Abstract：
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 O2 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.
摘要：
缺氧是实体瘤的突出特征之一。缺氧激活前药（HAP），选择性地杀死缺氧细胞，在精确治疗中具有将缺氧从令人讨厌转变为优势的潜力。表现出更显著的缺氧微环境，胶质瘤，作为最常见和无法治愈的神经肿瘤，为HAP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HAP的激活和生物利用度。在这里，设计并合成了一种新型的纳米颗粒iRGD@ZnPcTPZ，通过封装作为HAP的替拉帕明（TPZ）和作为光敏剂的酞菁锌（ZnPc）来增强缺氧，从而实现胶质瘤的抑制。iRGD@ZnPc+TPZ可以实现突破性BBB，深层渗透,并在神经胶质瘤中显著保留，这归因于iRGD介导的受体靶向和主动转运。被肿瘤细胞内化并辐射后，ZnPc有效消耗肿瘤内O2产生活性氧，不仅实现了肿瘤抑制，但也加强缺氧激活TPZ放大化疗。光敏剂增强的HAP激活抑制神经胶质瘤的生长。本研究为临床胶质瘤的治疗提供了一种新的致敏和激活HAP的策略。
