Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine Shandong University, Jinan, Shandong, 250012, PR China.
Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine Shandong University, Jinan, Shandong, 250012, PR China.
Biomaterials. 2021 Nov;278:121135. doi: 10.1016/j.biomaterials.2021.121135. Epub 2021 Sep 18.
The restricted tumor penetration has been regarded as the Achilles' Heels of most nanomedicines, largely limiting their efficacy. To address this challenge, a cluster-bomb-like nanoplatform named CPIM is prepared, which for the first time combines size-transforming and transcytosis strategies, thus enhancing both passive and active transport. For passive diffusion, the "cluster-bomb" CPIM (135 nm) releases drug-loaded "bomblets" (IR780/1-methyl-tryptophan (1 MT) loaded PAMAM, <10 nm) in response to the high reactive-oxygen-species (ROS) concentration in tumor microenvironment (TME), which promotes intratumoral diffusion. Besides, IR780 generates ROS upon NIR irradiation and intensifies this responsiveness; therefore, there exists a NIR-triggered self-destructive behavior, rendering CPIM spatiotemporal controllability. For active transport, the nanoplatform is proven to be delivered via transcytosis with/without NIR irradiation. Regarding the anti-cancer performance, CPIM strengthens the photodynamic therapy (PDT)/photothermal therapy (PTT) activity of IR780 and IDO pathway inhibition effect of 1 MT, thus exhibiting a strongest inhibitory effect on primary tumor. CPIM also optimally induces immunogenic cell death, reverses the "cold" TME to a "hot" one and evokes systemic immune response, thus exerting an abscopal and anti-metastasis effects. In conclusion, this work provides a facile, simple yet effective strategy to enhance the tumor penetration, tumor-killing effect and antitumor immunity of nanomedicines.
受限的肿瘤穿透性一直被认为是大多数纳米药物的阿喀琉斯之踵，在很大程度上限制了它们的疗效。为了应对这一挑战，我们制备了一种类似集束炸弹的纳米平台，名为 CPIM，它首次结合了尺寸转换和转胞运输策略，从而增强了被动和主动运输。对于被动扩散，“集束炸弹”CPIM（135nm）在肿瘤微环境（TME）中高活性氧（ROS）浓度的响应下释放载药“炸弹”（IR780/1-甲基色氨酸（1MT）负载的 PAMAM，<10nm），促进肿瘤内扩散。此外，IR780 在近红外（NIR）照射下产生 ROS，并增强这种响应性；因此，存在一种 NIR 触发的自毁行为，使 CPIM 具有时空可控性。对于主动运输，该纳米平台被证明可以通过转胞运输（有/无 NIR 照射）进行递送。关于抗癌性能，CPIM 增强了 IR780 的光动力治疗（PDT）/光热治疗（PTT）活性和 1MT 的 IDO 途径抑制作用，因此对原发性肿瘤表现出最强的抑制作用。CPIM 还最佳地诱导免疫原性细胞死亡，将“冷”TME 转变为“热”TME，并引发全身免疫反应，从而发挥远隔和抗转移作用。总之，这项工作提供了一种简便、简单而有效的策略，可增强纳米药物的肿瘤穿透性、肿瘤杀伤效应和抗肿瘤免疫。
