Integrin-Targeting Knottin Peptide-Drug Conjugates Are Potent Inhibitors of Tumor Cell Proliferation.
Integrin-Targeting Knottin Peptide-Drug Conjugates Are Potent Inhibitors of Tumor Cell Proliferation.
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DOI：
10.1002/anie.201603488
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发表时间：
2016-08-16
期刊：
影响因子：
--
通讯作者：
Cochran JR
中科院分区：
文献类型：
--
作者：
Cox N;Kintzing JR;Smith M;Grant GA;Cochran JR
与全身化疗相比，抗体-药物偶联物（adc）具有更高的疗效和更低的毒性。由于多肽-药物传递具有增加肿瘤渗透和易于合成的潜力，人们对其关注较少。我们报道了一种结蛋白肽-药物偶联物（KDC），并证明它可以选择性地将吉西他滨传递给表达肿瘤相关整合素的恶性细胞。KDC以低纳摩尔亲和力与肿瘤细胞结合，通过整合素介导的过程内化，在细胞内释放其有效载荷，是脑癌、乳腺癌、卵巢癌和胰腺癌细胞系的高效抑制剂。值得注意的是，这些特征使这种KDC能够绕过胰腺癌细胞中发现的吉西他滨耐药机制。这项工作扩大了结蛋白肽的治疗相关性，包括靶向药物递送，并进一步推动了扩大药物偶联物工具包的努力，包括非抗体蛋白支架。一种工程化的肿瘤靶向结蛋白为药物递送提供了一种新的途径。这种整合素结合的结蛋白肽-药物偶联物（KDC）明显小于抗体-药物偶联物，便于合成和偶联。含有核苷吉西他滨的KDC通过整合素介导的机制内化，在细胞内释放其有效载荷，并被证明是几种恶性细胞系的高效抑制剂。
Antibody-drug conjugates (ADCs) offer increased efficacy and reduced toxicity compared to systemic chemotherapy. Less attention has been paid to peptide-drug delivery, which has the potential for increased tumor penetration and facile synthesis. We report a knottin peptide-drug conjugate (KDC) and demonstrate that it can selectively deliver gemcitabine to malignant cells expressing tumor-associated integrins. This KDC binds to tumor cells with low-nanomolar affinity, is internalized by an integrin-mediated process, releases its payload intracellularly, and is a highly potent inhibitor of brain, breast, ovarian, and pancreatic cancer cell lines. Notably, these features enable this KDC to bypass a gemcitabine resistance mechanism found in pancreatic cancer cells. This work expands the therapeutic relevance of knottin peptides to include targeted drug delivery, and further motivates efforts to expand the drug-conjugate toolkit to include non-antibody protein scaffolds. An engineered tumor-targeted knottin miniprotein offers a new approach for drug delivery. This integrin-binding knottin peptide-drug conjugate (KDC) is significantly smaller than antibody-drug conjugates allowing for facile synthesis and conjugation. A KDC bearing the nucleoside gemcitabine is internalized by an integrin-mediated mechanism, releases its payload intracellularly, and is shown to be a highly potent inhibitor of several malignant cell lines.
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影响因子：
2.9
作者：
Kimura RH;Levin AM;Cochran FV;Cochran JR
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