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

Abstract

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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“…The ZP of FITC-NPs presented a decrease with respect to PLGA NPs (− 30 mV of PLGA NPs vs. − 18 mV of FITC-PLGA NPs, Table 1 ), which again is consistent with the implication of negatively charged PLGA carboxylic acid groups in the conjugation reaction. The ZP decrease due to the coupling of FITC to PLGA is consistent with the literature 34 , although comparisons should be made carefully when the conjugation is addressed with different coupling reactions.…”