A simple approach to cancer therapy afforded by multivalent pseudopeptides that target cell-surface nucleoproteins.

Recent studies have implicated the involvement of cell surface forms of nucleolin in tumor growth. In this study, we investigated whether a synthetic ligand of cell-surface nucleolin known as N6L could exert antitumor activity. We found that N6L inhibits the anchorage-dependent and independent growth of tumor cell lines and that it also hampers angiogenesis. Additionally, we found that N6L is a proapoptotic molecule that increases Annexin V staining and caspase-3/7 activity in vitro and DNA fragmentation in vivo. Through affinity isolation experiments and mass-spectrometry analysis, we also identified nucleophosmin as a new N6L target. Notably, in mouse xenograft models, N6L administration inhibited human tumor growth. Biodistribution studies carried out in tumor-bearing mice indicated that following administration N6L rapidly localizes to tumor tissue, consistent with its observed antitumor effects. Our findings define N6L as a novel anticancer drug candidate warranting further investigation.

"HFP" fluorinated cationic lipids for enhanced lipoplex stability and gene delivery.

Although a great number of cationic lipids have been designed and evaluated as gene delivery systems, there is still a need for improvement of nonviral vectors. Recently, cationic lipids incorporating terminal fluoroalkyl segments ("FHP" lipids) have been described to display remarkable transfection potency. Here, we describe the synthesis of a new family of fluorinated triblock cationic lipids in which a fluorous segment lays between the cationic and the lipophilic parts of the molecule ("HFP" lipids). The compounds were designed so their self-assembly would offer enhanced resistance toward the host's degradation mechanisms mediated by lipophilic insertion. Self-assembly properties of these cationic lipids were evaluated at the air-water interface where they collapse in a highly ordered liquid phase. The HFP lipids efficiently condense DNA, and the resulting lipoplexes display enhanced resistance to amphiphilic agents when compared to nonfluorinated or FHP cationic lipids. Transfection properties of the fluorinated vectors, alone or as mixtures with different helper lipids (DOPE and a fluorinated analogue of DOPE), were then investigated on different cell lines (BHK-21, HepG2, and HeLa) and compared to those of the reference cationic lipid DOTAP. Data show that impermeabilization of the lipidic phase by fluorous segments alter significantly the gene transfection activities. Remarkably, incorporation of DOPE within the lipoplexes provides the particles with high gene transfection activity without reducing their resistance to amphiphilic agents.