Nanoparticle-induced vascular blockade in human prostate cancer
Nanoparticle-induced vascular blockade in human prostate cancer
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DOI：
10.1182/blood-2010-03-274258
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发表时间：
2010-10-14
期刊：
影响因子：
20.3
通讯作者：
Ruoslahti, Erkki
中科院分区：
文献类型：
--
作者：
Agemy, Lilach;Sugahara, Kazuki N.;Ruoslahti, Erkki
肿瘤归巢五肽CREKA（Cys-Arg-Glu-Lys-Ala）通过与肿瘤血管中的纤维蛋白和纤维蛋白相关的凝结血浆蛋白结合而特异性归巢肿瘤。先前的结果表明，CREKA包被的超顺磁性氧化铁颗粒可以在肿瘤血管中引起额外的凝血，这为肽创造了更多的结合位点。我们已经使用这种自放大归巢系统来开发治疗诊断纳米颗粒，该纳米颗粒同时用作成像剂并通过血液凝固阻碍肿瘤循环来抑制肿瘤生长。将CREKA纳米颗粒与用另一种肿瘤归巢肽CRKDKC包被的纳米颗粒组合，并且使用具有细长形状（纳米颗粒）的纳米颗粒来改善结合功效。然后通过用非蛋白原对应物替换一些残基来增加CREKA肽的功效，这增加了肽在循环中的稳定性。用靶向药物治疗荷原位人前列腺癌肿瘤的小鼠引起肿瘤血管中的广泛凝血，而在正常组织的血管中未观察到凝血。光学和磁共振成像证实了肿瘤特异性靶向的药物，超声成像显示肿瘤血管中的血流减少。用多剂量的化合物治疗患有前列腺癌的小鼠诱导肿瘤坏死和肿瘤生长的高度显著减少。（Blood.2010;116（15）：2847-2856）
The tumor-homing pentapeptide CREKA (Cys-Arg-Glu-Lys-Ala) specifically homes to tumors by binding to fibrin and fibrin-associated clotted plasma proteins in tumor vessels. Previous results show that CREKA-coated superparamagnetic iron oxide particles can cause additional clotting in tumor vessels, which creates more binding sites for the peptide. We have used this self-amplifying homing system to develop theranostic nanoparticles that simultaneously serve as an imaging agent and inhibit tumor growth by obstructing tumor circulation through blood clotting. The CREKA nanoparticles were combined with nanoparticles coated with another tumor-homing peptide, CRKDKC, and nanoparticles with an elongated shape (nanoworms) were used for improved binding efficacy. The efficacy of the CREKA peptide was then increased by replacing some residues with nonproteinogenic counterparts, which increased the stability of the peptide in the circulation. Treatment of mice bearing orthotopic human prostate cancer tumors with the targeted nanoworms caused extensive clotting in tumor vessels, whereas no clotting was observed in the vessels of normal tissues. Optical and magnetic resonance imaging confirmed tumor-specific targeting of the nanoworms, and ultrasound imaging showed reduced blood flow in tumor vessels. Treatment of mice with prostate cancer with multiple doses of the nanoworms induced tumor necrosis and a highly significant reduction in tumor growth. (Blood.2010;116(15):2847-2856)