School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou 511442, PR China; National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou 510006, PR China.
School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou 511442, PR China; Guangdong Provincial Key Laboratory of Biomedical Engineering, South China University of Technology, Guangzhou 510006, PR China.
J Control Release. 2022 Aug;348:1004-1015. doi: 10.1016/j.jconrel.2022.06.046. Epub 2022 Jul 2.
Hypoxia-induced intratumoral heterogeneity poses a major challenge in tumor therapy due to the varying susceptibility to chemotherapy. Moreover, the spatial distribution patterns of hypoxic and normoxic tissues makes conventional combination therapy less effective. In this study, a tumor-acidity and bioorthogonal chemistry mediated in situ size transformable nanocarrier (NP@DOX plus iCPPA) was developed to spatially deliver two combinational chemotherapeutic drugs (doxorubicin (DOX) and PR104A) to combat hypoxia-induced intratumoral heterogeneity. DOX is highly toxic to tumor cells in normoxia state but less toxic in hypoxia state due to the hypoxia-induced chemoresistance. Meanwhile, PR104A is a hypoxia-activated prodrug has less toxic in normoxia state. Two nanocarriers, NP@DOX and iCPPA, can cross-link near the blood vessel extravasation sites through tumor acidity responsive bioorthogonal click chemistry to enhance the retention of DOX in tumor normoxia. Moreover, PR104A conjugated to the small-sized dendritic polyamidoamine (PAMAM) released under tumor acidity can penetrate deep tumor tissues for hypoxic tumor cell killing. Our study has demonstrated that this site-specific combination chemotherapy is better than the traditional combination chemotherapy. Therefore, spatial specific delivery of combinational therapeutics via in situ size transformable nanocarrier addresses the challenges of hypoxia induced intratumoral heterogeneity and provides insights into the combination therapy.
缺氧诱导的肿瘤内异质性给肿瘤治疗带来了重大挑战，因为化疗的敏感性不同。此外，缺氧组织和正常组织的空间分布模式使得传统的联合治疗效果较差。在这项研究中，开发了一种肿瘤酸度和生物正交化学介导的原位尺寸可变形纳米载体（NP@DOX 加 iCPPA），以空间递送至两种联合化疗药物（多柔比星（DOX）和 PR104A），以对抗缺氧诱导的肿瘤内异质性。在正常氧状态下，DOX 对肿瘤细胞具有高度毒性，但在缺氧状态下毒性较低，这是由于缺氧诱导的化疗耐药性所致。同时，PR104A 是一种缺氧激活的前药，在正常氧状态下毒性较小。两种纳米载体，NP@DOX 和 iCPPA，可以通过肿瘤酸度响应的生物正交点击化学在血管外渗部位交联，以增强 DOX 在肿瘤正常氧状态下的保留。此外，与小尺寸树枝状聚酰胺胺（PAMAM）偶联的 PR104A 在肿瘤酸度下释放，可以穿透深部肿瘤组织，杀死缺氧肿瘤细胞。我们的研究表明，这种部位特异性联合化疗优于传统联合化疗。因此，通过原位尺寸可变形纳米载体进行的联合治疗的空间特异性递送解决了缺氧诱导的肿瘤内异质性的挑战，并为联合治疗提供了新的思路。
