Abstract 2319: Target selective drug delivery through liposomes labeled with tetra-branched neurotensin peptides

Abstract

Abstract Aim of the study was to construct and test liposomes labeled with tetra-branched receptor-specific peptides for target selective drug delivery. Membrane receptors for endogenous peptides, like neurotensin (NT), are over-expressed by different human cancers and can be targeted as tumor-specific antigens. We found that peptide sequences, when synthesized in an oligo-branched form, become resistant to proteolysis and thanks to their multimericity are more efficient than corresponding monomers in binding cellular antigens (1). In previous works we developed tetra-branched NT peptides (NT4), which can be used as ‘theranostics’, by addition of different functional units to the tumor targeting sequence (2-4). Here we describe the synthesis of liposomes filled with the cytotoxic drug doxorubicin (Doxo) and functionalized on the external surface with a tetra-branched neurotensin peptide. The new functionalized liposomes, DOPC/NT4Lys(C18)2 (NT4-liposomes), are obtained by co-aggregation of the DOPC phospholipid with a new synthetic amphiphilic molecule, NT4Lys(C18)2, containing a lysine scaffold derivatized with a lypophilic moiety and the tetrabranched hydrophilic NT peptide. Selective internalization and cytotoxicity of NT4-liposomes and DOPC nude liposome, both loaded with doxorubicin, were tested in different human cancer cell lines. Peptide-functionalized liposomes showed a clear advantage with respect to DOPC nude liposomes in drug internalization, as followed either by confocal microscopy or cytofluorimetry. Cytotoxicity of NT4-Doxo-liposomes is increased with respect to DOPC-Doxo liposomes. The higher rate of internalization of NT4-Doxo-liposomes, might be due to a lower dissociation constant of the NT4-liposomes that bind the membrane onto a specific protein, differently to the DOPC liposomes that approach the plasma membrane unselectively. These results are highly encouraging for an in vivo use of NT4-liposomes, considering that we already proved that, thanks to their cell selectivity, drug armed NT4 are much more effective in mice cancer models than in in vitro cytotocity experiments. References. 1. Bracci et al. J Biol Chem. 2003, 278, 46590-5. 2. Falciani et al. Mol. Cancer Ther. 2007, 6, 2441-8. 3. Falciani et al. Curr. Cancer Drug Targets, 2010, 10, 695-04. 4. Falciani et al. ChemMedChem 2010, 5, 567-74. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2319. doi:10.1158/1538-7445.AM2011-2319