高分散共轭聚合物-金属有机框架纳米立方体的制备及抗肿瘤应用

doi:10.6023/A23030095

摘要/Abstract

纳米尺寸的金属有机框架材料兼具传统框架材料的规整孔隙、高比表面积, 和纳米材料在活体中的高渗透和长滞留效应, 被广泛应用于药物递送领域. 然而, 单纯递送化疗药物对肿瘤的治疗效果有限, 通常需要联合其他治疗方式以提高治疗效果. 本工作开发了一种普适的合成方案, 用于共轭聚合物-沸石咪唑酯骨架-8(ZIF-8)复合纳米立方体的制备. 借助表面活性剂十六烷基三甲基溴化铵, 将疏水共轭聚合物聚[2,6-(4,4-双-(2-乙基己基)-4H-环戊二烯并[2,1-b;3,4-b']二噻吩)-alt-4,7(2,1,3-苯并噻二唑)](PCPDTBT)包裹在ZIF-8中, 得到大小约60 nm的纳米立方体. 接着, 通过两亲性嵌段共聚物F127的修饰实现其在水溶液中的高分散性和胶体稳定性. 该复合材料能够高效负载抗肿瘤药物阿霉素并实现酸响应的药物释放, 有助于肿瘤的化疗. 同时, ZIF-8的包裹也将PCPDTBT的光热转换效率大幅提升至42.5%, 可用于高效的光热治疗. 动物实验表明, 通过化疗和光热治疗的联合, 载药后的复合纳米立方体能够在激光照射下显著抑制肿瘤的生长且不会对正常组织造成明显损伤, 是一种高效的抗肿瘤试剂.

关键词: 金属有机框架材料, 共轭聚合物, 纳米立方体, 光热效应, 联合治疗

Nano-sized metal-organic frameworks possess uniform pores and high specific surface area of traditional frameworks, and enhanced permeability and retention effect of the nanomaterials, can be used as a new class of drug carriers. Recently, these materials have been heavily explored in the fields of drug delivery and tumor theranostics. However, chemotherapy using these nanoparticles as drug delivery vehicles alone cannot lead to high tumor inhibition efficiency. Other therapeutic modalities should be combined to improve the therapeutic effect. In this work, a general approach for the synthesis of conjugated polymer (CP)-zeolitic imidazolate framework-8 (ZIF-8) nanocubes was developed. With the assistance of cetyl trimethyl ammonium bromide, hydrophobic conjugated polymer poly[2,6-(4,4-bis-(2-ethylhexyl)-4H-cyclopenta[2,1-b;3,4- b']dithiophene)-alt-4,7(2,1,3-benzothiadiazole)] (PCPDTBT) was transferred into aqueous solution through microemulsion method. After mixing with zinc ions and 2-methylimidazole, PCPDTBT can be encapsulated within ZIF-8, forming nanocubes with an average size of around 60 nm. After surface modification with amphiphilic block copolymer F127, the obtained nanocubes exhibited high dispersity and colloidal stability in aqueous solutions. The hydrodynamic diameter of the F127 coated nanocubes was around 62 nm, and did not change obviously after storing for 7 d. The nanocomposites exhibited high drug loading capacity, and can release drug in an acidic responsive manner, which was beneficial for chemotherapy. Due to the strong absorption of PCPDTBT in the near infrared region, the nanocubes can be used for photothermal therapy with a 730 nm laser. ZIF-8 coating also improved the photothermal conversion efficiency of PCPDTBT to around 42.5%, which can be useful for efficient photothermal therapy. Animal experiments were performed to demonstrate the antitumor ability of the nanocubes. With the combination of chemotherapy and photothermal therapy, the drug loaded nanocubes can inhibit the tumor growth in vivo efficiently under laser irradiation, and meanwhile, do not cause obvious damage to normal organs. Therefore, the obtained nanocubes can be effective antitumor agents.

Key words: metal-organic frameworks, conjugated polymer, nanocubes, photothermal effect, combined therapy

引用此文

孙博, 琚雯雯, 王涛, 孙晓军, 赵婷, 卢晓梅, 陆峰, 范曲立. 高分散共轭聚合物-金属有机框架纳米立方体的制备及抗肿瘤应用[J]. 化学学报, 2023, 81(7): 757-762.

Bo Sun, Wenwen Ju, Tao Wang, Xiaojun Sun, Ting Zhao, Xiaomei Lu, Feng Lu, Quli Fan. Preparation of Highly-dispersed Conjugated Polymer-Metal Organic Framework Nanocubes for Antitumor Application[J]. Acta Chimica Sinica, 2023, 81(7): 757-762.

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图/表 6

图1. 共轭聚合物-金属有机框架纳米立方体的制备及肿瘤联合治疗示意图

Figure 1. Schematic illustration of the fabrication of conjugated polymer-MOF nanocubes for the combination therapy of tumor

图2. 加入硝酸锌后(a)立即加入, (b)静置10 min后加入及(c)放置过夜后加入F127所得产物的透射电子显微镜图片; (d) ZIF-8@F127纳米立方体的水合粒径分布图

Figure 2. TEM images of the nanoparticles obtained by adding F127 (a) immediately, (b) 10 min, and (c) overnight after the injection of zinc nitrate; (d) hydrodynamic size distributions of ZIF-8@F127 nanocubes

图3. (a) CZF的透射电镜图; (b) CZF溶液的吸收光谱及PCPDTBT的结构式; (c)不同功率激光照射下CZF溶液的升温曲线; (d)激光照射下不同吸光度CZF的升温曲线; (e) CZF的光热稳定性; (f)时间和－ln θ的线性拟合曲线

Figure 3. (a) TEM image of CZF; (b) absorption spectrum of CZF solution and the chemical structure of PCPDTBT; temperature elevation of CZF solution after illuminated with 730 nm laser under (c) different power densities and (d) absorbance; (e) photothermal stability of CZF; (f) the linear fitting curve of the time data versus －ln θ

图4. (a)在不同条件下CZF/DOX的药物释放曲线; (b)与不同浓度CZF和CZF/DOX孵育后的细胞活性

Figure 4. (a) Cumulative release of DOX from CZF/DOX under different conditions; (b) cell viabilities after incubated with CZF and CZF/ DOX at different concentrations

图5. 注射生理盐水和CZF/DOX后, 小鼠在激光照射下的(a)红外热像图和(b)肿瘤部位的升温曲线; 小鼠在治疗过程中的(c)瘤体积及(d)体重变化; 治疗结束后小鼠的(e)瘤重和(f)相应肿瘤照片

Figure 5. (a) Infrared thermal images and (b) temperature elevation curves at the tumor sites of the mice under laser irradiation after the injection of saline and CZF/DOX solution; (c) tumor volumes and (d) body weights of the mice during different treatments; (e) the weights and (f) the photographs of the isolated tumors after the treatments

图6. 治疗结束后小鼠主要器官和肿瘤的H&E染色图片

Figure 6. H&E staining of the major organs and the tumors of the mice after the treatments

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