Synthesis of nucleoside-boronic esters hydrophobic pro-drugs: A possible route to improve hydrophilic nucleoside drug loading into polymer nanoparticles

Abstract

Nucleoside analogues are active therapeutic agents for different types of diseases e.g. Cancer and virus infections. However, they are associated with several side effects due to off-target accumulation. Particulate delivery systems such as nanoparticles (NP) may be able to selectively target drug into affected organs and lower or omit off-target accumulation. Hydrophilic nucleoside analogues are poorly incorporated into NP. This work has used boronic compounds to synthesize more hydrophobic biodegradable prodrugs of hydrophilic nucleosides to improve drug loading into NP. Ribavirin (RV) was used as a model hydrophilic nucleoside to test our hypothesis. RV is a broad antiviral agent, active against both RNA and DNA viruses. RV accumulates into Red Blood Cells (RBCs) causing haemolytic anaemia that restricts its therapeutic benefits. RBCs are reported to have no endocytic mechanisms. So, NP delivery should be advantageous. Two hydrophobic pro-drugs of RV were synthesized namely, ribavirin conjugated to phenylboronic acid and ribavirin conjugated to 4-butoxy-3, 5-dimethylphenylboronic acid and were encapsulated into polymer NP. It was shown that the pro-drugs were incorporated more effectively into polymer nanoparticles with a 1700 fold improved RV loading. Polymer NP had been prepared with biocompatible and biodegradable polymers, Poly(glycerol adipate) and its more hydrophobic derivatives.

An investigation of rhinovirus infection on cellular uptake of poly (glycerol-adipate) nanoparticles

“…The polymer was synthesized following a literature protocol ( Abo-zeid et al, 2018a ). Briefly, poly(glycerol-adipate) (PGA) was synthesized by dissolving equal amounts (250 mmol) of glycerol and divinyl-adipate (DVA) in dry tetrahydrofuran (THF, 30 ml) in presence of a catalytic enzyme, novozyme 435 (1.25 g).…”

Polyglycerol Hyperbranched Polyesters: Synthesis, Properties and Pharmaceutical and Biomedical Applications

“…Poly(glycerol adipate) (PGAd) is a polyester obtained from two non-toxic and bio-based monomers, glycerol and adipic acid (AdA) [41], which are both safe and FDA-approved compounds [42]. PGAd is encountered as a linear or a hyperbranched polymer, depending on the catalysis (Scheme 4).…”

“…One of the advantages of linear PGAd over PLA and PLGA, which are extensively used in biomedical applications, is the possibility to modify the pendent hydroxyl groups on the polymer backbone with a variety of acyl groups to change the hydrophobicity of the polymer. It is a smart strategy to produce polymers with completely different properties, based on the kind of acyl moieties used [10,42,58,59,62]. The physicochemical properties of the polymer can be adjusted according to the requirements of different drugs (hydrophilic or hydrophobic) allowing various drug incorporations.…”

“…The drug release from PGAd and acylated PGAd derivatives differed and showed stepwise patterns that involved an initial burst release, diffusion of the drug from the polymer matrix and eventually drug release possibly via a combined mechanism. Acylated PGAd NPs were also used in antiviral therapy, for the delivery of ribavirin, a broad antiviral agent active against both RNA and DNA viruses [42].…”

Poly (glycerol adipate) (PGA), an Enzymatically Synthesized Functionalizable Polyester and Versatile Drug Delivery Carrier: A Literature Update

“…PGA acylation with fatty acids has been intensively investigated both in terms of physical properties, self-assembling in NPs and for delivery of lipophilic and hydrophilic drugs [31,32,33,34]. The variation of both the fatty acid nature (butyrate, octanoate, laurate, stearate, behenate and oleate) and degrees of substitution have been analyzed for their influence on the final polymer amphiphilic balance, affecting NP shape, drug interactions, NP metabolism and cell uptake [33,35,36]. Weiss et al [33] reported that a low substitution of lauric, stearic or behenic acid decreased nanoparticle size relative to unmodified PGA, suggesting interactions of fatty acid chains in the particle core enhanced the packing of particles (Table 1).…”