Galactosylated Micelles for a Ribavirin Prodrug Targeting to Hepatocytes

Abstract

Polymeric micelles potentially able to carry to hepatocytes a ribavirin (RBV) prodrug, exploiting the presence of carbohydrate receptors, that is, ASGPR, were prepared starting from a galactosylated polylactide-polyaminoacid conjugate. This latter was obtained by chemical reaction of α,β-poly(N-2-hydroxyethyl) (2-aminoethylcarbamate)-dl-aspartamide (PHEA-EDA) with polylactic acid (PLA), and subsequent reaction with lactose, obtaining PHEA-EDA-PLA-GAL copolymer. To enhance the entrapment into obtained nanostructures, a hydrophobic RBV prodrug, that is, RBV tripalmitate, was synthesized and its capability to release RBV in the presence of an adequate enzymatic activity was demonstrated. Liver-targeted RBV tripalmitate-loaded micelles were obtained in aqueous media at low PHEA-EDA-PLA-GAL copolymer concentration value with nanometric size. By in vitro experiments, the specificity of RBV tripalmitate-loaded PHEA-EDA-PLA-GAL micelles toward HepG2 was demonstrated by using a competitive inhibition assay in the presence of free GAL. This finding raises hope in terms of future micelles-based liver-targeted drug delivery strategy for the hepatitis C treatment.

Galactosylated polymeric carriers for liver targeting of sorafenib

“…a,b-poly(N-2-hydroxyethyl)(2-aminoethylcarbamate)-D,Laspartamide (PHEA-EDA) copolymer is an appropriate starting macromolecule to design novel amphiphilic copolymers for biomedical application (Craparo et al, 2008;Craparo et al, 2013a;Licciardi et al, 2006).…”

“…Galactosylated PHEA-EDA-PLA copolymer (PHEA-EDA-PLA-GAL) was synthesized by a reductive amination of lactose with primary amine functions of PHEA-EDA-PLA in the presence of sodium cyanoborohydride, according to the procedure previously published and spectroscopic data were in agreement with the attributed structure (Craparo et al, 2013a The M w was found to be 24.3 kDa M w =M n ¼ 1:66 À Á . The amount of GAL grafted onto PHEA-EDA-PLA-GAL copolymer measured by using anthrone-sulphuric acid colorimetric method was 0.86 wt% (corresponding to 1.22 mol%) (Craparo et al, 2013a;Song et al, 2009).…”

“…a,b-poly(N-2-hydroxyethyl)-D,L-aspartamide (PHEA) was prepared via polysuccinimide (PSI) by polycondensation of D,Laspartic acid in the presence of H 3 PO 4 at 180 C, followed by reaction with ethanolamine in DMF solution, and purified according to a procedure elsewhere reported (Giammona et al, 1987 The synthesis of a,b-poly(N-2-hydroxyethyl)(2-aminoethylcarbamate)-D,L-aspartamide (PHEA-EDA) copolymer was performed according to the procedure previously published and spectroscopic data were in agreement with the attributed structure (Craparo et al, 2013a;Licciardi et al, 2006 (PLA) to obtain the copolymer PHEA-EDA-PLA copolymer was performed according to a procedure previously published and spectroscopic data were in agreement with the attributed structure (Craparo et al, 2008). The derivatization degree in PLA (DD PLA ) was calculated according to the method reported, resulted to be 0.73 AE 0.12 mol%.…”

“…The amount of GAL grafted onto PHEA-EDA-PLA-GAL copolymer measured by using anthrone-sulphuric acid colorimetric method was 0.86 wt% (corresponding to 1.22 mol%) (Craparo et al, 2013a;Song et al, 2009).…”

“…The critical aggregation concentration (CAC) of PHEA-EDA-PLA-GAL copolymer, determined by collecting steady-state fluorescence spectra of pyrene probe in the presence of increasing concentrations of that copolymer, resulted to be 4.1 Â10 À7 M (Craparo et al, 2013a).…”