一种新的双特异性配体导向毒素药物递送方法，可降低毒性并提高原位胰腺癌模型中的疗效。
A new drug delivery method of bispecific ligand-directed toxins, which reduces toxicity and promotes efficacy in a model of orthotopic pancreatic cancer.
机构信息
Therapeutic Radiology and daggerSurgery, University of Minnesota Cancer Center, Minneapolis, MN 55455, USA.
出版信息
Pancreas. 2010 Aug;39(6):913-22. doi: 10.1097/MPA.0b013e3181cbd908.
OBJECTIVE
Biologicals targeting epidermal growth factor (EGF) and interleukin 13 receptors not only react with overexpressed markers on cancer cells but also react with receptors on normal cells. Because we developed novel bispecific ligand-directed toxins synthesized by cloning EGF and interleukin 13 on the same molecule with toxin, our objective was to determine whether we could block normal receptors while still targeting receptors overexpressed on cancer cells, thereby decreasing toxicity while maintaining efficacy.
METHODS
A method, toxicity blocking (ToxBloc), was developed in which a bolus intraperitoneal dose of recombinant EGF13 (without toxin) was given to mice approximately 15 to 20 minutes before DTEGF13. Experiments were then performed to determine whether the maximal tolerated dose (MTD) was reduced and whether we were still able to eliminate progression of aggressive human, metastatic, pancreatic cancer induced by orthotopic injection (OT) in nude mice.
RESULTS
ToxBloc permitted us to safely exceed the DTEGF13 maximal tolerated dose by 15-fold. This approach permitted repetitive high dosing with the bispecific ligand-directed toxin resulting in tumor regression (P < 0.01). Tumor effects were documented using a tumor imaging model in which OT tumor growth was monitored noninvasively in real time. ToxBloc was selective because other bispecific peptides did not block.
CONCLUSIONS
ToxBloc represents a new method of drug delivery and a potential solution to the problem of toxicity.
目的
针对表皮生长因子（EGF）和白细胞介素 13 受体的生物制剂不仅与癌细胞上过度表达的标志物发生反应，而且与正常细胞上的受体发生反应。由于我们开发了新型双特异性配体导向毒素，通过在同一分子上克隆 EGF 和白细胞介素 13 并与毒素结合，我们的目标是确定是否可以在靶向癌细胞过度表达的受体的同时阻断正常受体，从而降低毒性而保持疗效。
方法
开发了一种毒性阻断（ToxBloc）方法，即在给予 DTEGF13 约 15 至 20 分钟前，给小鼠腹腔内推注重组 EGF13（无毒素）。然后进行实验以确定最大耐受剂量（MTD）是否降低，以及我们是否仍然能够消除通过原位注射（OT）在裸鼠中诱导的侵袭性、转移性、人胰腺癌细胞的进展。
结果
ToxBloc 使我们能够安全地将 DTEGF13 的最大耐受剂量增加 15 倍。这种方法允许重复使用双特异性配体导向毒素进行高剂量治疗，导致肿瘤消退（P < 0.01）。使用肿瘤成像模型记录肿瘤效应，其中实时非侵入性监测 OT 肿瘤生长。ToxBloc 具有选择性，因为其他双特异性肽不能阻断。
结论
ToxBloc 代表了一种新的药物输送方法，也是解决毒性问题的潜在解决方案。
Zotero 插件