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胰腺癌靶向纳米载体的合成、表征及其改善光动力治疗研究

Synthesis, Characterization and Application of Targeted Nanocarrier Improving Photodynamic Therapy for Pancreatic Cancer

  • 摘要: 采用点击化学方法合成了一种胰腺癌靶向纳米载体LL-PTP,物理包裹难溶性光敏药物酞菁锌(ZnPc)制备成LL-PTP/ZnPc纳米粒。LL-PTP临界聚集浓度为52.97 μg/mL,物理包载ZnPc形成的LL-PTP/ZnPc纳米粒为蓝色透明溶液,ZnPc包载量为20.1±1.4%,水合粒径为89.18±0.21 nm,具有良好的放置稳定性和血清稳定性,符合临床对注射剂型稳定性的要求,并且LL-PTP/ZnPc在肿瘤组织中释药比例可达到血清中的6倍以上,有利于纳米粒在肿瘤组织发挥治疗作用。分别经激光共聚焦显微镜和流式细胞术进行定性和定量研究LL-PTP/ZnPc靶向摄取行为,结果表明,LL-PTP/ZnPc通过Plectin-1介导的胞吞作用增加PANC-1细胞对纳米粒摄取,效率显著优于LL/ZnPc和游离ZnPc。探针DCFH-DA检测胞内ROS水平结果显示,光照LL-PTP/ZnPc诱导胞内ROS增加,有利于在胰腺癌中发挥更好的光动力治疗作用。综上,本研究成功制备了胰腺癌靶向纳米载体LL-PTP,并成功负载ZnPc,改善其光动力治疗效果。

     

    Abstract: LL-PTP, a pancreatic cancer-targeted nanocarrier, was synthesized via click chemistry. Subsequently, the insoluble photosensitive drug zinc phthalocyanine (ZnPc) was physically encapsulated within LL-PTP to fabricate LL-PTP/ZnPc nanoparticles. The critical aggregation concentration (CAC) of LL-PTP was determined to be 52.97 μg/mL. The LL-PTP/ZnPc nanoparticles, formed by the physical encapsulation of ZnPc, appeared as a blue transparent solution. Characterizations revealed that the ZnPc loading efficiency of these nanoparticles was 20.1 ± 1.4%, with a hydrated particle size of 89.18 ± 0.21 nm. Notably, the nanoparticles exhibited excellent storage stability and serum stability, fully meeting the stability requirements for injectable formulations in clinical applications. Furthermore, the release rate of LL-PTP/ZnPc in tumor tissue was found to be over 6-fold higher than that in serum—a property that significantly favors the therapeutic efficacy of the nanoparticles at the tumor site. To investigate the targeted uptake behavior of LL-PTP/ZnPc, qualitative and quantitative analyses were performed using confocal laser scanning microscopy (CLSM) and flow cytometry, respectively. The results demonstrated that LL-PTP/ZnPc enhanced the uptake of nanoparticles by PANC-1 cells (a pancreatic cancer cell line) through Plectin-1-mediated endocytosis. This uptake efficiency was significantly superior to that of LL/ZnPc (non-targeted control nanoparticles) and free ZnPc. Intracellular reactive oxygen species (ROS) levels were detected using the DCFH-DA probe. It was observed that LL-PTP/ZnPc, upon light irradiation, induced a marked increase in intracellular ROS production—an effect that is conducive to achieving enhanced photodynamic therapy (PDT) efficacy against pancreatic cancer. In conclusion, this study successfully developed LL-PTP, a targeted nanocarrier for pancreatic cancer, and achieved efficient loading of ZnPc. The resulting LL-PTP/ZnPc nanoparticles effectively improved the PDT effect against pancreatic cancer, highlighting their potential as a promising therapeutic platform for this malignancy.

     

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