[Targeted intracellular site-specific drug delivery: photosensitizer targeting to melanoma cell nuclei].
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 alpha-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.
Rozenkrants
A A
AA
Institute of Gene Biology, Russian Academy of Sciences, Department of Biophysics, Lomonosov Moscow State University, Moscow, Russia.
Lunin
V G
VG
Sergienko
O V
OV
Giliazova
D G
DG
Voronina
O L
OL
Ians
D E
DE
Kofner
A A
AA
Shumiantseva
M A
MA
Mironov
A F
AF
Sobolev
A S
AS
D000595:Amino Acid Sequence; D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D002352:Carrier Proteins / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D002451:Cell Compartmentation; D002467:Cell Nucleus / Q000187:drug effects*; D004167:Diphtheria Toxin / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D016503:Drug Delivery Systems / Q000379:methods; D004926:Escherichia coli / Q000235:genetics; D029968:Escherichia coli Proteins / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008969:Molecular Sequence Data; D009928:Organ Specificity; D017319:Photosensitizing Agents / Q000008:administration & dosage*; D010957:Plasmids / Q000235:genetics; D015202:Protein Engineering / Q000379:methods; D011994:Recombinant Proteins / Q000008:administration & dosage* / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D014407:Tumor Cells, Cultured; D000521:alpha-MSH / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism
D000952:Antigens, Polyomavirus Transforming; D000970:Antineoplastic Agents; D002352:Carrier Proteins; D004167:Diphtheria Toxin; D029968:Escherichia coli Proteins; D017319:Photosensitizing Agents; D011994:Recombinant Proteins; D000521:alpha-MSH