Selective occlusion of tumor blood vessels by targeted delivery of an antibody-photosensitizer conjugate
Selective occlusion of tumor blood vessels by targeted delivery of an antibody-photosensitizer conjugate
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DOI：
10.1002/ijc.21412
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发表时间：
2006-04-01
影响因子：
6.4
通讯作者：
Neri, P
中科院分区：
文献类型：
--
作者：
Fabbrini, M;Trachsel, E;Neri, P
实体瘤的不规则脉管系统和高间质压阻碍了细胞毒性剂向癌细胞的递送。因此，实现完全肿瘤根除所需的化疗剂量与不可接受的高毒性相关。肿瘤血管的选择性血栓形成已被假定为对抗癌症的替代途径，剥夺肿瘤的营养和氧气，并导致肿瘤细胞死亡的雪崩。对纤连蛋白的EDB结构域（血管生成的标志物）特异的人抗体L19能够在肿瘤血管周围选择性地体内定位，因此是用于将毒性有效载荷递送至肿瘤新血管系统的合适试剂。在这里，我们表明，L19抗体与光敏剂双（三乙醇胺）Sn（IV）二氢卟酚e（6）的化学缀合物，在静脉注射和红光照射后，引起皮下肿瘤小鼠肿瘤生长的停滞。相比之下，用具有相同药代动力学性质但不相关特异性的抗体获得的光敏剂缀合物没有表现出显著的治疗效果。这些结果证实，血管靶向策略，旨在选择性闭塞/破坏肿瘤血管，具有显着的抗癌治疗潜力，并鼓励使用抗体-光敏剂缀合物治疗浅表肿瘤和可能的其他血管生成相关的病理。(c)2005 Wiley-Liss，Inc.
The irregular vasculature and high interstitial pressure of solid tumors hinder the delivery of cytotoxic agents to cancer cells. As a consequence, the doses of chemotherapy necessary to achieve complete tumor eradication are associated with unacceptably high toxicities. The selective thrombosis of tumor blood vessels has been postulated as an alternative avenue for combating cancer, depriving tumors of nutrients and oxygen and causing an avalanche of tumor cell deaths. The human antibody L19, specific to the EDB domain of fibronectin, a marker of angiogenesis, is capable of selective in vivo localization around tumor blood vessels and is thus a suitable agent for delivering toxic payloads to the tumor neovasculature. Here we show that a chemical conjugate of the L19 antibody with the photosensitizer bis(triethanolamine)Sn(IV) chlorin e(6), after intravenous injection and irradiation with red light, caused an arrest of tumor growth in mice with subcutaneous tumors. By contrast, a photosensitizer conjugate obtained with an antibody of identical pharmacokinetic properties but irrelevant specificity did not exhibit a significant therapeutic effect. These results confirm that vascular targeting strategies, aimed at the selective occlusion/disruption of tumor blood vessels, have a significant anticancer therapeutic potential and encourage the use of anti body-photosensitizer conjugates for the therapy of superficial tumors and possibly other angiogenesis-related pathologies. (c) 2005 Wiley-Liss, Inc.