Porphyrin-based nanomaterials frequently require non-physiological conditions to promote non-covalent assembly limiting therapeutic utility. In the present studies, we demonstrate that single-stranded DNA (ssDNA) modulates non-covalent assembly of meso-tetra-4-pyridyl porphine (MTP) and that the resulting porphyrin:DNA nano-sized complexes (PDN) are stable indefinitely in aqueous solution under physiologically relevant conditions and undergo pH-dependent DNA release under moderately acidic conditions (pH 5.1) that protonate the pyridyl nitrogens of MTP. The biological utility of pH-dependent DNA release from PDN was demonstrated by endosomal release of DNA in cancer cells. PDN formation is DNA-dependent with the ratio of porphyrin:DNA being approximately two DNA nucleobases per porphyrin consistent with half the pyridyl side chains of MTP interacting with DNA nucleobases. Raman spectra display surface-enhanced features for the porphyrin in the context of PDN consistent with π-π stacking of porphyrins and DNA nucleobases being a principal driving force for PDN assembly, a result also consistent with enhanced PDN dissociation in more hydrophobic solvent systems. PDN produce reactive oxygen species (ROS) in a light-dependent manner under conditions that favor dissociation, such as in hydrophobic environments as occurs upon endocytosis or 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 resulted from ROS-mediated localized membrane damage with mass spectrometry confirming the generation of the lipid peroxidation products9- and 13-hydroxy octadecanoic acid. Our results demonstrate that PDN have properties useful for therapeutic applications, including cancer treatment.

Citation Format: William H. Gmeiner, Supratim Ghosh, Kamil B. Ucer, Richard T. Williams, Ralph D'Agostino, Ken Grant, Joseph Sirintrapun, Michael Thomas, Roy Hantgan, Manish Bharadwaj. Non-covalent assembly of meso-tetra-4-pyridyl porphine with single-stranded DNA to form nano-sized complexes with pH-dependent DNA release and anti-tumor activity. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-6. doi:10.1158/1538-7445.AM2013-LB-6