Targeted Molecular Construct for Bioorthogonal Theranostics of PD-L1-Expressing Cancer Cells.
Targeted Molecular Construct for Bioorthogonal Theranostics of PD-L1-Expressing Cancer Cells.
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DOI：
10.1021/jacsau.2c00328
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发表时间：
2022-07-25
期刊：
影响因子：
8
通讯作者：
Unciti-Broceta, Asier
中科院分区：
文献类型：
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作者：
Chow, Shiao Y;Unciti-Broceta, Asier
肿瘤过表达癌蛋白的分子靶向可以提高抗癌治疗的选择性和耐受性。免疫抑制性膜蛋白程序性死亡配体1（PD-L1）在某些肿瘤类型上高度表达，其使恶性细胞免受T细胞识别，并为癌症的生长和扩散创造了最佳环境。我们在这里报告了一种配体-四嗪缀合物（LTzC），其配备有PD-L1小分子抑制剂以选择性地靶向表达PD-L1的癌细胞并抑制PD-L1功能，并与四嗪模块和硫辛酰基缀合以将生物正交反应性和氧化应激增强剂并入构建体中。通过将LTzC与成像探针配对，我们已经建立了一种“跟踪-&-标签”系统，用于使用点击化学在活细胞上和活细胞中选择性标记PD-L1。我们通过点击释放激活前药和选择性杀死表达PD-L1的乳腺癌细胞，进一步显示了LTzC的特异性和多功能性，提供了一种新的多模式方法来“跟踪和治疗”能够逃避免疫系统的恶性细胞。
Molecular targeting of tumor-overexpressed oncoproteins can improve the selectivity and tolerability of anticancer therapies. The immunoinhibitory membrane protein programmed death ligand 1 (PD-L1) is highly expressed on certain tumor types, which masks malignant cells from T cell recognition and creates an optimal environment for the cancer to thrive and spread. We report here a ligand-tetrazine conjugate (LTzC) armed with a PD-L1 small molecule inhibitor to selectively target PD-L1-expressing cancer cells and inhibit PD-L1 function and conjugated to a tetrazine module and a lipoyl group to incorporate bioorthogonal reactivities and an oxidative stress enhancer into the construct. By pairing LTzC with an imaging probe, we have established a “track-&-tag” system for selective labeling of PD-L1 both on and in living cells using click chemistry. We have further shown the specificity and versatility of LTzC by click-to-release activation of prodrugs and selective killing of PD-L1-expressing breast cancer cells, offering a new multimodal approach to “track-&-treat” malignant cells that are capable of evading the immune system.