Tumour Targeting with Rationally Modified Cell-Penetrating Peptides |
| |
Authors: | Maarja M?e Outi Rautsi Juulia Enb?ck Mattias H?llbrink Katri Rosenthal Aizman Maria Lindgren Pirjo Laakkonen ülo Langel |
| |
Affiliation: | 1. Department of Neurochemistry, The Arrhenius Laboratories for Natural Sciences, Stockholm University, 106 91, Stockholm, Sweden 5. Department of Vascular Biology, MBB, Karolinska Institute, 171 77, Stockholm, Sweden 2. A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland 3. Department of Laboratory Medicine, Karolinska Institute, 14157, Huddinge, Sweden 6. Dilafortte AB, 17165, Solna, Sweden 4. Research Programs Unit, Molecular Cancer Biology and Institute of Biomedicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland
|
| |
Abstract: | Cell-penetrating peptides (CPPs) are short transport peptides with a well-established ability for delivery of bioactive cargoes inside the cells both, in vitro and in vivo. CPPs enter unselectively in a wide variety of cell lines, this is a desirable property for most in vitro applications, however, in vivo e.g. in tumor models, specific targeted accumulation is required. In order to achieve tumor targeting, a known CPP, YTA4, was modified by prolonging it C-terminally with mainly negatively charged amino acids. Additionally, a matrix metalloproteinase-2 cleavage site was introduced between the CPP and the inactivating sequence. This new peptide, named NoPe, is an inactive pro-form of YTA4. It can be selectively cleaved and thereby activated by MMPs. We have conjugated an imaging agent, fluoresceinyl carboxylic acid, and a cytostatic agent methotrexate, to this activable pro-form. NoPe activation was demonstrated in vitro by recombinant MMP-2 cleavage and the cleavage of the attenuating sequence was abolished with MMP-2 specific inhibitor. Furthermore, the fluoresceinyl-NoPe is selectively accumulated in the tumor tissue in MDA-MB-231 tumor bearing mice after intravenous injection. Thus, this strategy proves to be successful for in vivo tumor imaging. |
| |
Keywords: | |
本文献已被 SpringerLink 等数据库收录! |
|