A cleavable molecular adapter reduces side effects and concomitantly enhances efficacy in tumor treatment by targeted toxins in mice
A cleavable molecular adapter reduces side effects and concomitantly enhances efficacy in tumor treatment by targeted toxins in mice
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DOI：
10.1016/j.jconrel.2006.11.019
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发表时间：
2007-02-26
影响因子：
10.8
通讯作者：
Sutherland, Mark
中科院分区：
文献类型：
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作者：
Fuchs, Hendrik;Bachran, Christopher;Sutherland, Mark
在肿瘤治疗中与受体靶向毒素给药相关的两个主要问题是严重的全身性副作用和毒素在结合到肿瘤细胞表面后向胞质溶胶中的低转移。为了在这方面改进嵌合毒素，我们已经开发了连接毒性部分和配体的分子衔接子。适配器被设计为改善细胞溶质摄取，将毒素保留在细胞溶质内，并在细胞死亡后使药物解毒。植物毒素皂草素直接或通过接头连接到表皮生长因子（EGF），用于评估体内抑制肿瘤生长和减少副作用的功效。BALB/c小鼠的致死剂量是三倍以下的衔接子含有毒素（SAM）比衔接子自由构建体（SE）。此外，SE仅使诱导的肿瘤的平均重量减少33%，而SA 2 E处理的小鼠表现出71%的减少，在60%的情况下几乎完全抑制。此外，严重的副作用，如痛觉过敏，脱发和死亡，大大减少在SA 2 E治疗的动物。没有靶受体的肿瘤仅轻微受SAM影响，并且副作用的减少不太明显，表明靶受体表达细胞从血液中特异性消耗。(c)2006 Elsevier B. V.保留所有权利。
Two of the main problems associated with administration of receptor-targeted toxins in tumor therapy are severe systemic side effects and low transfer of the toxins into the cytosol after binding to the tumor cell surface. To improve chimeric toxins in this respect we have developed a molecular adapter that links the toxic moiety and ligand. The adapter is designed to improve cytosolic uptake, retain the toxin inside the cytosol and detoxify the drug after cell death. The plant toxin saporin linked either directly or via the adapter to epidermal growth factor (EGF) served to evaluate efficacy to inhibit tumor growth and reduce side effects in vivo. The lethal dose for BALB/c mice was three times less for the adapter-containing toxin (SAM) than for the adapter-free construct (SE). Furthermore, SE only reduced the average weight of induced tumors by 33% whereas SA2E-treated mice exhibited 71% reduction with an almost complete suppression in 60% of the cases. Additionally, severe side effects like hyperalgesia, alopecia and death were drastically reduced in SA2E-treated animals. Tumors without target receptor were only slightly affected by SAM and the reduction in side effects less pronounced indicating specific depletion from the blood by target receptor expressing cells. (c) 2006 Elsevier B.V. All rights reserved.