化学
生物正交化学
共轭体系
有效载荷(计算)
细胞毒性T细胞
组合化学
生物化学
点击化学
有机化学
计算机网络
网络数据包
计算机科学
体外
聚合物
作者
Pragya Adhikari,Guangmin Li,Mary Ann T. Go,Danielle Mandikian,Hanine Rafidi,Carl Ng,Sagana Anifa,Kevin M. Johnson,Linda Bao,Hilda Hernandez Barry,Rebecca K. Rowntree,Nicholas J. Agard,Cong Wu,Kang-Jye Chou,Donglu Zhang,Katherine R. Kozak,Thomas H. Pillow,Gail D. Lewis Phillips,Shang‐Fan Yu,C. Andrew Boswell,Jack Sadowsky
摘要
Antibody-drug conjugates (ADCs) for the treatment of cancer aim to achieve selective delivery of a cytotoxic payload to tumor cells while sparing normal tissue. In vivo, multiple tumor-dependent and -independent processes act on ADCs and their released payloads to impact tumor-versus-normal delivery, often resulting in a poor therapeutic window. An ADC with a labeled payload would make synchronous correlations between distribution and tissue-specific pharmacological effects possible, empowering preclinical and clinical efforts to improve tumor-selective delivery; however, few methods to label small molecules without destroying their pharmacological activity exist. Herein, we present a bioorthogonal switch approach that allows a radiolabel attached to an ADC payload to be removed tracelessly at will. We exemplify this approach with a potent DNA-damaging agent, the pyrrolobenzodiazepine (PBD) dimer, delivered as an antibody conjugate targeted to lung tumor cells. The radiometal chelating group, DOTA, was attached via a novel
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