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浙江大学学报（医学版）
J Zhejiang Univ (Med Sci)  2018, Vol. 47 Issue (5): 525-533    DOI: 10.3785/j.issn.1008-9292.2018.10.13
    
Application of mesenchymal stem cells in antineoplastic drugs delivery for tumor-targeted therapy
WANG Xiaoling1,2(),OUYANG Xumei1,2,SUN Xiaoyi1,*()
1. Department of Pharmacy, Zhejiang University City College, Hangzhou 310015, China
2. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
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Abstract  

In recent years, a large number of studies have achieved tumor targeting by mesenchymal stem cells (MSC)-based delivery system attributed to the tumor tropism of MSCs. Biomacromolecules and antineoplastic drugs loaded on MSC via internalization or cell membrane anchoring can be released or expressed at tumor site to perform their antitumor effects. The genetically modified MSC are extensively studied, however, the applications of MSCs in targeted delivery of antineoplastic drug with small molecules are not well summarized. In this review, MSCs homing mechanism and the distribution of injected MSCs in vivo is introduced; the examples of antitumor drug-primed MSCs and drug loaded MSCs are presented; the drug loading and releasing process from MSCs is also illustrated; finally, challenges and future perspectives of MSCs-based drug delivery system on realizing its full potential are prospected.

Key words： Neoplasms      Mesenchymal stem cells/cytology      Nanospheres      Antineoplastic agents      Drug delivery systems      Review     
Received: 11 May 2018      Published: 23 January 2019
CLC:  R979.1  
Corresponding Authors: SUN Xiaoyi     E-mail: lingxiaowangjy@163.com;sunxiaoyi@zucc.edu.cn
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WANG Xiaoling
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Cite this article:

WANG Xiaoling,OUYANG Xumei,SUN Xiaoyi. Application of mesenchymal stem cells in antineoplastic drugs delivery for tumor-targeted therapy. J Zhejiang Univ (Med Sci), 2018, 47(5): 525-533.

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http://www.zjujournals.com/med/10.3785/j.issn.1008-9292.2018.10.13     OR     http://www.zjujournals.com/med/Y2018/V47/I5/525


基于间充质干细胞的小分子化学药物肿瘤靶向递送系统研究进展

近年来，大量研究通过细胞内化或细胞膜结合的方式将生物大分子或小分子化学药物负载于间充质干细胞（MSC）上，利用其天然的肿瘤归巢特性实现药物的靶向递送，继而通过在靶部位药物的释放或基因表达，达到肿瘤治疗的目的。基因修饰MSC的研究较为成熟，而递送小分子化学药物的研究起步较晚。本文从MSC肿瘤迁移机制、细胞注射后体内分布特点入手，总结了MSC在小分子化学药物肿瘤靶向递送中的研究；同时介绍了MSC与原型药物、载药纳米粒构建的复合系统的载药、释药过程，展望了该系统遇到的挑战和应用前景。


关键词： 肿瘤,  间质干细胞/细胞学,  纳米球,  抗肿瘤药,  药物释放系统,  综述 
药物 MSC来源 肿瘤模型 MSC给药途径 递送效果 文献
  “—”：无相关资料; hTERT:人端粒酶逆转录酶.
紫杉醇 人骨髓 人前列腺癌(DU145)NOD/SCID小鼠皮下移植瘤、人胶质瘤(U87MG)裸鼠皮下移植瘤 MSC与肿瘤细胞混合接种 DU145瘤重为对照组的1/3；U87MG瘤重为对照组的60% [16]
人胸膜间皮瘤(NCI-H28)细胞系 — 每个MSC释放0.15 pg紫杉醇 [18]
人骨髓瘤(RPMI 8226)三维动态培养模型 — 引起肿瘤细胞凋亡和坏死 [19]
人急性T淋巴细胞白血病MOLT-4裸鼠皮下移植瘤 MSC与肿瘤细胞混合接种/MSC瘤内注射 混合接种2个月后未观察到肿瘤结节；瘤内注射后肿瘤体积是对照组的1/4 [20]
人羊膜 人胰腺癌(CFPAC-1)细胞系 — MSC在48 h内释放59%胞内药物，每个MSC约释放紫杉醇0.51 pg [17]
人牙龈 人胰腺癌(CFPAC-1)细胞系 — MSC释放紫杉醇，释放液具细胞毒性 [21]
人口腔鳞状细胞癌(SCC154)细胞系 — MSC在24 h内释放63%胞内药物，106个MSC约释放150 ng紫杉醇 [22]
hTERT/SV40永生化人脂肪 人胰腺癌(CFPAC-1)细胞系 — MSC通过微泡结构释放紫杉醇 [23]
BDF/1小鼠骨髓 人胰腺癌(CFPAC-1)细胞系 — 紫杉醇通过外泌体结构被MSC排出，每个MSC释放0.1 pg紫杉醇 [24]
鼠黑色素瘤(B16)C57BL16小鼠皮下移植瘤 MSC与肿瘤细胞混合接种 瘤重约为对照组的1/4 [16]
鼠黑色素瘤(B16)C57BL16小鼠肺转移模型 尾静脉注射 注射3次后转移瘤被治愈，MSC优先分布于结节周围血管 [25]
鼠淋巴细胞白血病(L1210) BDF/1小鼠原位瘤 腹腔注射 生存时间延长1倍 [20]
人胶质瘤(U87MG)免疫抑制Wistar大鼠原位移植瘤 颅内注射，MSC与肿瘤细胞同时接种于同侧半球，注射部位间距2~3 mm 具肿瘤归巢能力，胶质瘤细胞核发生紫杉醇诱发的典型变化，星形胶质细胞和周围神经元形态无显著变化 [26]
犬骨髓/犬脂肪 犬胶质瘤(J3T)细胞系、人胶质瘤(T98G/U87MG)细胞系 — 每个MSC释放0.09 pg紫杉醇，有效抑制肿瘤细胞增殖 [27]
阿霉素 人牙龈 人口腔鳞状细胞癌(SCC154)细胞系 — MSC可在24 h内释放100%胞内药物，106个MSC可释放669 ng阿霉素 [22]
人骨髓 人乳腺癌(MDA-MB-231/Rluc)裸鼠皮下移植瘤、人甲状腺癌(CAL62/Rluc)裸鼠皮下移植瘤 尾静脉注射 与5 μmol/L阿霉素孵育得到的载药MSC可迁移至肿瘤组织，肿瘤内药物浓度高于对照组 [28]
吉西他滨 人骨髓/人胰腺 人胰腺癌(CFPAC-1)细胞系 — 与2 μg/mL吉西他滨孵育后的载药MSC可抑制肿瘤细胞增殖 [29]
人牙龈 人口腔鳞状细胞癌(SCC154)细胞系 — MSC在24 h内释放92%胞内药物，106个MSC释放75 ng吉西他滨 [22]
顺铂、铂(Ⅱ)配合物 人脂肪 人胶质瘤(U87MG)细胞系、人胸膜间皮瘤(NCI-H28)细胞系 — MSC分别释放胞内36%的铂(Ⅱ)配合物和95%顺铂 [30]
索拉非尼 人骨髓 人胶质瘤(U87MG)裸鼠原位移植瘤 鼻腔给药 48 h释放60%药物, MSC广泛分布于肿瘤组织内，切片中细胞密度达403个/mm2，但无明显抑制肿瘤生长作用 [31]
Tab 1 Studies of drug-primed mesenchymal stem cells (MSC) for tumor-targeting therapy
载体类型 载体 载体修饰 药物 MSC来源 肿瘤模型 MSC给药途径 递送效果 文献
  “—”：无相关资料.PLGA:聚乳酸-羟基乙酸; PLA：聚乳酸；PAMAM:聚酰胺-胺型树枝状聚合物; PMMA:聚甲基丙烯酸甲酯；TPPS:四苯基卟啉磺酸盐.
高分子纳米粒 PLGA纳米粒 壳聚糖吸附 紫杉醇 大鼠骨髓 人结肠癌(HT-29)细胞系、人卵巢癌(Skov-3)细胞系、鼠肺癌(Lewis)细胞系 — Transwell系统中，向肿瘤细胞迁移效率HT-29> Skov-3>Lewis [33]
— 鼠胶质瘤(C6)大鼠原位移植瘤 颅内注射，对侧半球 生存期为MSC直接包载紫杉醇组及紫杉醇纳米粒组的1.5倍 [35]
人骨髓 人肺癌(A549)裸鼠原位移植瘤 尾静脉注射 较纳米组显著增加肺内分布，2 d后仍可测得荧光探针信号；AUC为溶液组或纳米粒组9倍，生存期为纳米粒组1.4倍 [34, 42]
鼠Lewis肺腺癌C57BL/6小鼠原位移植瘤 尾静脉注射 纳米粒组或溶液组剂量的1/48可获得相同的抗肿瘤效果 [42]
阿霉素 C57BL6小鼠脂肪 鼠黑色素瘤(B16F10) C57BL/6小鼠肺转移模型 尾静脉注射 肺重量和肺内节结数显著显著低于MSC直接包载阿霉素组 [43]
多烯紫杉醇 人胎盘 KrasLSL-G12D肺癌小鼠 尾静脉注射 纳米粒组剂量的1/8可获得相同的抗肿瘤效果 [4]
PLA纳米粒 — 6-香豆素 人骨髓 人胶质瘤(U87MG)裸鼠原位移植瘤 瘤内注射 注射7 d后，MSC和药物分布在肿瘤周围 [41]
PAMAM RGD偶联 阿霉素 大鼠骨髓 鼠胶质瘤(C6)ICR小鼠原位移植瘤 瘤内注射 较RGD偶联纳米粒生存期延长了46.8% [44]
PMMA纳米粒 — TPPS 人骨髓 人骨肉瘤(U2OS)细胞系 — 混合共培养，光触发产生活性氧杀灭肿瘤细胞 [45]
白蛋白纳米粒 铁离子螯合 阿霉素 人脐带 人乳腺癌(MCF-7)裸鼠皮下移植瘤 尾静脉注射 主要分布于肿瘤，瘤重及肿瘤体积显著低于溶液组或纳米粒组 [46]
无机纳米粒 介孔硅 — 阿霉素 人胎盘 N-甲基亚硝基脲诱发的大鼠乳腺癌模型 尾静脉注射 注射后3 d可在肿瘤组织内发现纳米粒 [47]
有序介孔有机硅纳米球 — 紫杉醇 Balb/C小鼠 人乳腺癌(MCF-7)裸鼠皮下移植瘤 瘤内注射 有效抑制肿瘤生长，但与纳米粒对照组差异无统计学意义 [48]
金纳米粒 柠康酰胺酸碱度敏感基团 — 人来源 人纤维瘤(HT-1080)裸鼠皮下移植瘤 尾静脉注射 肿瘤靶向效率比普通金纳米粒高37倍、瘤区温度高8.3 ℃，肿瘤几乎不可见 [49]
四氧化三铁/三氧化二铁磁性纳米粒 棕榈酸/棕榈酸钠 米托蒽醌 人脂肪 人骨肉瘤三维组织样结构 — 每细胞含1.22 pg米托蒽醌和9 pg磁性材料 [50]
脂质颗粒 类脂纳米囊 — 莫昔芬的二茂铁衍生物 人骨髓 人胶质瘤(U87MG)裸鼠皮下移植瘤 瘤内注射 可抑制肿瘤生长，但效果较弱 [51]
膜融合长循环超声纳米泡 — 喜树碱 C57BL/ 6JNarl小鼠脂肪 鼠黑色素瘤(B16F0) C57BL/6JNarl小鼠皮下移植瘤 瘤内注射 纳米泡可在肿瘤区域被示踪，可杀伤肿瘤细胞 [52]
Tab 2 Studies of nanoparticle-loaded mesenchymal stem cells (MSC) for tumor-targeting therapy
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