Patient-derived xenograft (PDX) models are powerful tools for understanding cancer biology and drug discovery. In this study, a polymeric nano-sized drug delivery system poly (OEGMA)-PTX@Ce6 (NPs@Ce6) composed of a photosensitizer chlorin e6 (Ce6) and a cathepsin B-sensitive polymer-paclitaxel (PTX) prodrug was constructed. The photochemical internalization (PCI) effect and enhanced chemo-photodynamic therapy (PDT) were achieved via a two-stage light irradiation strategy. The results showed that the NPs@Ce6 had great tumor targeting and rapid cellular uptake induced by PCI, thereby producing excellent anti-tumor effects on human bladder cancer PDX models with tumor growth inhibition greater than 98%. Bioinformatics analysis revealed that the combination of PTX chemotherapy and PDT up-regulated oxidative phosphorylation and reactive oxygen species (ROS) generation, blocked cell cycle and proliferation, and down-regulated the pathways related to tumor progression, invasion and metastasis, including hypoxia, TGF-β signaling and TNF-α signaling pathways. Western blots analysis confirmed that proteins promoting apoptosis (Bax, Cleaved caspase-3, Cleaved PARP) and DNA damage (γH2A.X) were up-regulated, while those inhibiting apoptosis (Bcl-2) and mitosis (pan-actin and α/β-tubulin) were down-regulated after chemo-PDT treatment. Therefore, this stimuli-responsive polymer-PTX prodrug-based nanomedicine with combinational chemotherapy and PDT evaluated in the PDX models could be a potential candidate for bladder cancer therapy.

源自患者的异种移植物 (PDX) 模型是了解癌症生物学和药物发现的有力工具。本研究构建了由光敏剂二氢卟酚e6（Ce6）和组织蛋白酶B敏感性聚合物-紫杉醇（PTX）前药组成的聚合物纳米级药物递送系统poly（OEGMA）-PTX@Ce6（NPs@Ce6） 。通过两阶段光照射策略实现了光化学内化(PCI) 效应和增强化学光动力疗法 (PDT)。结果表明，NPs@Ce6具有良好的肿瘤靶向性和PCI诱导的快速细胞摄取，从而对人膀胱癌PDX模型产生优异的抗肿瘤作用，肿瘤生长抑制率大于98%。生物信息学分析显示 PTX 化疗联合 PDT 上调氧化磷酸化和活性氧（ROS）的产生，阻断细胞周期和增殖，下调与肿瘤进展、侵袭和转移相关的通路，包括缺氧、TGF-β信号通路和TNF-α信号通路。Western印迹分析证实，促进细胞凋亡的蛋白质（Bax、Cleaved caspase-3、Cleaved PARP）和DNA损伤（γH2A.X）上调，而抑制细胞凋亡（Bcl-2）和有丝分裂的蛋白质（泛肌动蛋白和α/ β-微管蛋白）在化学-PDT 治疗后下调。因此，在 PDX 模型中评估的这种基于刺激响应性聚合物-PTX 前药的纳米药物结合化疗和 PDT 可能是膀胱癌治疗的潜在候选者。