Fuchs Hendrik, Bachran Christopher, Li Tongyu, Heisler Iring, Dürkop Horst, Sutherland Mark
Zentralinstitut für Laboratoriumsmedizin und Pathobiochemie, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, D-12200 Berlin, Germany.
J Control Release. 2007 Feb 26;117(3):342-50. doi: 10.1016/j.jconrel.2006.11.019. Epub 2006 Nov 28.
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 (SA2E) 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 SA2E and the reduction in side effects less pronounced indicating specific depletion from the blood by target receptor expressing cells.
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副作用以及毒素与肿瘤细胞表面结合后向细胞质的低转运率。为了在这方面改进嵌合毒素，我们开发了一种连接毒性部分和配体的分子适配器。该适配器旨在改善细胞质摄取，将毒素保留在细胞质内，并在细胞死亡后使药物解毒。直接或通过适配器与表皮生长因子（EGF）连接的植物毒素皂草素用于评估体内抑制肿瘤生长和减少副作用的功效。含适配器毒素（SA2E）对BALB/c小鼠的致死剂量比不含适配器的构建体（SE）低三倍。此外，SE仅使诱导肿瘤的平均重量减少了33%，而经SA2E处理的小鼠肿瘤重量减少了71%，60%的病例中几乎完全抑制。此外，SA2E处理的动物中，如痛觉过敏、脱发和死亡等严重副作用大幅减少。没有靶受体的肿瘤仅受到SA2E的轻微影响，副作用的减少不太明显，表明表达靶受体的细胞从血液中特异性清除。
