title: Targeting hepatic cancer cells with pegylated dendrimers displaying N-acetylgalactosamine and SP94 peptide ligands.
abstract: Poly(amidoamine) (PAMAM) dendrimers are branched water-soluble polymers defined by consecutive generation numbers (Gn) indicating a parallel increase in size, molecular weight, and number of surface groups available for conjugation of bioactive agents. In this article, we compare the biodistribution of N-acetylgalactosamine (NAcGal)-targeted [(14) C]1 -G5-(NH2 )5 -(Ac)108 -(NAcGal)14 particles to non-targeted [(14) C]1 -G5-(NH2 )127 and PEGylated [(14) C]1 -G5-(NH2 )44 -(Ac)73 -(PEG)10 particles in a mouse hepatic cancer model. Results show that both NAcGal-targeted and non-targeted particles are rapidly cleared from the systemic circulation with high distribution to the liver. However, NAcGal-targeted particles exhibited 2.5-fold higher accumulation in tumor tissue compared to non-targeted ones. In comparison, PEGylated particles showed a 16-fold increase in plasma residence time and a 5-fold reduction in liver accumulation. These results motivated us to engineer new PEGylated G5 particles with PEG chains anchored to the G5 surface via acid-labile cis-aconityl linkages where the free PEG tips are functionalized with NAcGal or SP94 peptide to investigate their potential as targeting ligands for hepatic cancer cells as a function of sugar conformation (α versus β), ligand concentration (100-4000 nM), and incubation time (2 and 24 hours) compared to fluorescently (Fl)-labeled and non-targeted G5-(Fl)6 -(NH2 )122 and G5-(Fl)6 -(Ac)107 -(cPEG)15 particles. Results show G5-(Fl)6 -(Ac)107 -(cPEG[NAcGalβ ])14 particles achieve faster uptake and higher intracellular concentrations in HepG2 cancer cells compared to other G5 particles while escaping the non-specific adsorption of serum protein and phagocytosis by Kupffer cells, which make these particles the ideal carrier for selective drug delivery into hepatic cancer cells.
authors.affiliation: University of Michigan, Department of Biomedical Engineering, 1101 Beal Avenue, Lurie Biomedical Engineering Building, Room 2150, Ann Arbor, MI 48109, USA, Web: www.bme.umich.edu/centlab.php.
authors.forename: Scott H
authors.initials: SH
authors.lastname: Medina
authors.forename: Gopinath
authors.initials: G
authors.lastname: Tiruchinapally
authors.forename: Maxim V
authors.initials: MV
authors.lastname: Chevliakov
authors.forename: Yasemin Yuksel
authors.initials: YY
authors.lastname: Durmaz
authors.forename: Rachell N
authors.initials: RN
authors.lastname: Stender
authors.forename: William D
authors.initials: WD
authors.lastname: Ensminger
authors.forename: Donna S
authors.initials: DS
authors.lastname: Shewach
authors.forename: Mohamed E H
authors.initials: ME
authors.lastname: Elsayed
mesh_terms: D000116:Acetylgalactosamine / Q000737:chemistry*; D000117:Acetylglucosamine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D000818:Animals; D019011:Antigens, CD7 / Q000737:chemistry / Q000378:metabolism; D002478:Cells, Cultured; D050091:Dendrimers / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D005456:Fluorescent Dyes / Q000737:chemistry; D006207:Half-Life; D056945:Hep G2 Cells; D006801:Humans; D007728:Kupffer Cells / Q000166:cytology / Q000187:drug effects; D008024:Ligands; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D010316:Particle Size; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D010587:Phagocytosis; D011092:Polyethylene Glycols / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D013997:Time Factors; D014018:Tissue Distribution; D014183:Transplantation, Heterologous
chemical_list: D019011:Antigens, CD7; D050091:Dendrimers; D005456:Fluorescent Dyes; D008024:Ligands; C104700:PAMAM Starburst; D010455:Peptides; D011092:Polyethylene Glycols; D000116:Acetylgalactosamine; D000117:Acetylglucosamine
keywords: N-acetylgalactosamine sugar ligands; PAMAM dendrimers; kupffer cells; particle opsonization; targeting hepatic cancer cells