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Angiogenesis Suppression and Cancer Treatment by Use of Neovascular Targeted Probe

利用新生血管靶向探针抑制血管生成和癌症治疗

基本信息

批准号：
12470507
负责人：
OKU Naoto
金额：
$ 9.09万
依托单位：
University of Shizuoka
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12470507/
关键词：
Cancer Angiogenesis Neovessel Cancer treatment Phage displayed library Liposome Drug delivery system Targeting

项目摘要

In this study, novel peptides specifically homing to angiogenic vasculature were successfully isolated from a phage-displayed peptide library. The results of homing studies with phage particle and liposomal formulation indicate that PRP and WRP sequences in pentadecapeptides are important for the targeting to angiogenic sites. One of selected peptides, ASSSYPLIHWRPWAR, suppressed in vivo anagiogenesis possibly through the inhibition of endothelial cell migration. Moreover, ASSSYPLIHWRPWAR and its fragment peptides containing WRP suppressed tumor growth. Moreover, WRP is clearly revealed to be a minimum and essential sequence for the activity. In therapeutic experiments, modification of liposomes with APRPG enhanced the anti-tumor activity of ADM and reduced the toxicity of the drug due to targeting effect. It is considered that ADM damages neovascular endthelial cells, since PRP-LipADM is expected to bind these growing cells efficiently from the results of both confocal observation and … More histochemical staining. The results of therapeutic experiment with DPP-CNDAC support this idea. Since lipophilic drugs should be delivered to the cells as liposomal form, the therapeutic efficacy reflects the damage of the cells to which liposome accesses rather than change in local concentration of the agent in tumor tissue. The therapeutic efficacy of PRP-LipCN is superior to LipCN, suggesting that the destruction of angiogenic endothelial cells is superior to the direct destruction of tumor cells in the tumor treatment. In fact, the bulk accumulation of DPP-CNDAC-containing liposomes in the tumor tissue was not so much different between APRPG-liposome and non-modified liposome. From the results obtained in this study, it would be expected that PRP-Lip could deliver anticancer agents for anti-neovascular therapy, or anti-angiogenic agents for tumor dormancy therapy. It is considered that APRPG may be useful for human cancer treatment, since PRP-Lip and PRPGAPLAGSWPGTS have affinity for VEGF-stimulated HUVECs and human tumor angiogenic endothelia respectively. Less

在这项研究中，新的肽特异性归巢血管生成的血管被成功地从噬菌体展示肽库分离。噬菌体颗粒和脂质体制剂的归巢研究结果表明，十五肽中的PRP和WRP序列对于靶向血管生成位点是重要的。所选的肽之一，ASSSYRPHWRPWAR，可能通过抑制内皮细胞迁移来抑制体内血管再生。此外，ASSSYRPHWRPWAR及其含有WRP的片段肽抑制肿瘤生长。此外，WRP被清楚地揭示为活动的最低和必要序列。在治疗实验中，用APRPG修饰脂质体增强了ADM的抗肿瘤活性，并由于靶向作用而降低了药物的毒性。认为ADM损伤新生血管内皮细胞，因为从共聚焦观察和共聚焦显微镜观察的结果来看， ...更多信息组织化学染色。DPP-CNDAC的治疗实验结果支持这一观点。由于亲脂性药物应该以脂质体形式递送至细胞，因此治疗功效反映脂质体进入的细胞的损伤，而不是肿瘤组织中药剂的局部浓度的变化。PRP-LipCN的治疗效果上级LipCN，提示在肿瘤治疗中破坏血管生成内皮细胞上级直接破坏肿瘤细胞。事实上，含有DPP-CNDAC的脂质体在肿瘤组织中的大量积累在APRPG-脂质体和未修饰的脂质体之间没有太大差异。从本研究中获得的结果，可以预期PRP-Lip可以递送用于抗新生血管治疗的抗癌剂，或用于肿瘤休眠治疗的抗血管生成剂。由于PRP-Lip和PRPGAPLAGSWPGTS分别对VEGF刺激的HUVECs和人肿瘤血管生成内皮细胞具有亲和力，因此认为APRPG可用于人类癌症治疗。少