吉西他滨
胰腺癌
整合素
癌症研究
药品
结合
肽
药物输送
药理学
化学
生物
化疗
细胞
癌症
医学
内科学
生物化学
数学
有机化学
数学分析
作者
Nick Cox,James R. Kintzing,Mark Smith,Gerald A. Grant,Jennifer R. Cochran
标识
DOI:10.1002/anie.201603488
摘要
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.
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