School of Materials Science and Engineering, Hebei University of Technology, Tianjin 300130, P. R. China.
Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, School of Life Sciences, Tianjin University, Tianjin 300071, P. R. China.
ACS Appl Mater Interfaces. 2022 Jul 20;14(28):31715-31726. doi: 10.1021/acsami.2c08503. Epub 2022 Jul 7.
The gated state of anion channels is involved in the regulation of proliferation and migration of tumors. Specific regulators are urgently needed for efficacious cancer ablation. For this purpose, it is essential to understand the molecular mechanisms of interaction between the regulators and anion channels and apply this knowledge to regulate anion channels. Transmembrane 16A (TMEM16A) is the molecular basis of the calcium-activated chloride channels. It is an anion channel activated by Ca, and the inhibition of TMEM16A is associated with a decrease in tumorigenesis. Herein, we characterized a natural compound procyanidin (PC) as an efficacious and selective inhibitor of TMEM16A with an IC of 10.6 ± 0.6 μM. Our research revealed the precise sites (D383, R535, and E624) of electrostatic interactions between PC and TMEM16A. Near-infrared (NIR)-light-responsive photothermal conjugated polymer nanoparticles encapsulating PC (CPNs-PC) were established to remotely target and regulate the TMEM16A anion channel. Upon NIR irradiation, CPNs-PC downregulated the signaling pathway downstream of TMEM16A and arrested the cell cycle progression of cancer cells and improved the bioavailability of PC. The tumor inhibition ratio of CPNs-PC was superior to PC by 13.4%. Our findings enabled the development of a strategy to accurately and remotely regulate anion channels to promote tumor regression using NIR-light-responsive conjugated polymer nanoparticles containing specific inhibitors of TMEM16A.
阴离子通道的门控状态参与肿瘤增殖和迁移的调节。迫切需要特定的调节剂来有效消融癌症。为此，了解调节剂与阴离子通道相互作用的分子机制并将此知识应用于调节阴离子通道至关重要。跨膜 16A（TMEM16A）是钙激活氯离子通道的分子基础。它是一种被 Ca 激活的阴离子通道，TMEM16A 的抑制与肿瘤发生减少有关。在此，我们将原花青素（PC）鉴定为 TMEM16A 的有效且选择性抑制剂，IC 为 10.6 ± 0.6 μM。我们的研究揭示了 PC 与 TMEM16A 之间静电相互作用的精确位点（D383、R535 和 E624）。建立了近红外（NIR）光响应光热共轭聚合物纳米粒子包裹 PC（CPNs-PC），以远程靶向和调节 TMEM16A 阴离子通道。NIR 照射后，CPNs-PC 下调了 TMEM16A 下游的信号通路，阻止了癌细胞的细胞周期进程，并提高了 PC 的生物利用度。CPNs-PC 的肿瘤抑制率比 PC 高 13.4%。我们的研究结果使我们能够开发一种策略，使用含有 TMEM16A 特异性抑制剂的近红外光响应共轭聚合物纳米粒子，准确且远程调节阴离子通道，以促进肿瘤消退。
