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TUMOR SELECTIVE DRUG DELIVERY BY NEUROTENSIN BRANCHED PEPTIDES
Author(s) -
Lorenzo Depau,
Jlenia Brunetti,
Chiara Falciani,
Barbara Lelli,
N. Ravenni,
Alessandro Pini,
Luisa Lozzi,
A. Accardo,
D. Tesauro,
G. Morelli,
Luisa Bracci
Publication year - 2012
Publication title -
journal of the siena academy of sciences
Language(s) - English
Resource type - Journals
eISSN - 2279-882X
pISSN - 2279-8811
DOI - 10.4081/491
Subject(s) - internalization , neurotensin , peptide , chemistry , drug delivery , oligopeptide , liposome , targeted drug delivery , biochemistry , receptor , biology , neuropeptide , organic chemistry
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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