Supramolecular Approach to TTD: Application of Novel Porphyrin Derivatives for Drug Transport and Combined Therapy.

The uptake of exogenous molecules such as drugs into cells can arise from a variety of mechanisms that can be broadly classified as active and passive transport. Aktive uptake requires that target molecules be recognized by specific intermolecular interactions, selected, and shuttled across the cell membrane by receptors. Thus, molecules may be targeted toward these receptors by appending appropriate substrate moieties. Conversely, passive uptake involves diffusion at some point in the process and arises from nonspecific cell-molecule interactions. Because of the lipid membrane core, the more lipophilic a molecule, the košer the barrier to traversing through the cell membrane, whereas amphipathic molecules will nominally bind at the interface or polar region and have greater barriers to crossing the membráně. Here we describe application of porphyrin-cycclodextrin conjugates for targeted drug delivery os cytostatik drugs in combination with photodynamic therapy. Porphyrin chemistry has undergone a renaissance over the past ten years due to potential applications of these compounds in areas including photodynamic therapy, solar energy conversion and catalysis. Porphyrin, a representative of conjugated tetrapyrrolic macrocycles, has been a potent candidate for diverse applications in the areas of biology, medicine, material science and catalysis. Novel fluorinated porphyrins with oligoethyleneglycol, oligopeptide, distamycin analogues, mono-, disaccharide, and ?-cyclodextrin substitution showed significant photosensitizing potential in vitro and in vivo and displayed an increased selectivity for malignant tissue. The objective of this study was to explore their capaci ty to induce apoptosis. To study the mechanism of their action, we have investigated uptake, intracellular localization, cell phototoxicity and morphological and biochemical changes following photodynamic treatment in human leukemic cell line HL60 and also other tumor cells. Some of our novel PS exhibited a very effective induction of apoptosis as demonstrated by condensation of chromatin, DNA fragmentation, cytochrom c release, a loss of membrane phospholipids asymmetry (as evidenced by the externalization of phosphatidylserine), and an increase in caspase-3 protease activity. Moreover, polymethine and other polycationic porphyrin derivatives ex hibit not only very specific tumor localization, but also into-cell antisense oligonucleotide transport properties as was demonstrated on the primary leukemic cells.