Tumor cell populations are highly heterogeneous, which limit the homogeneous distribution and optimal delivery of nanomedicines, thereby inducing insufficient therapeutic benefits. We develop tumor microenvironment activatable and external stimuli-responsive drug delivery system (^TAT+AzoNPs), which can improve photodynamic therapy (PDT) induced bioreductive chemotherapy in different tumor cells both proximal and distal to vessels. The TAT peptide on the surface of ^TAT+AzoNPs can both facilitate the cell uptake and the penetration of ^TAT+AzoNPs, owing to its responsiveness to tumor stimuli pH. ^TAT+AzoNPs can keep the cargoes (photosensitizer chlorine e6 (Ce6) and hypoxia activatable prodrug tirapazamine (TPZ)) and highly accumulate within tumor cells proximity and distal to vessels. The Azo-benzene bonds as the linkers between amphiphilic polymers remain stable under normoxia, but quite break at hypoxic conditions. Upon external laser irradiation, the intratumoral fate of ^TAT+AzoNPs involved two processes: 1) ^TAT+AzoNPs achieve efficient PDT on tumor cells proximal to vessel, since sufficient O₂ supply; and 2) PDT-induced more hypoxia can trigger TPZ release by breakage of Azo-benzene bond as well as accelerate the activation of TPZ for improved combination therapy efficacy in tumor cells distal to vessel. This study gives a direction for the development of stepwise-activatable hypoxia triggered nanosystem for PDT-induced bioreductive chemotherapy for tumor cells in different distance to vessel.

肿瘤细胞群是高度异质的，这限制了纳米药物的均匀分布和最佳递送，从而导致不足的治疗益处。我们开发了肿瘤微环境可激活和外部刺激响应药物递送系统（^{TAT + Azo} NPs），该系统可以改善光动力疗法（PDT）诱导的在血管近端和远端的不同肿瘤细胞中的生物还原化学疗法。的表面上的TAT肽^{TAT +偶氮}的NP既可以促进细胞摄取和渗透^{TAT +偶氮}的NP，由于其应答性肿瘤刺激的pH。^{TAT +偶氮}NP可以保持货物（光敏剂氯e6（Ce6）和低氧可激活的前药替拉帕明（TPZ））并在肿瘤细胞附近和远端血管内高度积聚。作为两亲聚合物之间的连接基的偶氮-苯键在常氧下保持稳定，但在缺氧条件下会断裂。在外部激光照射下，^{TAT + Azo} NPs的肿瘤内命运涉及两个过程：1）由于有足够的O ₂供给，^{TAT + Azo} NPs在靠近血管的肿瘤细胞上达到有效的PDT 。2）PDT引起的更多的缺氧可以通过偶氮的破坏触发TPZ释放-苯键并加速TPZ的活化，以改善血管远端肿瘤细胞的联合治疗功效。这项研究为逐步激活的缺氧触发纳米系统的开发提供了方向，该系统可用于PDT诱导的距血管不同距离的肿瘤细胞的生物还原化学疗法。