Department of Chemistry, Tsinghua University, Beijing 100084, China.
Research Center of Magnetic and Electronic Materials, College of Materials Science and Engineering, Zhejiang University of Technology, Hangzhou 310014, China.
ACS Appl Bio Mater. 2023 Sep 18;6(9):3902-3911. doi: 10.1021/acsabm.3c00566. Epub 2023 Aug 29.
Hypoxia may enhance the chemoresistance of cancer cells and can significantly compromise the effectiveness of chemotherapy. Many efforts have been made to relieve or reverse hypoxia by introducing more oxygen into the tumor microenvironment (TME). Acting in a diametrically opposite way, in the current study, a novel nanocarrier was designed to further exhaust the oxygen level of the hypoxic TME. By creating such an oxygen depleted TME, the hypoxia-selective cytotoxin can work effectively, and oxygen exhaustion triggered chemotherapy can be achieved. Herein, deoxygenation agent, FDA-approved perfluorocarbon (PFC) and photosensitizer indocyanine green (ICG) for oxygen depletion, along with the hypoxia-activating drug tirapazamine (TPZ), were coincorporated within the poly(lactic--glycolic acid) (PLGA) nanoemulsion (ICG/TPZ@PPs) for the treatment of hypoxic tumors. Following hypoxia amplifying through physical oxygen dissolution and photodynamic depletion in tumors, hypoxic chemotherapy could be effectively activated to improve multitreatment synergy. After achieving local tumor enrichment, PFC-mediated oxygen dissolution combined with further ICG-mediated photodynamic therapy (PDT) under near-infrared (NIR) laser irradiation could induce enhanced hypoxia, which would activate the antitumor activity of codelivered TPZ to synergize cytotoxicity. Remarkably, experimental results exhibited that deoxygenated ICG/TPZ@PPs-based photothermal therapy (PTT), PDT, and hypoxia activated chemotherapy have an excellent synergistic ablation of tumors without obvious side effects, and therefore, a broad prospect of application of this nanocarrier could be expected.
缺氧可能会增强癌细胞的化疗耐药性，并显著降低化疗的效果。为了缓解或逆转缺氧，人们已经做出了许多努力，例如向肿瘤微环境（TME）中引入更多的氧气。在当前的研究中，一种新型的纳米载体则采取了截然相反的策略，旨在进一步耗尽缺氧 TME 的氧气水平。通过创造这种缺氧的 TME，缺氧选择性细胞毒素可以更有效地发挥作用，从而实现氧耗竭触发的化疗。在此，脱氧剂、经美国食品和药物管理局批准的全氟碳（PFC）和用于氧耗竭的光敏剂吲哚菁绿（ICG）以及缺氧激活药物替拉扎胺（TPZ）被共包封在聚（乳酸-乙醇酸）（PLGA）纳米乳液（ICG/TPZ@PPs）中，用于治疗缺氧肿瘤。在肿瘤中通过物理氧气溶解和光动力作用来放大缺氧后，可有效激活缺氧化疗以提高多治疗协同作用。在实现局部肿瘤富集后，PFC 介导的氧气溶解与进一步的 ICG 介导的光动力治疗（PDT）在近红外（NIR）激光照射下联合使用，可诱导增强的缺氧，从而激活共递送的 TPZ 的抗肿瘤活性以协同增强细胞毒性。值得注意的是，实验结果表明，基于去氧 ICG/TPZ@PPs 的光热治疗（PTT）、PDT 和缺氧激活化疗具有出色的协同肿瘤消融效果，且没有明显的副作用，因此，这种纳米载体具有广阔的应用前景。
