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Background  Treatment of tumors with macromolecular toxins directed to cytoplasmic targets requires selective endocytosis followed by release of intact toxin from the endosomal/lysosomal compartment. The latter step remains a particular challenge. Claudins 3 and 4 are tight junction proteins that are over-expressed in many types of tumors. This study utilized the C-terminal 30 amino acid fragment of  C. perfringens  enterotoxin (CPE), which binds to claudins 3 and 4, to deliver a toxin in the form of recombinant gelonin (rGel) to the cytoplasm of the human ovarian carcinoma cell line 2008.    Results  CPE was fused to rGel at its N-terminal end via a flexible G 4 S linker. This CPE-G 4 S-rGel molecule was internalized into vesicles from which location it produced little cytotoxicity. To enhance release from the endosomal/lysosomal compartment a poly-arginine sequence (R 9 ) was introduced between the CPE and the rGel. CPE-R 9 -rGel was 10-fold more cytotoxic but selectivity for claudin-expressing cells was lost. The addition of a poly-glutamic acid sequence (E 9 ) through a G 4 S linker to R 9 -rGel (E 9 -G 4 S-R 9 -rGel) largely neutralized the non-selective cell membrane penetrating activity of the R 9  motif. However, introduction of CPE to the E 9 -G 4 S-R 9 -rGel fusion protein (CPE-E 9 -G 4 S-R 9 -rGel) further reduced its cytotoxic effect. Treatment with the endosomolytic reagent chloroquine increased the cytotoxicity of CPE-E 9 -G 4 S-R 9 -rGel. Several types of linkers susceptible to cleavage by furin and endosomal cathepsin B were tested for their ability to enhance R 9 -rGel release but none of these modifications further enhanced the cytotoxicity of CPE-E 9 -G 4 S-R 9 -rGel.    Conclusion  We conclude that while a claudin-3 and -4 ligand serves to deliver rGel into 2008 cells the delivered molecules were entrapped in intracellular vesicles. Incorporation of R 9  non-specifically increased rGel cytotoxicity and this effect could be masked by inclusion of an E9 sequence. However, the putative protease cleavable sequences tested were inadequate for release of R 9 -rGel from CPE-E 9 -G 4 S-R 9 -rGel.

bmc cancer

Challenges associated with the targeted delivery of gelonin to claudin-expressing cancer cells with the use of activatable cell penetrating peptides to enhance potency