2005 Fiscal Year Final Research Report Summary
Establishment of Antineovascular Therapy by use of Structure-recognizing targeting probes
| Project/Area Number |
15390050
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Medical pharmacy
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| Research Institution | UNIVERSITY OF SHIZUOKA |
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Principal Investigator |
OKU Naoto University of Shizuoka, School of Pharmaceutical Sciences, Professor, 薬学部, 教授 (10167322)
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| Co-Investigator(Kenkyū-buntansha) |
ASAI Tomohiro University of Shizuoka, School of Pharmaceutical Sciences, Assistant professor, 薬学部, 講師 (00381731)
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| Project Period (FY) |
2003 – 2005
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| Keywords | Antineovascular Therapy / Cancer / Drug Delivery System (DDS) / Liposome / Targeting / Active Targeting / Angiogenesis / Photodynamic Therapy |
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| Research Abstract |
We previously developed a new modality of cancer treatment by use of DDS technology, in which anticancer drugs are effectively delivered to the angiogenic endothelial cells of a solid tumor. Antineovascular therapy (ANET) may cause indirect lethal damage of tumor cells through the damage of newly formed blood vessels with reduced side effects. At first, we isolated peptides specific for tumor angiogenic vasculature using a phage-displayed peptide library. Thus obtained pentapeptide APRPG was used for the modification of liposomes. In the present study, we firstly synthesized APRPG-polyethyleneglycol (PEG)-lipid for the purpose of improving ANET. Positron Emission Tomography (PET) study indicated that APRPG-PEG-modified liposomes had long-circulating characteristics and accumulated in tumor in tumor-bearing mice. APRPG-PEG-modified liposomes encapsulating adriamycin caused strong tumor growth suppression through possible damaging of angiogenic endothelial cells. The accumulation of APRP
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G-PEG-liposomes was quite similar to that of control PEG-liposomes. However, intratumoral distribution of APRPG-PEG-liposomes was quite different from the control liposomes : The former colocalized with endothelial cells, and the latter accumulated the surrounding of the blood vessels when the intratumoral distribution of fluorescence-labeled liposomes was examined by confocal laser scanning microscopy. We also observed that the APRPG-PEG-liposomes were quite useful for antiangiogenic photodynamic therapy. To clarify the molecular mechanism of angiogenesis, and to provide novel targets for antineovascular therapy, we performed proteomic analysis of HUVEC treated with VEGF or cancer cells-conditioned medium by two-dimensional difference in-gel electrophoresis (2D-DIGE) and identified differentially expressed proteins by MALDI-TOF-MS. Proteomic analysis of HUVEC treated with VEGF detected >3500 protein spot and identified a number of differentially expressed proteins. This proteomic approach may improve ANET through providing structure-recognizing targeting probes to angiogenic site. Less
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