Ring-opening polymerization of ε-caprolactone initiated by ganciclovir (GCV) for the preparation of GCV-tagged polymeric micelles.

Alicia Sawdon,Ching-An Peng

doi:10.3390/molecules20022857

Abstract

Ganciclovir (GCV) is a nucleoside analogue with antiviral activity against herpes viral infections, and the most widely used antiviral to treat cytomegalovirus infections. However, the low bioavailability and short half-life of GCV necessitate the development of a carrier for sustained delivery. In this study, guanosine-based GCV was used as the initiator directly in ring-opening polymerization of ε-caprolactone (ε-CL) to form hydrophobic GCV-poly(caprolactone) (GCV-PCL) which was then grafted with hydrophilic chitosan to form amphiphilic copolymers for the preparation of stable micellar nanoparticles. Successful synthesis of GCV-PCL and GCV-PCL-chitosan were verified by 1H-NMR analysis. Self-assembled micellar nanoparticles were characterized by dynamic light scattering and zetasizer with an average size of 117 nm and a positive charge of 24.2 mV. The drug release kinetics of GCV was investigated and cytotoxicity assay demonstrated that GCV-tagged polymeric micelles were non-toxic. Our results showed that GCV could be used directly in the initiation of ring-opening polymerization of ε-CL and non-toxic polymeric micelles for GCV delivery can be formed.

Highlights

Ganciclovir (GCV), is the most widely used antiviral drug for the treatment of human cytomegalovirus (CMV) infections [1]
GCV-PCL was synthesized through ring-opening polymerization of ε-CL exclusively by GCV
According to the Michaelis-Menten model, we found that the dissociation constant (Kd) was equal to 2.79 which is much higher than the release of ACV from ACV-PCL-chitosan polymeric micelles reported previously [25]

Summary

Introduction

Ganciclovir (GCV), is the most widely used antiviral drug for the treatment of human cytomegalovirus (CMV) infections [1]. GCV is only slightly water soluble, and as a result, has poor oral and ocular bioavailability. It needs to be administered intravenously; due to its short biological half-life, frequent dosing is required, which may increase the risk of systemic toxicity and discomfort to the patient [1,2,3,4]. Polymeric micelles have been the focus of much interest as alternative vehicles for the solubilization of poorly water-soluble molecules rendering clear advantages over current solubilizing agents in drug delivery [10]. Polymeric micelles are expected to withstand the diluting effect of blood, stay in a micellar form, and even act as a circulating depot drug delivery system after intravenous administration. Due to the fact that micelles can be synthesized to increase a drug’s solubility and bioavailability, they are a model system for enhanced drug delivery [11,12,13,14]

Methods

Results

Conclusion