Targeted photodynamic therapy with multiply-loaded recombinant antibody fragments
Targeted photodynamic therapy with multiply-loaded recombinant antibody fragments
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DOI：
10.1002/ijc.23206
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发表时间：
2008-03-01
影响因子：
6.4
通讯作者：
Deonarain, Mahendra P.
中科院分区：
文献类型：
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作者：
Bhatti, Manpreet;Yahioglu, Gokhan;Deonarain, Mahendra P.
目前的癌症光动力治疗（PDT）受到肿瘤特异性靶向光敏剂效率低下的限制。虽然抗体正在被探索作为靶向载体，但它们面临着重大挑战，特别是在药代动力学和药物偶联方面。我们在这里描述了一种新的和有效的系统，可以将多个光敏剂分子（临床前的，焦磷酸盐-a和临床批准的，维替波特芬光敏剂）共价连接到单链Fvs上。此外，我们证明了所得到的光免疫偶联物不仅保留了光物理功能，而且比任何一种自由光敏剂都更有效，在体外和体内都能有效地杀死肿瘤细胞。例如，用一种光免疫偶联物治疗人类乳腺癌异种移植物，这种偶联物包括一种抗her -2 scFv，它与8-10个焦磷-a分子相连，可导致肿瘤显著消退。这些结果揭示了使scFvs成为PDT药物良好载体的重要特征，并为我们独特的靶向光动力治疗（tPDT）方法提供了概念证明。这有望显著改善目前用于治疗癌症的光动力疗法。(C) 2007 Wiley-Liss, Inc。
Current photodynamic therapy (PDT) of cancer is limited by inefficiencies involved in specifically targeting photosensitizers to tumors. Although antibodies are being explored as targeting vehicles, they present significant challenges, particularly in terms of pharmacokinetics and drug-coupling. We describe here a novel and effective system to covalently attach multiple photosensitizer molecules (both preclinical, pyropheophorbide-a and clinically approved, verteporfin photosensitizers) to single-chain Fvs. Further, we demonstrate that not only do the resulting photoimmunoconjugates retain photophysical functionality, they are more potent than either free photosensitizer, effectively killing tumor cells in vitro and in vivo. For example, treatment of human breast cancer xenografts with a photoimmunoconjugate comprising an anti-HER-2 scFv linked to 8-10 molecules of pyropheophorbide-a leads to significant tumor regression. These results give an insight into the important features that make scFvs good carriers for PDT drugs and provide proof of concept of our unique approach to targeted photodynamic therapy (tPDT). This promises to significantly improve on current photodynamic therapies for the treatment of cancer. (C) 2007 Wiley-Liss, Inc.