N-acetylgalactosamine-functionalized dendrimers as hepatic cancer cell-targeted carriers

Abstract

There is an urgent need for novel polymeric carriers that can selectively deliver a large dose of chemotherapeutic agents into hepatic cancer cells to achieve high therapeutic activity with minimal systemic side effects. PAMAM dendrimers are characterized by a unique branching architecture and a large number of chemical surface groups suitable for coupling of chemotherapeutic agents. In this article, we report the coupling of N-acetylgalactosamine (NAcGal) to generation 5 (G5) of poly(amidoamine) (PAMAM-NH2) dendrimers via peptide and thiourea linkages to prepare NAcGal-targeted carriers used for targeted delivery of chemotherapeutic agents into hepatic cancer cells. We describe the uptake of NAcGal-targeted and non-targeted G5 dendrimers into hepatic cancer cells (HepG2) as a function of G5 concentration and incubation time. We examine the contribution of the asialoglycoprotein receptor (ASGPR) to the internalization of NAcGal-targeted dendrimers into hepatic cancer cells through a competitive inhibition assay. Our results show that uptake of NAcGal-targeted G5 dendrimers into hepatic cancer cells occurs via ASGPR-mediated endocytosis. Internalization of these targeted carriers increased with the increase in G5 concentration and incubation time following Michaelis–Menten kinetics characteristic of receptor-mediated endocytosis. These results collectively indicate that G5-NAcGal conjugates function as targeted carriers for selective delivery of chemotherapeutic agents into hepatic cancer cells.

Galactosylated polymeric carriers for liver targeting of sorafenib

“…In this way, the grafting of each PLA residue permits to introduce a hydrophobic biodegradable tail that contributes to obtain stable micelles. The subsequent grafting of GAL moieties onto the PHEA-EDA-PLA backbone permits to obtain a sugar-targeted polymeric conjugate for a specific therapy of liver diseases, due to the presence of carbohydrate receptors in the liver, i.e., the asialoglycoprotein receptors (ASGPR) in hepatocytes (Craparo et al, 2013b;Fiume and Di Stefano, 2010;Li et al, 2010;Medina et al, 2011).…”

Synthesis of a Covalent Epirubicin-(C3-amide)-Anti-HER2/neuImmunochemotherapeutic Utilizing a UV-Photoactivated Anthracycline Intermediate

“…Second, maintaining maximum binding-avidity also directly facilitates efficient and more extensive internalization of epirubicin-(C 3 -amide)-[anti-HER2/neu] by mechanisms of ligand-induced receptor-mediated-endocytosis at HER2/neu overexpressed by mammary adenocarcinoma 7,26,30,120 and other neoplastic cell types. [121][122][123][124][125] Seemingly modest alterations in synthetic chemistry conditions, and elevations in chemotherapeutic molar-incorporation-indexes can profoundly influence the selective binding properties of immunoglobulin fractions. 29 Relatively higher anthracyclineimmunoglobulin molar-incorporation-indexes could have been attained during the synthesis of epirubicin-(C 3 -amide)-[anti-HER2/neu] utilizing succinimidyl 4,4-azipentanoate.…”

Recent Advances in Drug Delivery Systems

“…They have a remarkable well-defined control over size (comparable size to proteins) with narrow polydispersity [54][55][56]. In addition, they have a large surface functionality providing a wide range of applications such as drug [57] and gene delivery [58], biological adhesives [59], imaging agents (e.g. MRI) [56].…”

“…This modification can be made to the nature of the core and the scaffold giving polyfunction capacity to the dendritic structure. This can be copulated to an antibody and its production can be through divergent and convergent routes or other techniques such as self-assembling synthesis, lego chemistry and click chemisty [54,57]. Their size, molecular weight and number of surface functional groups can be modulated through the increase in generation number (1 nm per generation) [56,57].…”

“…This can be copulated to an antibody and its production can be through divergent and convergent routes or other techniques such as self-assembling synthesis, lego chemistry and click chemisty [54,57]. Their size, molecular weight and number of surface functional groups can be modulated through the increase in generation number (1 nm per generation) [56,57]. In general, dendrimers are terminated with amine surface groups (G1, G2, G..) but can also be terminated with carboxylate (G1.5, G2.5, G..) [62].…”