title: Cationic poly(amidoamine) dendrimer induces lysosomal apoptotic pathway at therapeutically relevant concentrations.
abstract: Poly(amidoamine) (PAMAM) dendrimers carrying different amounts of surface amino groups were synthesized and tested for their effects on cellular cytotoxicity, lysosomal pH, and mitochondria-dependent apoptosis. In KB cells, the PAMAM dendrimers were taken up into the lysosomal compartment, and they increased the lysosomal pH and cytotoxicity as a function of the number of surface amino groups on the dendrimer. PAMAM dendrimers that were surface-neutralized by acetylation of >80% of the surface amino groups failed to show any cytotoxicity. The positively charged, amine-terminated PAMAM dendrimer induced cellular apoptosis, as demonstrated by mitochondrial membrane potential changes and caspase activity measurements. These results suggest that PAMAM dendrimers are endocytosed into the KB cells through a lysosomal pathway, leading to lysosomal alkalinization and induction of mitochondria-mediated apoptosis.
authors.affiliation: Department of Internal Medicine, Division of Allergy, Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan, 9220 MSRB III, Box 0648, Ann Arbor, Michigan 48109, USA. thommey@umich.edu
authors.forename: Thommey P
authors.initials: TP
authors.lastname: Thomas
authors.forename: Istvan
authors.initials: I
authors.lastname: Majoros
authors.forename: Alina
authors.initials: A
authors.lastname: Kotlyar
authors.forename: Douglas
authors.initials: D
authors.lastname: Mullen
authors.forename: Mark M Banaszak
authors.initials: MM
authors.lastname: Holl
authors.forename: James R
authors.initials: JR
authors.lastname: Baker
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D050091:Dendrimers; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008247:Lysosomes / Q000187:drug effects*; D008928:Mitochondria / Q000187:drug effects; D011073:Polyamines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D050091:Dendrimers; C104700:PAMAM Starburst; D011073:Polyamines