English
往期目录
新闻公告
More
化学进展 2016, Vol. 28 Issue (2/3): 353-362 DOI: 10.7536/PC150915 前一篇   后一篇

• 综述与评论 •

外泌体:为高效药物投递策略提供天然的内源性纳米载体

李思迪, 侯信, 亓洪昭, 赵瑾*, 原续波   

  1. 天津大学材料科学与工程学院 天津市材料复合与功能化重点实验室 天津 300072
  • 收稿日期:2015-09-01 修回日期:2015-10-01 出版日期:2016-03-15 发布日期:2016-01-07
  • 通讯作者: 赵瑾 E-mail:zhaojin@tju.edu.cn
  • 基金资助:
    国家自然科学基金项目(No.51473119)资助
下载PDF ( 4253 ) 引用
导出 被引次数 ( 8 | 3 )

Exosomes:Provide Naturally Occurring Endogenous Nanocarriers for Effective Drug Delivery Strategies

Li Sidi, Hou Xin, Qi Hongzhao, Zhao Jin*, Yuan Xubo   

  1. School of Materials Science and Engineering, Tianjin Key Laboratory of Composite and Functional Materials, Tianjin University, Tianjin 300072, China
  • Received:2015-09-01 Revised:2015-10-01 Online:2016-03-15 Published:2016-01-07
  • Supported by:
    The work was supported by the National Natural Science Foundation of China (No. 51473119).
在细胞通讯过程中,细胞分泌的大小在40~100 nm之间的外泌体具有负载"货物"并将其传递给靶细胞的能力。外泌体是细胞通讯重要的调节者,当疾病发生时,外泌体的组成会发生变化,在诊断和治疗方面均具有重要作用。外泌体作为药物的天然内源性载体具有独特优势,如其免疫原性低,在血液中的稳定性高,向细胞运输药物的效率高,和更强的增强渗透滞留效应(EPR)。目前,外泌体已经成功运载基因类药物、抗癌药物和抗炎症药物等其他类型药物。作为基因类药物载体,外泌体有助于同时提高转染效率和降低副作用。作为抗癌类和抗炎症类药物载体,外泌体可较好地保护药物免遭人体清除。本文按照外泌体负载"货物"的种类综述外泌体作为药物载体的最新进展,并简要讨论构建外泌体药物运输系统所需考虑的外泌体的来源、提纯方法、载药种类、载药方式以及载药系统的使用方式等关键因素对外泌体药物运输系统的影响,展望外泌体药物运输系统临床应用所面临的挑战和可能的解决途径。
关键词： 外泌体, 药物运输, 基因载体, 抗肿瘤药物, 抗炎症药物
Nano-sized exosomes originated from cells with a diameter of 40~100 nm can carry and transport "cargo" in cell-to-cell communication. They are important mediators of intercellular communication and regulators of the cellular niche. Their altered characteristics in many diseases suggest their important roles in diseases diagnosis and therapy, thus prompting the idea of using exosomes as drug delivery vehicles. As naturally occurring endogenous carriers of drugs, exosomes have unique advantages such as limited immunogenicity, great stability in blood, high delivery efficiency, targeting ability, and the improvement of enhanced permeability and retention effect (EPR). So far, genetic drugs, anticancer drugs, anti-inflammatory drugs and etc. have been successfully delivered by exosomes. In these cases, exosomes contribute to improving transfection efficiency of gene and reducing their side effects, as well as protecting therapeutic drugs from clearance by human bodies. This review covers the latest developments in the field of exosome-based drug delivery systems with regard to "cargo" species. Key components of exosome-based drug delivery system, such as the sources and purification methods of exosomes, choice of therapeutic cargo, loading methods, and administration routes are briefly discussed. At last, the challenges of exosomes as drug carriers in clinical practice are raised and the possible solutions are proposed.

Contents
1 Exosomes and their biofunction
2 Exosomes as drug carriers
2.1 Key components of exosomes as drug carriers
2.2 Exosomes as genetic drug carriers
2.3 Exosomes as anticancer drug carriers
2.4 Others
3 Conclusion and outlook

Key words: exosome, drug delivery, genetic vector, anti-tumor drug, anti-inflammatory drug

中图分类号: 

()
[1] Kooijmans S A A, Vader P, van Dommelen S M, van Solinge W W, Schiffelers R M. Int. J. Nanomed., 2012, 7:1525.
[2] Johnsen K B, Gudbergsson J M, Skov M N, Pilgaard L, Moos T, Duroux M. Biochimica. et. Biophysica. Acta, 2014, 1846:75.
[3] Qin J, Xu Q. Acta Pol. Pharm., 2014, 71:537.
[4] Lakhal S, Wood M J. Bioessays, 2011, 33:737.
[5] Zocco D, Ferruzzi P, Cappello F, Kuo W P, Fais S. Front. Oncol., 2014, 4:2.
[6] Jang S C, Kim O Y, Yoon C M, Choi D S, Roh T Y, Park J, Nilsson J, Lötvall J, Kim Y K, Gho Y S. ACS Nano, 2013, 7:7698.
[7] Chen L, Wang Y, Pan Y, Zhang L, Shen C, Qin G, Ashraf M, Weintraub N, Ma G, Tang Y. Biochem. Biophys. Res. Commun., 2013, 431:566.
[8] Bryniarski K, Ptak W, Jayakumar A, Püllmann K, Caplan M J, Chairoungdua A, Lu J, Adams B D, Sikora E, Nazimek K, Marquez S, Kleinstein S H, Sangwung P, Iwakiri Y, Delgato E, Redegeld F, Blokhuis B R, Wojcikowski J, Daniel A W, Kormelink T G, Askenase P W. J. Allergy Clin. Immunol., 2013, 132:170.
[9] Yu L, Yang F, Jiang L, Chen Y, Wang K, Xu F, Wei Y, Cao X, Wang J, Cai Z. Eur. J. Immunol., 2013, 43:2461.
[10] Sun D M, Zhuang X, Xiang X, Liu Y, Zhang S, Liu C, Barnes S, Grizzle W, Miller D, Zhang H G, Mol. Ther., 2010, 18:1606.
[11] Yousefpour P, Chilkoti A. Biotechnol. Bioeng., 2014, 111:1699.
[12] 陈孟婕(Chen M J), 姚晋荣(Yao J R), 邵正中(Shao Z Z),陈新(Chen X). 化学进展(Progress in Chemistry), 2011, 23(1):202.
[13] Kalra H, Adda C G, Liem M, Ang C S, Mechler A, Simpson R J, Hulett M D, Mathivanan S. Proteomics, 2013, 13:3354.
[14] Nakamura H, Jun F, Maeda H. Expert Opin. Drug Deliv., 2015, 12:53.
[15] Kobayashi H, Watanabe R, Choyke P L. Theranostics, 2014, 4:81.
[16] Alvarez-Erviti L, Seow Y, Yin H, Betts C, Lakhal S, Wood M J A. Nat. Biotechnol., 2011, 29:341.
[17] Katakowski M, Buller B, Zheng X, Lu Y, Rogers T, Osobamiro O, Shu W, Jiang F, Chopp M. Cancer Lett., 2013, 335:201.
[18] Bryniarski K, Ptak W, Jayakumar A, Püllmann K, Caplan M J, Chairoungdua A, Lu J, Adams B D, Sikora E, Nazimek K, Marquez S, Kleinstein S H, Sangwung P, Iwakiri Y, Delgato E, Redegeld F, Blokhuis B, Wojcikowski J, Daniel A W, Kormelink T G, Askenase P. J. Allergy Clin. Immunol., 2013, 132:170.
[19] Pascucci L, Coccè V, Bonomi A, Ami D, Ceccarelli P, Ciusani E, Viganò L, Locatelli A, Sisto F, Doglia S M, Parati E, Bernardo M E, Muraca M, Alessandri G, Bondiolotti G, Pessina A. J. Control Release, 2014, 192:262.
[20] Tian Y, Li S, Song J, Ji T, Zhu M, Anderson G, Wei J, Nie G. Biomaterials, 2014, 35:2383.
[21] Dai S, Wei D, Wu Z, Zhou X, Wei X, Huang H, Li G. Mol. Ther., 2008, 16:782.
[22] Mizrak A, Bolukbasi M F, Ozdener G B, Brenner G J, Madlener S, Erkan E P, Ströbel T, Breakefield X O, Saydam O. Mol. Ther., 2013, 21:101.
[23] Ohno S I, Takanashi M, Sudo K, Ueda S, Ishikawa A, Matsuyama N, Fujita K, Mizutani T, Ohgi T, Ochiya T, Gotoh N, Kuroda M. Mol. Ther., 2013, 21:185.
[24] Wahlgren J, Karlson T D L,Brisslert M, Vaziri Sani F, Telemo E, Sunnerhagen P, Valadi H. Nucleic Acids Res., 2012, 40:e130.
[25] Shtam T A, Kovalev R A, Varfolomeeva E Y, Makarov E M, Kil Y V, Filatov M V. Cell Commun. Signal., 2013, 11:88.
[26] Gehl J. Acta Physiol. Scand, 2003, 177:437.
[27] Hood J L, Scott M J, Wickline S A. Anal. Biochem., 2014, 448:41.
[28] Lai R C, Yeo R W Y, Tan K H, Lim S K. Biotechnol. Adv., 2013, 31:543.
[29] Kosaka N, Iguchi H, Yoshiok Y, Hagiwara K, Takeshita F, Ochiya T. J. Biol. Chem., 2012, 287:1397.
[30] Rupp A K, Rupp C, Keller S, Brase J C, Ehehalt R, Fogel M, Moldenhauer G, Marmé F, Sültmann H, Altevogt P. Gynecol. Oncol., 2011, 122:437.
[31] Suresh P S, Venkatesh T, Tsutsumi R. Endocr. J., 2014, 61:655.
[32] Ibraheem D, Elaissari A, Fessi H. Int. J. Pharm., 2014, 459:70.
[33] Naidu S, Magee P, Garofalo M. J. Hematol. Oncol., 2015, 8:68.
[34] Reddy K B. Cancer Cell Int., 2015, 15:38.
[35] De Mendoza C, Barreiro P, Benitez L, Soriano V. Expert Opin. Biol. Ther., 2015, 15:319.
[36] Stan R, Zaia J A. Curr. HIV/AIDS Rep., 2014, 11:11.
[37] Bradshaw A C, Baker A H. Vasc. Pharmacol., 2013, 58:174.
[38] Williams P D, Kingston P A. Cardiovasc. Res., 2011, 91:565.
[39] Griesenbach U, Pytel K M, Alton E W F W. Hum. Gene Ther., 2015, 26:266.
[40] Armstrong D K, Cunningham S, Davies J C, Alton E W F W. Arch. Dis. Child., 2014, 99:465.
[41] Pike-Overzet K, van der Burg M, Wagemaker G, van Dongen J J M, Staal F J T. Mol. Ther., 2007, 15:1910.
[42] Guedon, J M G, Wu S B, Zheng X, Churchill C C, Glorioso J C, Liu C H, Liu S, Vulchanova L, Bekker A, Tao Y X, Kinchington P R, Goins W F f, Fairbanks C A, Hao S. Mol. Pain, 2015, 11:27.
[43] Severino P, Szymanski M, Favaro M, Azzoni A R, Chaud M V, Santana M H A, Silva A M, Souto E B. Eur. J. Pharm. Sci., 2015, 66:78.
[44] Yin H, Kanasty R L, Eltoukhy A A, Vegas A J, Dorkin J R, Anderson D G. Nat. Rev. Genet., 2014, 15:541.
[45] 张悦(Zhang Y), 于奡(Yu A), 王永健(Wang Y J). 化学进展(Progress in Chemistry), 2008, 20(5):740.
[46] Such G K, Yan Y, Johnston A P R, Gunawan S T, Caruso F. Adv. Mater., 2015, 27:2278.
[47] Pan Q, Ramakrishnaiah V, Henry S, Fouraschen S, de Ruiter P E, Kwekkeboom J, Tilanus H W, Janssen H L A, van der Laan L J W. Gut., 2012, 61:1330.
[48] Xu C F, Wang J. Asian J. Pharm. Sci., 2015, 10:1.
[49] Zhang J, Li X, Huang L. J. Control. Release, 2014, 190:440.
[50] Gary D J, Puri N, Won Y Y. J. Control. Release, 2007, 121:64.
[51] Whitehead K A, Langer R, Anderson D G. Nat. Rev.Drug Discov., 2009, 8:129.
[52] Trompeter H I, Dreesen J, Hermann E, Iwaniuk K M, Hafner M, Renwick N, Tuschl T, Wernet P. BMC Genomics, 2013, 14:111.
[53] Zhang Y, Wang Z, Gemeinhart R A. J. Control. Release, 2013, 172:962.
[54] Wang H, Jiang Y, Peng H, Chen Y, Zhu P, Huang Y. Adv. Drug Deliver. Rev., 2015, 81:142.
[55] Ben-Shushan D, Markovsky E, Gibori H, Tiram G, Scomparin A, Satchi-Fainaro R. Drug Deliver. Transl. Res., 2014, 4:38.
[56] Muthiah M, Park I K, Cho C S. Expert Opin. Drug Delier., 2013, 10:1259.
[57] Liu X Q, Song W J, Sun T M, Zhang P Z, Wang J. Mol. Pharm., 2011, 8:250.
[58] Chen L, Charrier A, Zhou Y, Chen R, Yu B, Agarwal K, Tsukamoto H, Lee L J, Paulaitis M E, Brigstock D R. Hepatology, 2014, 59:1118.
[59] Zhang Y, Liu D, Chen X, Li J, Li L, Bian Z, Sun F, Lu J, Yin Y, Cai X, Sun Q, Wang K, Ba Y, Wang Q, Wang D, Yang J, Liu P, Xu T, Yan Q, Zhang J, Zen K,Zhang C Y. Mol. Cell, 2010, 39:133.
[60] Momen-Heravi F, Bala S, Bukong T, Szabo G. Nanomed. Nanotechnol., 2014, 10:1517.
[61] Munoz J L, Bliss S A, Greco S J, Ramkissoon S H, Ligon K L, Rameshwar P. Mol. Ther. Nucleic Acids, 2013, 2:e126.
[62] Dubois L G, Campanati L, Righy C, D'Andrea-Meira I, Spohr T C L S, Porto-Carreiro I, Pereira C M, Balça-Silva J, Kahn S A, DosSantos M F, Oliveira M A R, Ximenes-da-Silva A, Lopes M C, Faveret E, Gasparetto E L, Moura-Neto V. Front. Cell. Neurosci., 2014, 8:418.
[63] Yang J, Wei F, Schafer C, Wong D T W. PLoS ONE, 2014, 9:e0110641.
[64] Canitano A, Venturi G, Borghi M, Ammendolia M G, Fais S. Cancer Lett., 2013, 337:193.
[65] Le Garrec D, Ranger M, Leroux J C. Am. J. Drug Deliver., 2004, 2:15.
[66] Deng C, Jiang Y, Cheng R, Meng F, Zhong Z, Nano Today, 2012, 7:467.
[67] Kim C K, Lim S J. Arch. Pharm. Res., 2002, 25:229.
[68] Wang X, Guo Z. Chem. Soc. Rev., 2013, 42:202.
[69] Escudier B, Dorval T, Chaput N, André F, Caby M P, Novault S, Flament C,Leboulaire C, Borg C, Amigorena S, Boccaccio C, Bonnerot C, Dhellin O, Movassagh M, Piperno S, Robert C, Serra V, Valente N, Le Pecq J B, Spatz A, Lantz O, Tursz T, Angevin E, Zitvogel L. J. Transl. Med., 2005, 3:10.
[70] Morse M A, Garst J, Osada T, Khan S, Hobeika A, Clay T M, Valente N, Shreeniwas R, Sutton M A, Delcayre A, Hsu D H, Le Pecq J B, Lyerly H K. J. Transl. Med., 2005, 3:9.
[71] Anand P, Kunnumakkara A B, Newman R A, Aggarwal B B. Mol. Pharm., 2007, 4:807.
[72] Sharma R A, Gescher A J, Steward W P. Eur. J. Cancer, 2005, 41:1955.
[73] Hatcher H, Planalp R, Cho J, Torti F M, Torti S V. Cell. Mol. Life Sci., 2008, 65:1631.
[74] Zhuang X, Xiang X, Grizzle W, Sun D, Zhang S, Axtell R C, Ju S b, Mu J, Zhang L, Steinman L, Miller D, Zhang H G. Mol. Ther., 2011, 19:1769.
[75] Chattopadhyay I, Biswas K, Bandyopadhyay U, Banerjee R K. Curr. Sci. India, 2004, 87:44.
[76] Chen W, Wang J, Shao C, Liu S, Yu Y, Wang Q, Cao X. Eur. J. Immunol., 2006, 36:1598.
[77] Eloy J O, Claro de Souza M, Petrilli R, Barcellos J P A, Lee R J, Marchetti J M. Colloid. Surface. B, 2014, 123:345
[78] Kataoka K, Harada A, Nagasaki Y. Adv. Drug Deliver. Rev., 2001, 47:113.
[79] Allen T M, Cullis P R. Science, 2004, 303:1818.
[80] Wang H, Xu, F, Li D, Liu X, Jin Q, Ji J. Polym. Chem. UK, 2013, 4:2004.
[81] Salvage J P, Thom C, Lewis A L, Phillips G J, Lloyd A W. J. Mater. Sci. Mater. Med., 2015, 26:14.
[82] Peer D, Karp J M, Hong S, Farokhzad O C, Margalit R, Langer R. Nat. Nanotechnol., 2007, 2:251.
[83] 刘儒涛(Liu R T),王世伟(Wang S W),刘晶(Liu J). 生物化学与生物物理进展(Prog. Biochem. Biophys),2013, 40(8):719.
[84] Jang S C, Gho Y S. Nanomedicine, 2014, 9:177.
[1] 陈晓峰, 王开元, 梁芳铭, 姜睿祺, 孙进. 外泌体递药系统及其在肿瘤治疗中的应用[J]. 化学进展, 2022, 34(4): 773-786.
[2] 孙子茹, 刘胜男, 高清志. 靶向葡萄糖转运蛋白(GLUTs)抗癌药物的开发[J]. 化学进展, 2020, 32(12): 1869-1878.
[3] 乔斌, 陈虹妃, 张卉, 蔡称心. 肿瘤外泌体的分析检测[J]. 化学进展, 2019, 31(6): 847-857.
[4] 白凌闯, 赵静, 冯亚凯. 多功能基因递送系统促进内皮细胞增殖[J]. 化学进展, 2019, 31(2/3): 300-310.
[5] 徐子悦, 张运昌, 林佳乐, 王辉, 张丹维, 黎占亭. 药物输送体系构筑中的超分子组装策略[J]. 化学进展, 2019, 31(11): 1540-1549.
[6] 孙悦文, 金素星, 王晓勇, 郭子建. 金属配合物在肿瘤化学免疫治疗中的应用前景[J]. 化学进展, 2018, 30(10): 1573-1583.
[7] 付开乔, 张光彦, 蒋序林. 聚天冬酰胺衍生物药物/基因载体的合成和应用[J]. 化学进展, 2016, 28(8): 1196-1206.
[8] 刘雯, 张立, 杨静, 郝雪芳, 李茜, 冯亚凯. 靶向性载体/基因复合物促进内皮细胞增殖[J]. 化学进展, 2016, 28(6): 954-960.
[9] 刘亚杰, 张鹏, 杜建委, 王幽香. 微纳米粒子的形貌调控及其对药物/基因传递体系的影响[J]. 化学进展, 2016, 28(1): 67-74.
[10] 古晓晓, 杜宝吉, 李云辉, 高莹*, 李丹, 汪尔康. 基于纳米材料的基因载体[J]. 化学进展, 2015, 27(8): 1093-1101.
[11] 徐妮为, 刘梦艳, 洪诗斌, 颜蔚, 付继芳, 邓维. 基于环糊精构建的基因载体进展[J]. 化学进展, 2014, 26(0203): 375-384.
[12] 孙盟盟, 何勇, 杨万泰, 尹梅贞. 磷酸乙二酯类聚合物的合成及其生物应用[J]. 化学进展, 2013, 25(12): 2093-2102.
[13] 杜可杰, 王忆, 梁捷雯, 计亮年, 巢晖*. DNA拓扑异构酶抑制剂[J]. 化学进展, 2013, 25(04): 545-554.
[14] 杨婵丽, 董雄伟, 江南, 章丹, 刘长林*. 细胞研究中的金属配合物-核酸相互作用[J]. 化学进展, 2013, 25(04): 555-562.
[15] 董博, 闫熙博, 牛玉洁, 王欣, 王连永, 王燕铭* . 聚酰胺-胺型树枝状大分子及其衍生物在基因传递中的应用[J]. 化学进展, 2012, 24(12): 2352-2358.