversed into parent drug GCV. LLGCV showed the highest degradation rate, followed by LDGCV and DLGCV. Conclusion: LLGCV, LDGCV and DLGCV released from NP exhibited superior uptake and bioreversion in corneal cells.

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“…We selected a prodrug that would increase the lipophilic character of acyclovir, optimizing its permeation through the cornea, and simultaneously the appropriate nanotechnology to provide prolonged release of acyclovir at the absorption site. Each of these approaches has been widely studied: macromolecular complex, amino acid ester, and dipeptide prodrugs of acyclovir were found to be more stable, more soluble, and capable of improving the bioavailability of ACV after oral and ocular administration [17], [19], [20], [21], [38] and [39], and colloidal carriers have been widely exploited to enhance corneal permeation, control drug release at the absorption site, and obtain a selective target of acyclovir [35], [40] and [41].…”

Section: Discussionmentioning

confidence: 99%

Nonpolymeric nanoassemblies for ocular administration of acyclovir: Pharmacokinetic evaluation in rabbits

Stella

Berlier

Rocco

et al. 2012

European Journal of Pharmaceutics and Biopharmaceutics

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The aim of this study was to increase bioavailability of the antiviral drug acyclovir (ACV) when administered by the ocular route. For this purpose, a new lipophilic derivative of acyclovir was synthesized, both possessing greater lipophilicity and providing the formation of a homogeneous water dispersion with higher amount of ACV than the aqueous solution of the parent drug. This was done by chemically linking acyclovir to the isoprenoid chain of squalene, obtaining 4′-trisnorsqualenoylacyclovir (SQACV), in which squalene is covalently coupled to the 4′-hydroxy group of acyclovir. This new prodrug was then formulated as nonpolymeric nanoassemblies through nanoprecipitation; the resulting particles were characterized in terms of mean diameter, zeta potential, and stability. The pharmacokinetic profile of the prodrug in the tear fluid and in the aqueous humor of rabbits was evaluated and compared to that of the parent drug. Data showed that SQACV nanoassemblies increased the amount of ACV in the aqueous humor of rabbits compared to free ACV solution. This new amphiphilic prodrug of acyclovir is a very promising tool to increase the ocular bioavailability of the parent drug.

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Synthesis, metabolism and cellular permeability of enzymatically stable dipeptide prodrugs of acyclovir

Cited by 48 publications

References 21 publications

Ocular Sustained Release Nanoparticles Containing Stereoisomeric Dipeptide Prodrugs of Acyclovir

Ocular Sustained Release Nanoparticles Containing Stereoisomeric Dipeptide Prodrugs of Acyclovir

Uptake and bioconversion of stereoisomeric dipeptide prodrugs of ganciclovir by nanoparticulate carriers in corneal epithelial cells

Nonpolymeric nanoassemblies for ocular administration of acyclovir: Pharmacokinetic evaluation in rabbits

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