多功能介孔氧化硅基纳米诊疗剂的研究进展

doi:10.3724/SP.J.1077.2012.12082

摘要/Abstract

摘要：

无机介孔纳米生物材料在药物靶向输送、组织工程、基因传输治疗、分子影像、无创手术增效治疗等医学领域具有广阔的应用前景, 对于诸如癌症等重大疾病的早期诊断与高效治疗具有重要的意义。本文以医学应用需求为背景, 以纳米合成化学为基础, 从多功能介孔纳米生物材料的设计入手, 结合本课题组的研究进展, 综述了介孔基纳米诊疗剂的研究现状和未来发展的趋势。通过对介孔SiO₂纳米粒子进行功能化修饰, 赋予其特定的功能, 不仅可以作为临床分子影像(核磁共振成像、荧光成像以及各种成像模式的复合)的造影剂对疾病进行诊断, 并能同时高效地包覆和传输药物对疾病进行治疗(化疗、基因治疗、光动力学治疗或者无创手术治疗)。随着纳米生物技术的发展和纳米合成化学的进步, 设计和制备具有特定功能的满足临床需求的介孔氧化硅基纳米生物材料, 并系统地评价其细胞生物学效应和生物安全性, 将会真正实现其在临床上的应用, 从而造福人类。

关键词: 介孔, 纳米材料, 纳米诊疗剂, 生物材料, 分子影像, 癌症, 综述

Abstract:

Inorganic mesoporous nano-biomaterials have broad application potentials in molecular imaging, targeted drug delivery, tissue engineering, gene therapy, and non-invasive surgical therapy, etc., which are of great significance in the early diagnosis and efficient therapy of serious diseases such as cancer. This article reviews the most recent research advances and outlooks future development trends of mesoporous nanotheranostics based on clinical requirements, the principle of nano-synthetic chemistry and the design strategy of multifunctional mesoporous nano-biomaterials, by combining the recent achievements of our group. By integrating various functions into mesoporous silica nanoparticles to endow them with special capabilities, the mesoporous nanotheranostics could act as the contrast agents for clinical molecular imaging (magnetic resonance imaging, fluorescent imaging and the combinations of various imaging modalities), as well as the carriers for the encapsulation and delivery of drugs for the therapy of diseases (chemotherapy, gene therapy, photodynamic therapy and non-invasive surgical therapy). With the development of bio-nanotechnology and nano-synthetic chemistry, mesoporous nanotheranostics are expected to satisfy the clinical requirements following the systematic investigation of their biological effects and bio-safety, and finally find their applications in clinical practices to benefit human beings.

Key words: mesoporous, nanomaterials, nanotheranostics, biomaterials, molecular imaging, cancer, review

中图分类号:

TQ174

施剑林, 陈雨, 陈航榕. 多功能介孔氧化硅基纳米诊疗剂的研究进展[J]. 无机材料学报, 2013, 28(1): 1-11.

SHI Jian-Lin, CHEN Yu, CHEN Hang-Rong. Progress on the Multifunctional Mesoporous Silica-based Nanotheranostics[J]. Journal of Inorganic Materials, 2013, 28(1): 1-11.

图/表 8

图1 通过氧化-还原法制备Mn顺磁中心均匀分散的介孔SiO2(Mn-MSNs)的示意图[38]

Fig. 1 Schematic representation for the preparation of manganese oxide-dispersed MSNs (Mn-MSNs) by the oxidation- reduction strategy[38]

图2 氧缺失产生荧光特性的介孔SiO2的制备示意图[41]

Fig. 2 Schematic illustration of the synthesis of oxygen-deficient fluorescent MSNs[41]

图3 氧缺失的荧光介孔SiO2的激发(a)和发射(b)光谱图; 荧光MSNs用于细胞标记(c)和阿霉素传输(d)的共聚焦图像(图像e是图像c和图像d的融合图像)[41]

Fig. 3 (a) Luminescent excitation and (b) emission spectra of oxygen-deficient fluorescent MSNs; (c) cell labeling and (b) doxorubicin delivery by obtained fluorescent MSNs (e is the merged figure of c and d)[41]

图4 (a)MFNEs的制备示意图; (b)MFNEs标记乳腺癌细胞MCF-7的共聚焦显微镜照片; (c1-c4)体内荷瘤大鼠注射MFNEs前(c1)和注射后(c2: 0.5 h、c3: 1 h、c4: 1.5 h)的MRI-T2图像[19]

Fig. 4 (a) Synthetic procedures of MFNEs; (b) Confocal fluorescent microscopic images of breast cancer MCF-7 cells labeled with MFNEs; (c1-c4) In vivo MRI of a tumor-bearing mouse before (c1) and after injection of MFNEs for different time intervals (c2: 0.5 h, c3: 1 h, c4: 1.5 h)[19]

图5 (a)NaYF4:Tm/Yb/Gd@mSiO2的TEM照片; (b) NaYF4:Tm/Yb/Gd@mSiO2标记MCF-7细胞的共聚焦显微镜照片; (c)荷瘤大鼠在注射NaYF4:Tm/Yb/Gd@mSiO2前(左图)后(右图)的MRI-T1图像; (d)荷瘤大鼠在注射NaYF4:Tm/Yb/Gd@mSiO2后的上转换活体荧光图像, 从左到右分别为明场、荧光和融合后的图像[43]

Fig. 5 (a) TEM images of NaYF4:Tm/Yb/Gd@mSiO2 nanocomposites; (b) Confocol images of MCF-7 cells incubated with NaYF4:Tm/Yb/Gd@mSiO2; (c) In vivo MRI-T1 images of tumor (left: pre-injection, right: post-injection); (d) In vivo upconversion luminescence imaging of a tumor-bearing mouse after local injection at the tumor site, from left to right: bright field, upconversion luminescence and overlay images[43]

图6 (a)Au棒复合的磁性介孔纳米药物载体(GMMNs)的微观结构示意图; (b-d)注射GMMNs后肿瘤部位在1 W/cm2(b)和 2 W/cm2(c)的808 nm激光辐照下不同时间后的热成像监控图像, 其中(d)为注射PBS参照样在2 W/cm2的808 nm激光辐照下热成像监控图像; (e)不同处理条件下MCF-7细胞生长被抑制的速率, 其中紫色为GMMNs-NIR, 红色为GMMNx-DOX, 绿色为GMMNs-DOX-NIR[44]

Fig. 6 (a) Microscopic structure of GMMNs; (b-d) Thermographic surveillance of photothermal heating at different time points in GMMNs -injected tumor under 1 W/cm2 (b) and 2 W/cm2 (c) irradiations and PBS solution-injected tumor under 2 W/cm2 irradiation (d); (e) Comparison of inhibition rates for MCF cells treated by GMMNs-NIR (purple), GMMNs-DOX (red) and GMMNs-DOX-NIR (green)[44]

图7 (a)超声引导下HIFU治疗的示意图。通过超声成像, 为HIFU的辐照寻找治疗的靶点, 治疗过程又可以通过超声成像进行监控。体外实验以脱气牛肝为HIFU辐照评价基体, 体内实验以兔子为模型动物; (b)将PBS(200 μL)、PFH/ PBS (200 μL)、IMNCs/PBS(200 μL)和PFH-IMNCs/PBS(200 μL)注射到脱气牛肝后, 在相同的HIFU辐照条件下(150 W/cm2, 5 s; *P < 0.1, **P < 0.05)组织消融体积, 其中b中的插图为不同实验条件下消融后组织的数码照片图[45]

Fig. 7 (a) Schematic illustration of the high intensity focused ultrasound (HIFU) therapeutic principle. The HIFU radiates to the targeted site of the body and the process is monitored by the outside ultrasound imaging. The ex vivo experiment was conducted using bovine liver as a radiation substrate (left digital picture) while the in vivo experiment was carried out using rabbits as a model animal (the right digital picture); (b) Coagulated tissue volume of bovine liver by the intra-tissue injection of different agents such as PBS (200 μL), PFH/PBS (200 μL), IMNCs/PBS (200 μL) and PFH-IMNCs/PBS (200 μL) under the same irradiation power and duration (150 W/cm2, 5 s; *P < 0.1, **P < 0.05). Insets in b are the macroscopic appearances of bovine liver tissues exposed to HIFU with or without using the synergistic agents[45]

图8 耳静脉注射不同试剂前(a1, b1和c1)后(5 min: a2, b2和c2; 15 min: a3, b3和c3; 30 min: a4, b4和c4)兔VX2肿瘤模型的MRI-T1图像(PBS: a1-a4; MCNCs/PBS: b1-b4; PFH-MCNCs/PBS: c1-c4), 箭头指向肿瘤部位; (d)注射PFH-MCNCs/PBS前后肿瘤部位的MRI-T1信号值(**P < 0.005); (e)在辐照功率为150 W/cm2, 辐照时间为5 s的条件下体内兔VX2肿瘤部位消融坏死的体积, 其中插图为相应的肿瘤消融组织的数码照片[18]

Fig. 8 In vivo T1-weighted MR imaging of rabbits bearing VX2 liver tumor before (a1, b1 and c1) and after (5 min: a2, b2 and c2; 15 min: a3, b3 and c3; 30 min: a4, b4 and c4) administration of different agents (PBS: a1-a4; MCNCs/PBS: b1-b4; PFH-MCNCs/PBS: c1-c4) via ear vein. Arrows indicate the tumor. (d) T1-weighted MRI signal intensities of tumor tissue before and after intravenous administration of PFH-MCNCs/PBS (**P < 0.005); (e) In vivo coagulated necrotic tumor volume by MRI-guided HIFU exposure under the irradiation power of 150 W/cm2 and duration of 5 s in rabbit liver tumors after receiving different agents via ear vein (inset: digital pictures of tumor tissue after HIFU exposure)[18]

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