A new drug delivery method of bispecific ligand-directed toxins, which reduces toxicity and promotes efficacy in a model of orthotopic pancreatic cancer.
A new drug delivery method of bispecific ligand-directed toxins, which reduces toxicity and promotes efficacy in a model of orthotopic pancreatic cancer.
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DOI：
10.1097/mpa.0b013e3181cbd908
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发表时间：
2010-08
期刊：
影响因子：
2.9
通讯作者：
Vallera DA
中科院分区：
文献类型：
--
作者：
Oh S;Stish BJ;Vickers SM;Buchsbaum DJ;Saluja AK;Vallera DA
靶向 EGFR 和 IL-13R 的生物制剂与癌细胞上过度表达的标记物发生反应，但也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定向毒素 (BLT)，通过将 EGF 和 IL-13 克隆到与毒素相同的分子上而合成，我们的目标是确定是否可以阻断正常受体，同时仍然靶向癌细胞上过度表达的受体，从而在保持疗效的同时降低毒性。开发了一种名为 ToxBloc 的方法，其中在 DTEGF13 之前约 15-20 分钟向小鼠腹腔注射重组 EGF13（不含毒素）。然后进行实验以确定 MTD 是否降低，以及我们是否仍然能够消除裸鼠原位注射诱导的侵袭性人类、转移性、系统性胰腺癌的进展。 ToxBloc 使我们能够安全地超过 DTEGF13 MTD 15 倍。这种方法允许重复高剂量 BLT 治疗，从而导致肿瘤消退 (p<0.01)。使用肿瘤成像模型记录肿瘤影响，其中肿瘤生长被实时无创监测。 ToxBloc 具有选择性，因为其他双特异性肽不能阻断。 ToxBloc 代表了一种新的药物输送方法和毒性问题的潜在解决方案。
Biologicals targeting EGFR and IL-13R react with over-expressed markers on cancer cells, but also react with receptor on normal cells. Since we developed novel bispecific ligand directed toxins (BLT) synthesized by cloning EGF and IL-13 on the same molecule with toxin, our objective was to determine whether we could block normal receptors while still targeting receptors over-expressed on cancer cells thereby decreasing toxicity while maintaining efficacy. A method, ToxBloc, was developed in which a bolus IP dose of recombinant EGF13 (without toxin) was given to mice about 15-20 minutes prior to DTEGF13. Experiments were then performed to determine if the MTD was reduced and whether we still were able to eliminate progression of aggressive human, metastatic, systemic pancreatic cancer induced by orthotopic injection in nude mice. ToxBloc permitted us to safely exceed the DTEGF13 MTD by 15-fold. This approach permitted repetitive high dosing with the BLT resulting in tumor regression (p<0.01). Tumor affects were documented using a tumor imaging model in which tumor growth was monitored noninvasively in real time. ToxBloc was selective since other bispecific peptides did not block. ToxBloc represents a new method of drug delivery and a potential solution to the toxicity problem.