title: Surface conjugation of triphenylphosphonium to target poly(amidoamine) dendrimers to mitochondria.
abstract: Dendrimers have emerged as promising carriers for the delivery of a wide variety of pay-loads including therapeutic drugs, imaging agents and nucleic acid materials into biological systems. The current work aimed to develop a novel mitochondria-targeted generation 5 poly(amidoamine) (PAMAM) dendrimer (G(5)-D). To achieve this goal, a known mitochondriotropic ligand triphenylphosphonium (TPP) was conjugated on the surface of the dendrimer. A fraction of the cationic surface charge of G(5)-D was neutralized by partial acetylation of the primary amine groups. Next, the mitochondria-targeted dendrimer was synthesized via the acid-amine-coupling conjugation reaction between the acid group of (3-carboxypropyl)triphenyl-phosphonium bromide and the primary amines of the acetylated dendrimer (G(5)-D-Ac). These dendrimers were fluorescently labeled with fluorescein isothiocyanate (FITC) to quantify cell association by flow cytometry and for visualization under confocal laser scanning microscopy to assess the mitochondrial targeting in vitro. The newly developed TPP-anchored dendrimer (G(5)-D-Ac-TPP) was efficiently taken up by the cells and demonstrated good mitochondrial targeting. In vitro cytotoxicity experiments carried out on normal mouse fibroblast cells (NIH-3T3) had greater cell viability in the presence of the G(5)-D-Ac-TPP compared to the parent unmodified G(5)-D. This mitochondria-targeted dendrimer-based nanocarrier could be useful for imaging as well as for selective delivery of bio-actives to the mitochondria for the treatment of diseases associated with mitochondrial dysfunction.
authors.affiliation: Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, 312 Mugar Hall, 360 Huntington Ave. Boston, MA 02115, USA.
authors.forename: Swati
authors.initials: S
authors.lastname: Biswas
authors.forename: Namita S
authors.initials: NS
authors.lastname: Dodwadkar
authors.forename: Aleksandr
authors.initials: A
authors.lastname: Piroyan
authors.forename: Vladimir P
authors.initials: VP
authors.lastname: Torchilin
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D050091:Dendrimers / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry*; D005434:Flow Cytometry; D016650:Fluorescein-5-isothiocyanate / Q000737:chemistry; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000737:chemistry*; D041681:NIH 3T3 Cells; D009943:Organophosphorus Compounds / Q000737:chemistry*; D011073:Polyamines / Q000737:chemistry*
chemical_list: D050091:Dendrimers; D009943:Organophosphorus Compounds; C104700:PAMAM Starburst; C531249:Poly(amidoamine); D011073:Polyamines; D016650:Fluorescein-5-isothiocyanate