Study On Targeting For Tumor Cells Detecting VEGER2

Presently, chemotherapy is an essential and efficient therapeutic modality of tumor. But that normal chemotherapeutic drug without targeting can kill both tumor cells and normal cells have a risk of toxic and side effects. In oncology, there is a growing need for simpler and more selective methods to deliver drug therapies directly to the tumor site. Presently, a kind of nanoscale carrier-Liposomal has been followed and applied in loading antineoplastic drugs which are hydrophobic or hydrophilic for its excellent biocompatibility and active targeting. But after liposomes enter the body, that drugs may release before they are loaded in the target would influence curative effect of drugs. Meanwhile, as the diversity and specificity of tumor, simplex therapeutic schedule cannot make it, so now one of the most effective therapeutic schedule is combination therapies.For combination therapies, simultaneous targeted delivery of multiple drugs would represent a significant improvement. In contrast to previous work that took a de novo approach, we constructed a novel two-in-one liposomal system (TWOLips) from two single drug-loaded liposomes. Our results demonstrated that TWOLips could be prepared by a simple process, through silica coating of one liposome and incubation with the second liposome. After liposomes are characterized by transmission electron microscope, infrared spectrum and laser confocal microscop, we find that they have lipid-silica-lipid multiple compound structure. This result tells us TWOLips is available. TWOLips had a mean diameter of 100 nm, relatively high drug loading rates (96.8±0.9% for Doxorubicin and 78.4±1.2% for Combretastatin), high storage stability and good release characteristics.TWOLips modification by adding a targeting moiety, an all D-amino acid peptide derived from a natural vascular endothelial growth factor, resulted in strong, selective binding to vascular endothelial growth factor receptor 2 (VEGFR2), a tumorigenesis marker, in vitro and in vivo. VEGFR2 is over expressed on the tumor cells and tumor microenvironment, and VEGF/VEGFR2 signaling pathway can promote the formation of tumor blood vessels. So we can inhibit the growth and metastasis of tumor cells by blocking the signaling pathway. RIV peptide is proved to highly target for VEGFR2 by the evaluation of the cellular uptake test in vitro and in vivo imaging technology. And RIV peptide-modified TWOLips system also exhibits similar targeting for VEGFR2. The results of pharmacodynamic test in vitro show that TWOLips system mediated by RIV peptide (RIV-L[CD]) decrease the IC50 values of A375 cells and HUVEC cells, compared with other preparations (Doxorubicin(DOX), Doxorubicin Liposome(L[D]), Doxorubicin Liposome mixture with Combretastatin Liposome (L[D]+L[C]), TWOLips system without RIV peptide), and they also show that combined administration, sequential release and RIV peptide-mediation have positive effect to active targeting of drug loading system. TWOLips significantly inhibited tumor growth and angiogenesis and enhanced survival in mice with A375 melanoma xenografts. The TWOLips system had a low potential risk of toxicity, it can be applied in the future.In conclusion, the novel two-in-one liposomal system (TWOLips) that we constructed not only improves the shortage that normal liposome is instable, but also increases its anti-tumor effects. Meanwhile, it is also a safe drug loading with low toxicity. Besides, we can add more single drug-loaded liposomes as required. Since the stepwise assembly could be carried further (additional drug-loaded liposomes), TWOLips shows potential as a treatment for many cancers, especially those that require multiple drugs.