School of Biomedical Sciences and Engineering, Guangzhou International Campus, South China University of Technology, Guangzhou, 511442, PR China; National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou, 510006, PR China.
School of Medicine, South China University of Technology, Guangzhou, 510006, PR China.
Biomaterials. 2022 May;284:121480. doi: 10.1016/j.biomaterials.2022.121480. Epub 2022 Apr 1.
Photodynamic therapy (PDT) can aggravate the hypoxia aggravation and be further utilized for the activation of hypoxia-activated prodrug (HAP). Ideally, photosensitizers (PSs) are mainly administrated to tumor vasculatures adjacent to regions with high oxygen to effectively generate reactive oxygen species (ROS) effectively and further aggravate tumor hypoxia, while the HAP is delivered to the inner tumor as far as possible for efficient activation. However, a delivery system capable of transporting PSs and HAP to the desired region respectively for the optimum effect is urgently needed. Here, we developed a bioorthogonal click chemistry and illumination controlled programmed size-changeable nanomedicine for synergistic photodynamic and hypoxia-activated therapy. It utilized tumor acidity responsive bioorthogonal click reaction for crosslinking nanoparticles to construct a drug depot with tumor vasculatures adjacent region retention for PDT in normoxia. Under laser illumination, cleavage of the ROS-responsive thioketal (TK) crosslinker to release small sized poly(amidoamine) (PAMAM) dendrimer conjugated with HAP for enhanced tumor penetration into the hypoxic region. Therefore, this strategy could differentially deliver PSs and HAP in desired spatial distribution, eventually achieving the enhanced synergistic enhancement in the combined PDT and hypoxia-activated therapy.
光动力疗法 (PDT) 可加重缺氧恶化，并进一步用于激活缺氧激活前药 (HAP)。理想情况下，光敏剂 (PS) 主要施用于邻近高氧区域的肿瘤血管，以有效地有效产生活性氧 (ROS)，进一步加重肿瘤缺氧，而 HAP 则尽可能输送到肿瘤内部，以实现高效激活。然而，迫切需要一种能够将 PS 和 HAP 分别输送到所需区域以达到最佳效果的输送系统。在这里，我们开发了一种生物正交点击化学和光照控制的程序大小可变换纳米医学，用于协同光动力和缺氧激活治疗。它利用肿瘤酸度响应生物正交点击反应交联纳米颗粒，在正常氧条件下构建具有肿瘤血管邻近区域保留的药物库，用于 PDT。在激光照射下，ROS 响应硫代缩酮 (TK) 交联剂的裂解释放与 HAP 偶联的小尺寸聚酰胺胺 (PAMAM) 树枝状聚合物，增强了药物向缺氧区域的渗透。因此，该策略可以在所需的空间分布中差异地递送 PS 和 HAP，最终实现联合 PDT 和缺氧激活治疗的协同增强。
