Target‐Selective Drug Delivery through Liposomes Labeled with Oligobranched Neurotensin Peptides

Abstract

The structure and the in vitro behavior of liposomes filled with the cytotoxic drug doxorubicin (Doxo) and functionalized on the external surface with a branched moiety containing four copies of the 8-13 neurotensin (NT) peptide is reported. The new functionalized liposomes, DOPC-NT₄Lys(C₁₈)₂, are obtained by co-aggregation of the DOPC phospholipid with a new synthetic amphiphilic molecule, NT₄ Lys(C₁₈)₂, which contains a lysine scaffold derivatized with a lipophilic moiety and a tetrabranched hydrophilic peptide, NT8-13, a neurotensin peptide fragment well known for its ability to mimic the neurotensin peptide in receptor binding ability. Dynamic light scattering measurements indicate a value for the hydrodynamic radius (RH) of 88.3±4.4 nm. The selective internalization and cytotoxicity of DOPC-NT₄ Lys(C₁₈)₂ liposomes containing Doxo, as compared to pure DOPC liposomes, were tested in HT29 human colon adenocarcinoma and TE671 human rhabdomyosarcoma cells, both of which express neurotensin receptors. Peptide-functionalized liposomes show a clear advantage in comparison to pure DOPC liposomes with regard to drug internalization in both HT29 and TE671 tumor cells: FACS analysis indicates an increase in fluorescence signal of the NT₄-liposomes, compared to the DOPC pure analogues, in both cell lines; cytotoxicity of DOPC-NT₄ Lys(C₁₈)₂-Doxo liposomes is increased four-fold with respect to DOPC-Doxo liposomes in both HT29 and TE671 cell lines. These effects could to be ascribed to the higher rate of internalization for DOPC-NT₄ Lys(C₁₈)₂-Doxo liposomes, due to stronger binding driven by a lower dissociation constant of the NT₄-liposomes that bind the membrane onto a specific protein, in contrast to DOPC liposomes, which approach the plasma membrane unselectively.

Influence of PEGylation and RGD loading on the targeting properties of radiolabeled liposomal nanoparticles

“…38,39 Previous studies have described the influence of PEG loading on targeting properties in vivo; 7 therefore, it was decided to investigate this behavior in vitro with RLPs carrying varying amounts of PEG. In vitro binding to isolated α v β 3 integrin receptors revealed the highest binding when no PEG building block was used ( Figure 3) and binding decreased with higher PEG loading of the RLPs.…”

Liposomes derivatized with multimeric copies of KCCYSL peptide as targeting agents for HER-2-overexpressing tumor cells

“…[16][17][18] Recently, some evidence that these properties are also maintained when the peptide is bounded on the external liposomal surface have been demonstrated. 19,20 Liposomes were chosen as the vector since they can accommodate large quantities of relevant therapeutic drugs in their lumen. Moreover, the addition of a large amount of the amphiphilic gadolinium complex (C18) 2 DTPA(Gd) to the liposomal formulation allows its use a potential contrast agent for magnetic resonance imaging (MRI).…”

Application of liposomes in drug development – focus on gastroenterological targets

“…108 Functionalization with neurotensin peptides significantly improved the ability of liposomes to deliver chemotherapeutics into CRC cells and resulted in a four fold increase in cytotoxicity. 109 Her2 and VEGFR are overexpressed in many cancer types including gastric cancer 110 and CRC. 111 Anti-Her2 and anti-VEGFR immunoliposomes provide a novel tool for safe and efficient immnochemotherapy of Her2 or VEGFR positive GI cancers.…”