Although chemo-photodynamic therapy demonstrates promising synergetic therapeutic effect in malignant cancers, the currently available nanocarriers offer the limited capabilities for selective toxicity, drug release and tumor penetration. Herein, we developed photoactivatable nanomicelles, which are constructed by self-assembling of poly (ethylene glycol) (PEG)-stearamine (C18) conjugate (PTS) with a ROS-sensitive thioketal linker (TL) and co-loaded with doxorubicin (DOX) and photosensitizer pheophorbide A (PhA), for enhanced locoregional chemo-photodynamic therapy. Upon accumulation in tumor region, the resulting PTS nanomicelles loaded with Dox and PhA (PTS-DP) demonstrated reactive oxygen species (ROS) cascade responsive release of the DOX and PhA loaded inside. Initial intracellular release of DOX and PhA from the PTS-DP was triggered by the intrinsic presence of endogenous ROS within cancer cells. Furthermore, upon laser irradiation on the tumor region, enhanced singlet oxygen (1O2) was generated by PhA released initially in cancer cells, which in turns accelerated the cytoplasmic release of DOX through rapid dissociation of nanomicelles. The gradual elevation of local ROS level generated by light-activated PhA subsequent ROS-triggered release of DOX synergistically inhibited tumor growth and enhances the anti-tumor immunity. Findings of our study suggested that ROS-sensitive PTS nanomicelles could be a promising and innovative nanocarrier for locoregional chemo-photodynamic therapy.

中文翻译：

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具有肿瘤局部活化作用和ROS的长循环光活化纳米胶束触发了自加速药物释放，从而增强了局部化学光动力疗法。

尽管化学光动力疗法在恶性肿瘤中显示出有希望的协同治疗效果，但目前可用的纳米载体在选择性毒性，药物释放和肿瘤渗透方面的能力有限。本文中，我们开发了可光活化的纳米胶束，该胶束通过将聚乙二醇（PEG）-硬脂胺（C18）共轭物（PTS）与ROS敏感的硫缩酮连接体（TL）自组装而构建，并与阿霉素（DOX）共载）和光敏剂脱镁叶绿酸A（PhA），用于增强局部化学光动力疗法。在肿瘤区域中积累时，所得的装载有Dox和PhA的PTS纳米胶束（PTS-DP）表现出活性氧（ROS）级联响应释放内部装载的DOX和PhA。癌细胞内源性ROS的内在存在触发了DOX和PhA从PTS-DP的初始细胞内释放。此外，在激光照射肿瘤区域时，最初在癌细胞中释放的PhA产生增强的单线态氧（1O2），这又通过纳米胶束的快速解离而加速了DOX的细胞质释放。由光激活的PhA随后由ROS触发释放DOX所产生的局部ROS水平逐渐升高，协同抑制了肿瘤的生长并增强了抗肿瘤免疫力。我们的研究结果表明，ROS敏感的PTS纳米胶束可能是局部化学光动力疗法的有前途和创新的纳米载体。最初在癌细胞中释放的PhA产生增强的单线态氧（1O2），而后者又通过纳米胶束的快速解离而加速了DOX的细胞质释放。由光激活的PhA随后由ROS触发释放DOX所产生的局部ROS水平逐渐升高，协同抑制了肿瘤的生长并增强了抗肿瘤免疫力。我们的研究结果表明，ROS敏感的PTS纳米胶束可能是局部化学光动力疗法的有前途和创新的纳米载体。最初在癌细胞中释放的PhA产生增强的单线态氧（1O2），而后者又通过纳米胶束的快速解离而加速了DOX的细胞质释放。由光激活的PhA随后由ROS触发释放DOX所产生的局部ROS水平逐渐升高，协同抑制了肿瘤的生长并增强了抗肿瘤免疫力。我们的研究结果表明，ROS敏感的PTS纳米胶束可能是局部化学光动力疗法的有前途和创新的纳米载体。由光激活的PhA随后由ROS触发释放DOX所产生的局部ROS水平逐渐升高，协同抑制了肿瘤的生长并增强了抗肿瘤免疫力。我们的研究结果表明，ROS敏感的PTS纳米胶束可能是局部化学光动力疗法的有前途和创新的纳米载体。由光激活的PhA随后由ROS触发释放DOX所产生的局部ROS水平逐渐升高，协同抑制了肿瘤的生长并增强了抗肿瘤免疫力。我们的研究结果表明，ROS敏感的PTS纳米胶束可能是局部化学光动力疗法的有前途和创新的纳米载体。