Angiogenesis Suppression and Cancer Treatment by Use of Neovascular Targeted Probe

在这项研究中，我们成功地从噬菌体展示的肽库中分离出了专门指向血管生成血管的新肽。噬菌体颗粒和脂质体的归巢研究结果表明，五肽中的PRP和WRP序列对于靶向血管生成位点具有重要意义。其中一种肽ASSSYPLIHWRPWAR可能通过抑制内皮细胞迁移来抑制体内血管增生。ASSSYPLIHWRPWAR及其含有WRP的片段肽抑制肿瘤生长。此外，WRP显然是活动的最小和基本序列。在治疗实验中，APRPG修饰脂质体增强了ADM的抗肿瘤活性，并且由于靶向作用降低了药物的毒性。从共聚焦观察和组织化学染色的结果来看，PRP-LipADM有望有效地结合这些生长中的细胞，因此认为ADM损害了新生血管内皮细胞。DPP-CNDAC的治疗实验结果支持这一观点。由于亲脂性药物以脂质体的形式进入细胞，所以治疗效果反映的是脂质体所进入细胞的损伤程度，而不是药物在肿瘤组织中局部浓度的变化。PRP-LipCN的治疗效果优于LipCN，提示在肿瘤治疗中破坏血管生成内皮细胞优于直接破坏肿瘤细胞。事实上，aprpg脂质体与未修饰脂质体在肿瘤组织中含有dpp - cndac的脂质体的大量堆积并无太大差异。从本研究的结果来看，可以预期PRP-Lip可以为抗新血管治疗提供抗癌药物，或为肿瘤休眠治疗提供抗血管生成药物。由于PRP-Lip和PRPGAPLAGSWPGTS分别对vegf刺激的huvec和人肿瘤血管生成内皮具有亲和力，因此APRPG可能对人类癌症治疗有用。少

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