基于UiO-66-NH₂的智能药物递送体系的构建及其协同抗肿瘤活性研究

A Smart Drug Delivery System Based on UiO-66-NH₂ and Its Synergistic Antitumor Activity

摘要: 目的：以阿霉素(DOX)和内消旋–四(4-羧基苯基)卟吩(meso-tetra(4-carboxyphenyl)porphine:TCPP)为模型药物，UiO-66-NH₂为纳米载体，构建了一种能响应肿瘤微环境的复合纳米载药体系，并对其性能进行研究。方法：将TCPP通过配位作用引入到金属–有机框架的周期性结构中，负载DOX，构建了UiO-66-NH₂@TCPP@DOX复合纳米载药体系。通过SEM、XRD、IR和荧光光谱进行形貌和结构的表征。同时，研究了其在不同pH缓冲溶液中药物的释放情况、细胞外和细胞内单线态氧产量及对B₁₆F₁₀肿瘤细胞的细胞毒活性。结果：纳米载药体系平均粒径约为200 nm，DOX的负载量为31 wt%，TCPP的负载量为10.9 wt%。在pH为5.0的缓冲液中，时间108 h内DOX的累积释放率为47.2%，TCPP的累积释放率为76.8%，高于在pH为7.0的缓冲溶液中的相应释放量。此外，UiO-66-NH₂@TCPP@DOX在细胞外和细胞内都有较高的单线态氧产量，细胞毒实验证明其在体外能够明显杀伤肿瘤细胞B₁₆F₁₀，在660 nm激光照射下，细胞存活率为55%，表明UiO-66-NH₂@TCPP@DOX中光敏剂协同化疗药物对肿瘤细胞的高效杀伤效果。结论：本实验通过构建复合纳米载药体系UiO-66-NH₂@TCPP@DOX有效避免了光敏剂的聚集，提高了DOX负载量，增强了靶向性，从而实现了光敏剂和化疗药的有效递送和对肿瘤细胞的协同杀伤作用。

Abstract: Purpose: A smart composite nano-drug delivery system, which was responsive to the acid tumor microenvironment was developed based on UiO-66-NH₂, loading doxorubicin and meso-tetra(4- carboxyphenyl)porphine(TCPP). Its properties were also studied in detail. Methods: TCPP was in-troduced into the periodic porous metal-organic frameworks (MOFs) by the coordination ability of TCPP. UiO-66-NH₂@TCPP@DOX was constructed after DOX was loaded into the pores of UiO-66- NH₂@TCPP. After all, the morphology and structure were characterized by SEM, XRD, IR and fluo-rescence spectra. At the same time, the properties including the drugs release in different buffer solutions, the extracellular and intracellular singlet oxygen production and cytotoxic activities against B₁₆F₁₀ were also investigated. Results: The average diameter of nanoparticles was about 200 nm and 31 wt% of DOX, 10.9 wt% of TCPP existed in the composite nano particles respectively. In the buffer solution with a pH of 5.0, the cumulative release rate of DOX and TCPP was 47.2% and 76.8% respectively within 108h, which were higher than that in the buffer solution with a pH of 7.0. In addition, UiO-66-NH₂@TCPP @DOX exhibited high efficient singlet oxygen generation, which was confirmed by the extracellular and intracellular experiments. Cytotoxic experiments have shown that it can kill tumor cells B₁₆F₁₀in vitro effectively. The cell survival rate was 55% under irradiation of 660 nm laser, indicating that the photosensitizer combined with chemotherapeutic drugs in UiO-66-NH₂@TCPP@DOX has a high killing effect on tumor cells. Conclusion: The composite nano-drug loading system can effectively avoid the aggregation of photosensitizers, improve the loading capacity of DOX and enhance the targeting ability, so as to realize the effective delivery of photosensitizers and chemotherapeutic drugs, which have synergistic effects in the treatment of cancer.