Targeted Intracellular Site-Specific Drug Delivery: Photosensitizer Targeting to Melanoma Cell Nuclei |
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Authors: | A A Rosenkranz V G Lunin O V Sergienko D G Gilyazova O L Voronina D E Jans A A Kofner M A Shumiantseva A F Mironov A S Sobolev |
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Institution: | (1) Institute of Gene Biology, Russian Academy of Sciences, Moscow, 119334, Russia;(2) Department of Biophysics, Biological faculty, Moscow State University, Moscow, 119899, Russia;(3) All-Russia Institute of Agricultural Biotechnology, Russian Academy of Agricultural Sciences, Moscow, 127550, Russia;(4) Bach Institute of Biochemistry, Russian Academy of Sciences, Moscow, 119071, Russia;(5) Curtin Higher School of Medical Research, Australian National University, POB 334 Canberra, Australia;(6) Department of Chemistry and Technology of Fine Chemicals, Lomonosov Moscow Academy of Fine Chemical Technology, Moscow, 117571, Russia |
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Abstract: | A number of drugs are regarded as possessing local activity because their effects take place at an extremely short distance from their location site in the cell. The response of different cellular compartments to these effects is different. Such substances as photosensitizers (PSs), which are used in photodynamic cancer therapy, should be targeted to the cell compartments where their effect is the most pronounced. This study describes the construction and properties of the chimeric modular recombinant transporters (MRTs) expressed in Escherichia coli and used for PS targeting. These constructs include (1) the -melanocyte-stimulating hormone as a ligand module, which is internalized by the target cells (mouse melanoma); (2) the optimized SV40 large T-antigen nuclear localization signal; (3) the hemoglobin-like protein from E. coli as a carrier module; (4) the endosomolytic module, the translocation domain of the diphtheria toxin. These MRTs were used for PS targeting to the mouse melanoma cell nuclei, the most PS-damaged intracellular compartment, which resulted in a PS photocytotoxic effect increase of several orders of magnitude. In our opinion, MRTs, which target locally active drugs into the desired cell compartment and thereby enhance the drug response, represent a new generation of the pharmacological agents. |
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