通过下调HIF-1α和GSH的耗竭而采用光触发的协同抗肿瘤疗法的自送和自监测化学光动力学纳米粒子。,ACS Applied Materials & Interfaces

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通过下调HIF-1α和GSH的耗竭而采用光触发的协同抗肿瘤疗法的自送和自监测化学光动力学纳米粒子。
ACS Applied Materials & Interfaces ( IF 8.3 ) Pub Date : 2020-01-16 , DOI: 10.1021/acsami.9b23325
Zhongtao Zhang ₁ , Ruyi Wang ₁ , Xiaoxian Huang ₁ , Renjie Luo ₂ , Jingwei Xue _{3,

4} , Jing Gao _{3,

5} , Wenyuan Liu _{2,

6} , Fulei Liu _{3,

7} , Feng Feng _{1,

8,

9} , Wei Qu _{1,

9}

Affiliation

光动力疗法（PDT）是一种临床认可的癌症治疗方法，它面临着许多限制其应用的缺点。例如，缺氧诱导的缺氧诱导因子-1α（HIF-1α）升高可能会使肿瘤对PDT脱敏，并且癌细胞中高浓度的谷胱甘肽（GSH）也可以中和PDT期间产生的活性氧（ROS），导致治疗不足。此外，始终需要用于成像引导的可视化治疗的额外探针来跟踪药物的释放或分布，同时它可能会减少药物输送系统（DDS）的药物负荷。在本研究中，我们设计并制备了一种新型的多功能联合治疗纳米颗粒（ZnPc @ Cur-S-OA NPs），其中姜黄素（Cur）不仅用作化学药物，通过下调HIF-1α和消耗B16F10细胞中的GSH来实现与PDT的联合治疗，还被设计为小分子ROS触发的释放前药以递送光敏剂（ PS）。纳米颗粒（NPs）中PS的红色荧光可用于跟踪NPs的分布，而Cur的绿色荧光显示“ OFF-ON”激活，这使附加成像和实时自我监控功能成为可能。这些结果证明，与单一疗法相比，所制备的联合疗法NPs在抑制B16F10小鼠黑素瘤肿瘤生长方面更有效，而不会在体内或体外引起全身毒性，这表明联合治疗NPs是通过下调HIF-1α和消耗GSH来提高PDT疗效的有效方法。因此，使用多功能天然产物作为刺激响应载体以及具有PDT的增效剂通过多种途径增强抗肿瘤功效的策略可能会开辟一条替代途径，以制造新的自我递送组合疗法纳米药物。此外，该药物发出的荧光可用于药物释放和分布的实时自我监测，在临床上具有针对不同肿瘤类型和阶段调整个体化治疗剂量和照射时间的巨大潜力。使用多功能天然产物作为刺激反应载体以及与PDT协同作用以通过多种途径增强抗肿瘤功效的策略可能会开辟一条替代途径，以制造新的自递送组合疗法纳米药物。此外，该药物发出的荧光可用于药物释放和分布的实时自我监测，在临床上具有针对不同肿瘤类型和阶段调整个体化治疗剂量和照射时间的巨大潜力。使用多功能天然产物作为刺激响应载体以及与PDT协同作用以通过多种途径增强抗肿瘤功效的策略可能会开辟一条替代途径，以制造新的自递送组合疗法纳米药物。此外，该药物发出的荧光可用于药物释放和分布的实时自我监测，在临床上具有针对不同肿瘤类型和阶段调整个体化治疗剂量和照射时间的巨大潜力。

"点击查看英文标题和摘要"

Self-Delivered and Self-Monitored Chemo-Photodynamic Nanoparticles with Light-Triggered Synergistic Antitumor Therapies by Downregulation of HIF-1α and Depletion of GSH.

Photodynamic therapy (PDT), a clinically approved cancer treatment, has faced many drawbacks that restricted its applications. For example, the hypoxia-induced elevated hypoxia-inducible factor-1α (HIF-1α) may desensitize tumors to PDT, and the high concentration of glutathione (GSH) in cancer cells can also neutralize the generated reactive oxygen species (ROS) during PDT, resulting in insufficient therapy. Moreover, extra probes for imaging-guided visualization therapy are always needed to track drug release or distribution, while it may decrease the drug loading of the drug delivery system (DDS). In the present study, we have designed and prepared a novel multifunctional combined therapy nanoparticle (ZnPc@Cur-S-OA NPs), in which curcumin (Cur) was not only used as a chemotherapy drug to achieve a combination therapy with PDT via downregulating HIF-1α and depleting GSH in B16F10 cells but also designed as a small-molecule ROS-triggered release prodrug to deliver the photosensitizer (PS). The red fluorescence of PS in the nanoparticles (NPs) can be used to track the NPs distribution, while the green fluorescence of Cur showed an "OFF-ON" activation, which enables additional imaging and real-time self-monitoring capabilities. These results proved that the prepared combined therapy NPs were more effective to inhibit the growth of B16F10 mouse melanoma tumor than was monotherapy without eliciting systemic toxicity either in vitro or in vivo, which indicated the combined therapy NPs as an effective way to improve the PDT efficacy via downregulation of HIF-1α and depletion of GSH. Thus, the strategy of using a multifunctional natural product as the stimuli-responsive carrier as well as the synergist with PDT for enhancing antitumor efficacy via multiple pathways may open an alternative avenue to fabricate new self-delivery combination therapy nanodrugs. Besides, the fluorescence emitted from the drug can be used for real-time self-monitoring of drug release and distribution, which has great potential in clinic to adjust the administration dose and irradiation time for different tumor types and stages for individual therapy.

更新日期：2020-01-26

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