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.

• Authors: Scott H Medina, Venkatesh Tekumalla, Maxim V Chevliakov, Donna S Shewach, William D Ensminger, Mohamed E H El-Sayed
• Journal: Biomaterials (Biomaterials) Vol. 32 Issue 17 Pg. 4118-29 (Jun 2011) ISSN: 1878-5905 [Electronic] Netherlands
• PMID: 21429574 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2011 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Dendrimers
• Drug Carriers
• Poly(amidoamine)
• Polyamines
• Polymers
• Acetylgalactosamine

Topics

• Acetylgalactosamine (pharmacokinetics)
• Antineoplastic Agents (pharmacology)
• Biological Transport
• Dendrimers (chemical synthesis, pharmacokinetics)
• Drug Carriers (chemical synthesis)
• Drug Delivery Systems (methods)
• Endocytosis
• Hep G2 Cells
• Humans
• Polyamines (chemistry, pharmacology)
• Polymers