title: 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.affiliation: Department of Biomedical Engineering, Cellular Engineering and Nano-Therapeutics Laboratory, University of Michigan, 1101 Beal Avenue, Ann Arbor, MI 48109, USA.
authors.forename: Scott H
authors.initials: SH
authors.lastname: Medina
authors.forename: Venkatesh
authors.initials: V
authors.lastname: Tekumalla
authors.forename: Maxim V
authors.initials: MV
authors.lastname: Chevliakov
authors.forename: Donna S
authors.initials: DS
authors.lastname: Shewach
authors.forename: William D
authors.initials: WD
authors.lastname: Ensminger
authors.forename: Mohamed E H
authors.initials: ME
authors.lastname: El-Sayed
mesh_terms: D000116:Acetylgalactosamine / Q000493:pharmacokinetics*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001692:Biological Transport; D050091:Dendrimers / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D004337:Drug Carriers / Q000138:chemical synthesis*; D016503:Drug Delivery Systems / Q000379:methods; D004705:Endocytosis; D056945:Hep G2 Cells; D006801:Humans; D011073:Polyamines / Q000737:chemistry / Q000494:pharmacology*; D011108:Polymers
chemical_list: D000970:Antineoplastic Agents; D050091:Dendrimers; D004337:Drug Carriers; C531249:Poly(amidoamine); D011073:Polyamines; D011108:Polymers; D000116:Acetylgalactosamine