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

Nanomedicine. 2014 Feb;10(2):451-61. doi: 10.1016/j.nano.2013.07.019. Epub 2013 Aug 27.

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.

From the clinical editor: 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.

Keywords: Cancer therapy; Multi-modality nanoparticle; Photodynamic therapy; Porphyrin: DNA assembly.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry*
  • Cell Death
  • Cell Line, Tumor
  • Cell Membrane / metabolism
  • DNA, Single-Stranded / chemistry*
  • Endosomes
  • Female
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Lipid Peroxidation
  • Mice
  • Mice, Nude
  • Nanomedicine
  • Neoplasm Transplantation
  • Neoplasms / drug therapy*
  • Photosensitizing Agents / chemistry
  • Porphyrins / chemistry*
  • Reactive Oxygen Species
  • Stearic Acids / chemistry
  • Urinary Bladder Neoplasms / therapy

Substances

  • Antineoplastic Agents
  • DNA, Single-Stranded
  • Photosensitizing Agents
  • Porphyrins
  • Reactive Oxygen Species
  • Stearic Acids
  • tetra(4-N-methylpyridyl)porphine