Targeted Delivery of Auristatin-Modified Toxins to Pancreatic Cancer Using Aptamers.
Targeted Delivery of Auristatin-Modified Toxins to Pancreatic Cancer Using Aptamers.
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DOI：
10.1016/j.omtn.2017.11.013
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发表时间：
2018-03-02
期刊：
影响因子：
--
通讯作者：
Levy M
中科院分区：
文献类型：
--
作者：
Kratschmer C;Levy M
胰腺癌是最致命的恶性肿瘤之一。一线药物吉西他滨治疗通常不成功，因为它与其他传统化疗药物一样，是非特异性的，导致脱靶效应，需要给予亚治疗剂量。或者，单甲基澳瑞他汀E（MMAE）和单甲基澳瑞他汀F（MMAF）是需要配体靶向递送的高毒性小分子。MMAE已获得FDA批准，作为抗CD 30抗体-药物偶联物维布妥昔单抗的组分。然而，与抗体相比，适体具有明显的优势。它们是化学品，这使得它们能够合成生产，并促进具有临床适用性的诊断和治疗的快速发展。此外，它们的小尺寸可以增强组织分布和快速全身清除。在此，我们测定了与抗转铁蛋白受体适体Waz和抗表皮生长因子受体适体E07缀合的MMAE和MMAF对胰腺癌细胞系Panc-1、MIA PaCa-2和BxPC 3的毒性。在体外，我们的研究结果表明，这些适体是一个可行的选择，有针对性地提供有毒的有效载荷到胰腺癌细胞。
Pancreatic cancer is one of the most lethal malignancies. Treatment with the first-line agent, gemcitabine, is often unsuccessful because it, like other traditional chemotherapeutic agents, is non-specific, resulting in off-target effects that necessitate administration of subcurative doses. Alternatively, monomethyl auristatin E (MMAE) and monomethyl auristatin F (MMAF) are highly toxic small molecules that require ligand-targeted delivery. MMAE has already received FDA approval as a component of an anti-CD30 antibody-drug conjugate, brentuximab vedotin. However, in contrast to antibodies, aptamers have distinct advantages. They are chemicals, which allows them to be produced synthetically and facilitates the rapid development of diagnostics and therapeutics with clinical applicability. In addition, their small size allows for enhanced tissue distribution and rapid systemic clearance. Here, we assayed the toxicity of MMAE and MMAF conjugated to an anti-transferrin receptor aptamer, Waz, and an anti-epidermal growth factor receptor aptamer, E07, on the pancreatic cancer cell lines Panc-1, MIA PaCa-2, and BxPC3. In vitro, our results indicate that these aptamers are a viable option for the targeted delivery of toxic payloads to pancreatic cancer cells.
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