Chow Shiao Y, Unciti-Broceta Asier
Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XR, U.K.
JACS Au. 2022 Jul 1;2(7):1747-1756. doi: 10.1021/jacsau.2c00328. eCollection 2022 Jul 25.
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 () 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 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 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.
对肿瘤过表达癌蛋白进行分子靶向可提高抗癌疗法的选择性和耐受性。免疫抑制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，这使得恶性细胞能够逃避T细胞识别，并为癌症的生长和扩散创造了最佳环境。我们在此报告一种配体-四嗪缀合物（），其携带PD-L1小分子抑制剂，以选择性靶向表达PD-L1的癌细胞并抑制PD-L1功能，该缀合物还与四嗪模块和硫辛酰基相连，以便将生物正交反应性和氧化应激增强剂引入构建体。通过将与成像探针配对，我们利用点击化学建立了一种“追踪与标记”系统，用于在活细胞内外选择性标记PD-L1。我们还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，进一步展示了的特异性和多功能性，为“追踪与治疗”能够逃避免疫系统的恶性细胞提供了一种新的多模态方法。
