Guanosine-based antiviral acyclovir incorporated in ring-opening polymerization of ɛ-caprolactone

Abstract

Disease prevention, diagnosis and treatment are constantly being advanced thanks to many possible offerings from nanoscale technologies. Nanoparticles encompass a wide variety of devices including but not limited to: carbon nanotubes, self-assembled polymeric nanoconstructs and nanobiosensors which can mimic or alter biological processes. Due to the fact that nanoparticles can be prepared using a variety of polymers, biodegradable polymers have been studied extensively. Considerable research has been conducted in the preparation of a variety of biodegradable polymeric nanoparticles for drug delivery. Polymeric nanoparticles are a choice delivery system because they can easily be manipulated and tailored to a drug or delivery sites’ specific needs. At the very least, a good drug carrier requires at least two criteria: first, is the ability to enhance a drug’s bioavailability and second, is controlled release of the drug. Ideal polymer nanocarriers therefore require multiple components which together enhance the drug’s efficiency. Acyclovir (ACV), commercially known as Zovirax, is a guanosine-based drug most commonly used for the treatment of infections caused by herpes simplex virus (HSV) type 1 and 2, varicella zoster virus and to a lesser extent cytomegalovirus and Epstein-Barr virus. Therapeutic benefits of using ACV to treat ocular infections and cutaneous infections caused by HSV type 1 and 2 have been extensively studied. In addition, studies have shown that ACV is an effective prodrug for gene-directed enzyme prodrug therapy (GDEPT), particularly, in regards to herpes simplex type-1 thymidine kinase (HSV-tk). Delivery of ACV to the basal epidermis, ophthalmic epithelium or even to cancer cells for GDEPT has proven difficult due to ACV’s poor water solubility and ensuing low bioavailability. Methods reported to increase the solubility of ACV are by coupling it to a biocompatible hydrophilic polymer (i.e., poly(ethylene glycol)) or polysaccharide (i.e. dextran). Alternative approaches to improve delivery efficiency of ACV to the targeted cells is through biocompatible drug delivery systems in a nano-sized platform such as polymeric micelles. Polycaprolactone (PCL), due to its low toxicity, biodegradability and biocompatibility, has been widely used in biomedical applications such as tissue engineering and drug delivery systems. Hydrophobic polyester PCL is commonly synthesized via ring-opening polymerization of e-caprolactone (e-CL) initiated by the primary hydroxyl group of an alcohol in the presence of a metal catalyst. Direct activation of monomer at the carbonyl oxygen with Sn(II)2-ethylhexanoate (Sn(Oct)2) is the mechanism for lactone polymerization. Using Sn(Oct)2 as a catalyst is favored for a variety of reasons, including its low cost, low toxicity and high efficiency. As a first step towards the formation of ACV-containing polymeric micelles for drug delivery, we developed in this study a novel technique for direct synthesis of ACV-PCL through the ring-opening polymerization of e-CL initiated by the primary hydroxyl group on ACV. Through H NMR, FTIR and GPC analysis, the structure of newly synthesized ACV-PCL was characterized and confirmed.