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

Scott H. Medina, Venkatesh Tekumalla, Maxim V. Chevliakov, Donna S. Shewach, William D. Ensminger, Mohamed E.H. El-Sayed

Research output: Contribution to journalArticle

72 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)4118-4129
Number of pages12
JournalBiomaterials
Volume32
Issue number17
DOIs
StatePublished - Jun 1 2011

All Science Journal Classification (ASJC) codes

  • Bioengineering
  • Ceramics and Composites
  • Biophysics
  • Biomaterials
  • Mechanics of Materials

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    Medina, S. H., Tekumalla, V., Chevliakov, M. V., Shewach, D. S., Ensminger, W. D., & El-Sayed, M. E. H. (2011). N-acetylgalactosamine-functionalized dendrimers as hepatic cancer cell-targeted carriers. Biomaterials, 32(17), 4118-4129. https://doi.org/10.1016/j.biomaterials.2010.11.068