Recombinant modular transporters for cell-specific nuclear delivery of locally acting drugs enhance photosensitizer activity

Date

2003

Authors

Rosenkranz, Andrey
Lunin, Vladimir
Gulak, Pavel
Sergienko, Olga
Schumiantseva, Maria
Voronina, Olga
Gilyazova, Dinara
John, Anna
Kofner, Anna
Mironov, Andrey

Journal Title

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Volume Title

Publisher

Federation of American Societies for Experimental Biology

Abstract

The search for new pharmaceuticals that are specific for diseased rather than normal cells in the case of cancer and viral disease has raised interest in locally acting drugs that act over short distances within the cell and for which different cell compartments have distinct sensitivities. Thus, photosensitizers (PSs) used in anti-cancer therapy should ideally be transported to the most sensitive subcellular compartments in order for their action to be most pronounced. Here we describe the design, production, and characterization of the effects of bacterially expressed modular recombinant transporters for PSs comprising 1) alpha-melanocyte-stimulating hormone as an internalizable, cell-specific ligand; 2) an optimized nuclear localization sequence of the SV40 large T-antigen; 3) an Escherichia coli hemoglobin-like protein as a carrier; and 4) an endosomolytic amphipathic polypeptide, the translocation domain of diphtheria toxin. These modular transporters delivered PSs into the nuclei, the most vulnerable sites for the action of PSs, of murine melanoma cells, but not non-MSH receptor-overexpressing cells, to result in cytotoxic effects several orders of magnitude greater than those of nonmodified PSs. The modular fusion proteins described here for the first time, capable of cell-specific targeting to particular subcellular compartments to increase drug efficacy, represent new pharmaceuticals with general application.

Description

Keywords

Keywords: alpha intermedin; antineoplastic agent; bacteriochlorin; dihydropteridine reductase; drug carrier; Escherichia coli protein; hemoprotein; hmp protein, E coli; hybrid protein; oxidoreductase; photosensitizing agent; porphyrin; animal; article; biological m

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Source

FASEB Journal

Type

Journal article

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