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化学进展 2021, Vol. 33 Issue (3): 394-405 DOI: 10.7536/PC200571 前一篇   后一篇

• 综述 •

基于树状大分子的SPECT成像造影剂的构建及其应用

赵平平1, 杨军星1, 施健辉1, 朱静怡1,*()   

  1. 1 南京工业大学 药学院 南京 211800
  • 收稿日期:2020-05-27 修回日期:2020-08-06 出版日期:2021-03-20 发布日期:2020-12-28
  • 通讯作者: 朱静怡
  • 作者简介:
    * Corresponding author e-mail:
  • 基金资助:
    国家自然科学基金项目(21807059); 江苏省自然科学基金项目(BK20180711); 江苏省高等学校自然科学研究面上项目(17KJB350005); 江苏省研究生科研与实践创新计划项目(KYCX20_1122)
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Construction and Application of Dendrimer-Based SPECT Imaging Agent

Pingping Zhao1, Junxing Yang1, Jianhui Shi1, Jingyi Zhu1,*()   

  1. 1 School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 211800, China
  • Received:2020-05-27 Revised:2020-08-06 Online:2021-03-20 Published:2020-12-28
  • Contact: Jingyi Zhu
  • Supported by:
    the National Natural Science Foundation of China(21807059); the Natural Science Foundation of Jiangsu Province(BK20180711); the Natural Science Foundation for Colleges and Universities in Jiangsu Province(17KJB350005); and the Postgraduate Research & Practice Innovation Program of Jiangsu Province(KYCX20_1122)

树状大分子具有精准的化学结构,包括小分子内核、多分枝形成的内部空腔以及表面大量的官能团,可用于负载多种纳米颗粒及进行功能化修饰。此外,基于树状大分子的优异性能,具有良好的生物相容性及稳定性,经过功能化修饰后,其可在体内实现较长时间的血液循环和较高的组织特异性。因此,近年来常将树状大分子作为构建SPECT成像造影剂的理想载体使用。通过不同功能基团修饰树状大分子,降低纳米载体的细胞毒性,提高肿瘤部位的富集等,以实现精准高效的SPECT成像。SPECT成像主要通过监测放射性核素的体内分布、流动及代谢情况以在分子层面上监测病灶部位的生理、病理学变化。相比于小分子的放射性核素,以树状大分子为载体构建的SPECT成像造影剂体内循环时间更长,且经过功能化修饰后可实现体内特异性分布。本文围绕各类放射性核素标记的功能化树状大分子进行了详细阐述,并总结归纳其制备方法及生物医学应用。最后,对这类基于树状大分子的SPECT成像造影剂在肿瘤早期诊断中的应用前景进行了展望。

关键词： 分子影像学, 纳米造影剂, 树状大分子, SPECT成像, 生物医学应用

Dendrimer owns a precise chemical structure, including a small molecular core, an internal space induced by multiple branches, and large numbers of functional groups on the surface, which can be used to load a variety of nanoparticles and perform functional modification. In addition, based on the excellent properties of dendrimer, it demonstrates good biocompatibility and stability. After functional modification, it could achieve long blood circulation and high tissue specificity in vivo. Therefore, dendrimer has often been used as an ideal carrier for constructing SPECT imaging agents in recent years. Through multifunctional modification with various functional groups, the cytotoxicity of the generated nanocarrier is decreased and its accumulation at tumor site is improved, which faciliates accurate and efficient SPECT imaging. SPECT imaging monitors the physiological and pathological changes of lesions at the molecular level via monitoring the distribution, flow and metabolism of radionuclides in vivo. Compared with small molecular radionuclides, dendrimer-based SPECT imaging agents demonstrate longer circulation time and could achieve specific distribution after functional modification in vivo. In this review, various radionuclides labeled functional dendrimers are described in detail, their preparation methods and biomedical applications are summarized. Finally, the applications of these dendrimer-based SPECT imaging agents in the early diagnosis of tumor are prospected.

Key words: molecular imaging, nanoparticle-based contrast agents, dendrimer, SPECT imaging, biomedical application
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表1 用于SPECT成像的放射性核素
Table 1 Radionuclides for SPECT imaging
Radionuclide 99mTc 111In 67Ga 201Tl 131I 125I
Emission type γ γ γ γ(81.7%)
β(89.9%) 		γ
Emission energy/keV 140 173, 247 93, 184, 300, 393 135~167 284, 364, 606 27.4~35.4
Half-life 6 h 2.83 d 78.3 h 74 h 8.01 d 60 d
图1 树状大分子结构示意图
Fig.1 Schematic representation of the dendrimer structure
图2 99mTc-Au-Ac DENPs和99mTc-Au-Gly DENPs的纳米结构图(a)和合成示意图(b)[34]
Fig.2 Schematic representation of the nanostructure(a) and the synthesis procedure(b) of99mTc-Au-Ac DENPs and99mTc-Au-Gly DENPs[34]
图3 注射{(Au0)6-G2-DTPA(99mTc)-PEG-FA} DENPs(a)和{(Au0)6-G2-DTPA(99mTc)-mPEG} DENPs(b)后不同时间点下的SPECT/CT成像图、肿瘤部位SPECT信号强度(c)和肿瘤/肌肉SPECT信号比(d)[35]
Fig.3 SPECT/CT images of tumors(a and b), SPECT signal intensity of tumors(c), and SPECT signal ratio(tumor/muscle)(d) after intravenous injection of the {(Au0)6-G2-DTPA(99mTc)-PEG-FA} DENPs(a) and {(Au0)6-G2-DTPA(99mTc)-mPEG} DENPs(b) at different time points postinjection[35]
图4 DOX治疗3 d后,分别注射99mTc-duramycin-Au DENPs和99mTc-Au DENPs不同时间点下的C6移植瘤裸鼠的SPECT成像图(a)和肿瘤的相对信号强度(b)、注射8 h后离体肿瘤的SPECT成像图(c)[36]
Fig.4 SPECT images(a) and tumor relative signal intensities(b) of the nude mice bearing C6 xenografted tumors after 3 days of DOX treatment at different time points post-intravenous injection of the99mTc-duramycin-Au DENPs or 99mTc-Au DENPs. SPECT images of ex vivo tumors at 8 h post-injection(c)[36]
图5 大鼠体内G1-[111In(do3a-pyNO-C)](A)和G4-[111In(do3a-pyNO-C)](B)的生物分布图[37]
Fig.5 Biodistribution of G1-[111In(do3a-pyNO-C)](A) and G4-[111In(do3a-pyNO-C)](B) in rats[37]
图6 PAMAM(G1.5,2)、DAB(G3.5)、DAE(G2)和CSi-PEO(G1)树状大分子的结构示意图[39]
Fig.6 Structures of the PAMAM(G1.5, 2), DAB(G3.5), DAE(G2), and CSi-PEO(G1) dendrimers[39]
图7 131I-G5.NHAc-HPAO-PEG-FA的合成示意图[41]
Fig.7 Schematic illustration of the synthesis of the131I-G5.NHAc-HPAO-PEG-FA[41]
图8 注射131I-G5.NHAc-HPAO-(PEG-BmK CT)-(mPEG)和131I-G5.NHAc-HPAO-(PEG-MAL)-(mPEG)后,不同时间点下C6移植瘤的SPECT成像图(A)、离体肿瘤的SPECT成像图(B)及肿瘤部位对应的SPECT信号值(C)[42]
Fig.8 SPECT images(A), SPECT images of ex vivo tumors(B) and the relative SPECT signal intensities(C) of C6 xenografts tumors at different time points post injection of 131I-G5.NHAc-HPAO-(PEG-BmK CT)-(mPEG) and 131I-G5.NHAc-HPAO-(PEG-MAL)-(mPEG)[42]
图9 经不同试剂处理后的C6荷瘤鼠的肿瘤体积生长曲线[42]
Fig.9 The tumor volume growth curve of C6 xenografts tumors mice treated with different reagents[42]
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