title: Non-covalent assembly of meso-tetra-4-pyridyl porphine with single-stranded DNA to form nano-sized complexes with hydrophobicity-dependent DNA release and anti-tumor activity.
abstract: DNA and porphyrin based therapeutics are important for anti-cancer treatment. The present studies demonstrate single-stranded DNA (ssDNA) assembles with meso-tetra-4-pyridyl porphine (MTP) forming porphyrin:DNA nano-complexes (PDN) that are stable in aqueous solution under physiologically relevant conditions and undergo dissociation with DNA release in hydrophobic environments, including cell membranes. PDN formation is DNA-dependent with the ratio of porphyrin:DNA being approximately two DNA nucleobases per porphyrin. PDN produce reactive oxygen species (ROS) in a light-dependent manner under conditions that favor nano-complex dissociation in the presence of hydrophobic solvents. PDN induce light-dependent cytotoxicity in vitro and anti-tumor activity towards bladder cancer xenografts in vivo. Light-dependent, PDN-mediated cell death results from ROS-mediated localized membrane damage due to lipid peroxidation with mass spectrometry indicating the generation of the lipid peroxidation products 9- and 13-hydroxy octadecanoic acid. Our results demonstrate that PDN have properties useful for therapeutic applications, including cancer treatment.
  
  
  BACKGROUND
  In this study, porphyrin-DNA nanocomplexes were investigated as anti-cancer therapeutics inducing ROS production in a light-dependent manner. Efficacy is demonstrated in vitro as well as a in a bladder cancer xenograft model.
authors.affiliation: Program in Molecular Genetics, Wake Forest School of Medicine, Winston-Salem, NC, USA; Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Supratim
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: Department of Physics, Wake Forest University, Winston-Salem, NC, USA.
authors.forename: Kamil B
authors.initials: KB
authors.lastname: Ucer
authors.affiliation: Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Ralph
authors.initials: R
authors.lastname: D'Agostino
authors.affiliation: Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Ken
authors.initials: K
authors.lastname: Grant
authors.affiliation: Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Sirintrapun
authors.affiliation: Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Thomas
authors.affiliation: Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Roy
authors.initials: R
authors.lastname: Hantgan
authors.affiliation: Department of Genrontology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Manish
authors.initials: M
authors.lastname: Bharadwaj
authors.affiliation: Program in Molecular Genetics, Wake Forest School of Medicine, Winston-Salem, NC, USA; Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC, USA; Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, NC, USA. Electronic address: bgmeiner@wakehealth.edu.
authors.forename: William H
authors.initials: WH
authors.lastname: Gmeiner
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry*; D016923:Cell Death; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D004277:DNA, Single-Stranded / Q000737:chemistry*; D011992:Endosomes; D005260:Female; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D015227:Lipid Peroxidation; D051379:Mice; D008819:Mice, Nude; D050997:Nanomedicine; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy*; D017319:Photosensitizing Agents / Q000737:chemistry; D011166:Porphyrins / Q000737:chemistry*; D017382:Reactive Oxygen Species; D013229:Stearic Acids / Q000737:chemistry; D001749:Urinary Bladder Neoplasms / Q000628:therapy
chemical_list: D000970:Antineoplastic Agents; D004277:DNA, Single-Stranded; D017319:Photosensitizing Agents; D011166:Porphyrins; D017382:Reactive Oxygen Species; D013229:Stearic Acids; C021096:tetra(4-N-methylpyridyl)porphine
keywords: Cancer therapy; Multi-modality nanoparticle; Photodynamic therapy; Porphyrin: DNA assembly