TUMOR SELECTIVE DRUG DELIVERY BY NEUROTENSIN BRANCHED PEPTIDES

Submitted: 16 May 2012
Accepted: 16 May 2012
Published: 16 May 2012
Abstract Views: 838
PDF: 1076
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Detection of new tumor-selective targets, which allow either cancer cell tracing or therapy, is a crucial issue in cancer research. Membrane receptors for endogenous peptides such as Neurotensin are over-expressed in many human cancers and could therefore be used as tumor-specific antigen, while peptide ligands might act as targeting agents. The development of peptides as drug has always been limited by their short half-life, due to degradation by peptidases and proteases. Chemical modification, which can stabilize the molecules, may modify peptide affinity or specificity. More- over, coupling of peptides to effector units for imaging or therapy, may interfere with biological activity. We demonstrated that peptide sequences, when synthesized in an oligo-branched form, be- come resistant to proteolysis and thank to their multimericity are more efficient than correspon- ding monomers in binding cellular antigens1. Moreover, the branched core allow coupling of effector units without affecting peptide activity. Drug-armed tetra-branched neurotensin peptides (NT4) were synthesized with different conjugation methods, resulting either in uncleavable adducts or drug-releasing molecules2-4. Recently we de- veloped DOPC liposomes filled with the cytotoxic drug Doxorubicin (Doxo) and functionalized with NT4. Armed DOPC liposomes showed a clear advantage with respect to nude liposomes in drug internalization and their cytotoxicity is fourfold increased with respect to the same nude lipo- somes. Conjugation to NT4 switches drug internalization to a peptide-receptor mediated mechanism, which greatly increases drug selectivity and also might allow by-passing drug cell resistance. In vitro and in vivo results indicated that branched NT peptides are valuable tools for tumor selective targeting.

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Depau, L., Brunetti, J., Falciani, C., Lelli, B., Ravenni, N., Pini, A., Lozzi, L., Accardo, A., Tesauro, D., Morelli, G., & Bracci, L. (2012). TUMOR SELECTIVE DRUG DELIVERY BY NEUROTENSIN BRANCHED PEPTIDES. Journal of the Siena Academy of Sciences, 2(1), 57. https://doi.org/10.4081/jsas.2010.491