Ocular Sustained Release Nanoparticles Containing Stereoisomeric Dipeptide Prodrugs of Acyclovir

Abstract

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.

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

“…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).…”

“…The peptidases and esterases are stereospecific and have high affinity for L-isomers. Therefore, incorporation of D-isomer in the prodrug can improve enzymatic stability of the prodrug in tissue (Talluri et al, 2009;Jwala et al, 2011). It was reported that L-valine in the terminal position increases the affinity of prodrugs to the peptide transporter protein in rabbit primary corneal epithelial cells (rPCEC) (Jwala et al, 2011).…”

SN-38-Cyclodextrin Complexation and Its Influence on the Solubility, Stability, and In Vitro Anticancer Activity Against Ovarian Cancer

“…Cytotoxicity of SN-38-SBEβCD complex on ovarian cancer cell lines A2780 and 2008 was evaluated by MTT assay (27)(28)(29) and compared with the cytotoxicity of SN-38 and irinotecan. As SN-38 is not soluble in water, a stock solution was made in DMSO and suitable dilutions were made in growth medium, keeping the final DMSO concentration less than 0.1%.…”

Stereoisomeric Prodrugs to Improve Corneal Absorption of Prednisolone: Synthesis and In Vitro Evaluation

“…These influx transporters have been demonstrated to be highly expressed on the apical surface of the corneal epithelium (21)(22)(23). This transporter has previously been targeted with amino acid and dipeptide prodrugs to improve corneal transport of poorly permeable drugs (23)(24)(25)(26)(27)(28)(29). Amino acids employed to generate amino acid and dipeptide prodrugs are of L-configuration as L-isomers possess high affinity and specificity towards peptide transporters (30,31).…”

“…In fact, L-valine-D-valine-acyclovir (LDACV), D-valine-L-valine acyclovir (DLACV), and D-valine-D-valine-acyclovir (DDACV) displayed significant enzymatic stability in corneal cell and ocular tissue homogenates (24). The main objective of the present study is to investigate enhanced corneal absorption of stereoisomeric prodrug approach by improving aqueous solubility, corneal permeability, and circumvention of Pgp-mediated cellular efflux of prednisolone.…”