State Key Laboratory of Fine Chemicals, Frontiers Science Center for Smart Materials Oriented Chemical Engineering, Dalian University of Technology, 2 Linggong Road, Dalian, 116024, China.
Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital and Institute, Shenyang, 110801, PR China.
Biomaterials. 2022 Oct;289:121770. doi: 10.1016/j.biomaterials.2022.121770. Epub 2022 Sep 1.
Hypoxia is one of the prominent features of solid tumors. Hypoxia activated prodrugs (HAPs), selectively killing hypoxic cells, possess the potential to transform hypoxia from a nuisance to an advantage in precision therapy. Exhibiting a more significant hypoxic microenvironment, gliomas, as the most frequent and incurable neurological tumors, provide HAPs a more attractive therapeutic prospect. However, the insufficient hypoxia and the obstruction of the blood-brain barrier (BBB) severely limit the activation and bio-availability of HAPs. Herein, a novel nanoparticle iRGD@ZnPc + TPZ was designed and synthesized to achieve gliomas inhibition by encapsulating tirapazamine (TPZ) as a HAP and zinc phthalocyanine (ZnPc) as a photosensitizer to enhance hypoxia. iRGD@ZnPc + TPZ can realize breakthrough BBB, deep penetration, and significant retention in gliomas, which is attributed to the iRGD-mediated receptor targeting and active transport. After being internalized by tumor cells and radiated, ZnPc efficiently consumes intratumoral O to produce reactive oxygen species, which not only implements tumor suppression, but also intensify hypoxia to activate TPZ for amplifying chemotherapy. The photosensitizer-enhanced activation of HAPs inhibits gliomas growth. This study provides a new strategy with sensitizing and activating HAPs for gliomas treatment in clinical.
缺氧是实体瘤的显著特征之一。缺氧激活前药（HAPs）选择性地杀伤缺氧细胞，有可能将缺氧从精准治疗中的一个麻烦转化为一个优势。作为最常见和无法治愈的神经肿瘤，脑胶质瘤表现出更显著的低氧微环境，为 HAPs 提供了更有吸引力的治疗前景。然而，缺氧不足和血脑屏障（BBB）的阻塞严重限制了 HAPs 的激活和生物利用度。在此，设计并合成了一种新型的纳米粒子 iRGD@ZnPc + TPZ，通过封装替拉扎明（TPZ）作为 HAP 和锌酞菁（ZnPc）作为光敏剂来增强缺氧，从而实现对脑胶质瘤的抑制。iRGD@ZnPc + TPZ 可以实现突破 BBB、深层渗透和在脑胶质瘤中的显著滞留，这归因于 iRGD 介导的受体靶向和主动转运。在被肿瘤细胞内化并辐射后，ZnPc 有效地消耗肿瘤内的 O 来产生活性氧，这不仅实现了肿瘤抑制，还增强了缺氧以激活 TPZ 来放大化疗。光敏剂增强的 HAPs 激活抑制了脑胶质瘤的生长。本研究为脑胶质瘤的临床治疗提供了一种新的策略，即敏化和激活 HAPs。
