Dendrimer-based BH3 conjugate that targets human carcinoma cells.
Our previous studies have demonstrated the efficacy of generation 5 poly(amidoamine) dendrimers (G5-PAMAM) as a platform for the targeted delivery of chemotherapeutics. However, anticancer therapy can be subverted by anti-apoptotic changes in cancer cells. Bcl-2 and several of its peptides are commonly overexpressed in a number of cancers. A means to reverse this anti-apoptotic mechanism is to expose the cells to BH3 peptide, which has a homology to the anti-apoptotic Bcl-2 protein. This cannot be done indiscriminately because it can induce apoptosis in normal cells. In order to specifically target BH3 peptides to cancer cells, we synthesized a trifunctional, G5-PAMAM-based nanodevice to which folic acid was conjugated as a targeting agent, along with fluorescein isothiocyanate as the reporter agent and BH3 peptides that were used to induce apoptosis. The results show, for the first time, the therapeutic potential of targeted BH3 peptides as a means of inducing apoptosis by interfering with anti-apoptotic proteins within specific cells.
Myc
Andrzej
A
Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan Medical School, BSRB, Ann Arbor, MI 48109-0648, USA. myca@umich.edu
Patri
Anil K
AK
Baker
James R
JR
D017209:Apoptosis; D001672:Biocompatible Materials / Q000737:chemistry; D045744:Cell Line, Tumor; D050091:Dendrimers; D005434:Flow Cytometry; D016650:Fluorescein-5-isothiocyanate / Q000494:pharmacology; D005492:Folic Acid / Q000737:chemistry; D006801:Humans; D019169:Jurkat Cells; D046911:Macromolecular Substances / Q000737:chemistry; D008856:Microscopy, Fluorescence; D053758:Nanoparticles / Q000737:chemistry; D049329:Nanostructures / Q000737:chemistry; D010446:Peptide Fragments / Q000378:metabolism; D010455:Peptides / Q000737:chemistry; D011073:Polyamines / Q000737:chemistry; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D013778:Tetrazolium Salts / Q000737:chemistry
C474007:Bax protein (53-86); D001672:Biocompatible Materials; D050091:Dendrimers; D046911:Macromolecular Substances; C104700:PAMAM Starburst; D010446:Peptide Fragments; D010455:Peptides; D011073:Polyamines; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D013778:Tetrazolium Salts; C059087:2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-((phenylamino)carbonyl)-2H-tetrazolium hydroxide; D005492:Folic Acid; D016650:Fluorescein-5-isothiocyanate