Adenoviruses synergize with nuclear localization signals to enhance nuclear delivery and photodynamic action of internalizable conjugates containing chlorin e 6

Tamara V. Akhlynina, David A. Jans, Natalia V. Statsyuk, Irina Y. Balashova, Gabor Toth, Imre Pavo, Andrey A. Rosenkranz, Boris S. Naroditsky, Alexander S. Sobolev

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Abstract

Photosensitizers, molecules that produce active oxygen species upon activation by visible light, are currently being used in photodynamic therapy (PDT) to treat cancer and other conditions, where limitations include normal cells and tissue damage and associated side effects, and the fact that cytotoxic effects are largely restricted to the plasma and other peripheral membranes. In this study, we used insulin-containing conjugates to which variants of the simian-virus-SV40 large-tumor antigen (T-ag) nuclear localization signal (NLS) were linked in order to target the photosensitizer chlorin e 6 to the nucleus. NLSs were included either as peptides coupled co- valently to the carrier bovine serum albumin, or within the coding sequence of β-galactosidase fusion proteins. The most potent photosensitizing conjugate was the NLS-containing T-ag β-galactosidase fusion protein (P10)- (chlorin e 6 )-insulin, exhibiting an EC 50 more than 2400-fold lower than the value for free chlorin e 6 , and more than 15-fold lower than that of an NLS-deficient β-galactosidase(chlorin e 6 )-insulin construct, thus demonstrating that NLSs can increase the photosensitizing activity of chlorin e 6 . Attenuated adenoviruses were used to increase the nuclear delivery of conjugates through its endosomal-membrane-disrupting activity. In the case of the NLS-containing P10-conjugate, co-incubation with adenovirus increased the proportion of cells whose nuclear photosensitizing activity was higher than that in the cytoplasm by 2.5-fold. This use of adenoviruses in conjunction with photosensitizers has clear implications for achieving efficient cell- type-specific PDT.

Original languageEnglish
Pages (from-to)734-740
Number of pages7
JournalInternational Journal of Cancer
Volume81
Issue number5
DOIs
Publication statusPublished - 18 May 1999
Externally publishedYes

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