微球和纳米颗粒在经动脉化疗栓塞治疗肝细胞癌中的应用

张楚悦; 史家宁; 王明达; 吴寒; 史立军; 杨田

doi:10.12449/JCH240428

微球和纳米颗粒在经动脉化疗栓塞治疗肝细胞癌中的应用

DOI: 10.12449/JCH240428

张楚悦¹,
史家宁²,
王明达³,
吴寒³,
史立军¹,
杨田^3, , ,

1.
哈尔滨医科大学附属第一医院消化内科，哈尔滨 150007
2.
同济大学医学院附属上海东方医院内镜中心，上海 200120
3.
中国人民解放军海军军医大学第三附属医院肝胆外科，上海 200438

基金项目:

国家自然科学基金 (82273074)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：张楚悦、史家宁负责撰写论文；吴寒、王明达、杨田负责修改论文；史立军、杨田负责拟定写作思路，指导撰写文章并最后定稿。张楚悦、史家宁对文本贡献等同，同为第一作者。

详细信息

通信作者:
杨田， yangtian6666@hotmail.com （ORCID： 0000-0003-1544-0976）

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出版历程
- 收稿日期: 2023-07-25
- 录用日期: 2023-08-10
- 出版日期: 2024-04-11

Advances in the application of microspheres and nanoparticles in transcatheter arterial chemoembolization for the treatment of hepatocellular carcinoma

1.
Department of Gastroenterology，The First Affiliated Hospital of Harbin Medical University，Harbin 150007，China
2.
Endoscopy Center，Shanghai East Hospital，Tongji University School of Medicine，Shanghai 200120，China
3.
Department of Hepatobiliary Surgery，The Third Affiliated Hospital of Navy Medical University，Shanghai 200438，China

Research funding:

National Natural Science Foundation of China (82273074)

More Information

Corresponding author: YANG Tian， yangtian6666@hotmail.com （ORCID： 0000-0003-1544-0976）

摘要

摘要: 近年来，经动脉化疗栓塞（TACE）是治疗肝细胞癌（HCC）的常用方法。然而，随着栓塞剂技术的不断发展，微球和纳米颗粒方面的新进展为提高TACE的治疗效果和安全性带来了新的希望。本文综述了微球和纳米颗粒在HCC行TACE中的最新进展和应用。首先，介绍了TACE作为治疗手段的背景，以及微球和纳米颗粒技术的兴起。接着，叙述了TACE中不同类型的微球和纳米颗粒的使用情况，并探讨了理想栓塞剂的特性。文章着重描述了在材料科学和工程领域的进展，以及药物释放微球和纳米颗粒与传统TACE在临床效果方面的对比。另外，对影像学在TACE手术中的重要性进行了讨论，并总结了放射性和磁共振可见的栓塞剂的研究进展。文章从多个角度讨论了TACE治疗的未来发展方向和面临的挑战。指出了微球和纳米颗粒与其他治疗方法结合、个性化和精准医学在TACE中的应用，以及TACE在临床转化应用中的潜在方案。同时，提出了伦理和监管方面的问题需要加以探讨。认为先进微球和纳米颗粒在TACE中具有潜在影响，为HCC治疗模式的创新以及通过TACE改善患者预后提供了理论基础和技术支持。
- 微球 /
- 纳米球 /
- 癌，肝细胞 /
- 化学栓塞，治疗性
Abstract: In recent years， transcatheter arterial chemoembolization （TACE） has emerged as a common treatment modality for the treatment of hepatocellular carcinoma （HCC）. However， with the ongoing development of embolic agent techniques， the new advances in microspheres and nanoparticles have brought new hope for improving the efficacy and safety of TACE. This article reviews the latest advances and applications of microspheres and nanoparticles in TACE for HCC. First， this article introduces the background of TACE as a therapeutic approach and the emergence of microsphere and nanoparticle techniques， and then it describes the application of various types of microspheres and nanoparticles in TACE and discusses the requisite attributes of an ideal embolic agents. The article focuses on the advances in material science and engineering， as well as the clinical efficacy of drug-eluting microspheres and nanoparticles versus conventional TACE. Furthermore， it discusses the importance of radiological examination in TACE and summarizes the research advances in the radiopaque and magnetic resonance-visible embolic agents. This article also explores the future development directions and challenges of TACE. It also points out the combination of microspheres and nanoparticles with other treatment modalities， the application of personalized and precision medicine in TACE， and the potential regimen of TACE in clinical translation， and meanwhile， it raises the issues of ethics and regulation that need to be further discussed. It is believed that microspheres and nanoparticles have a potential effect in TACE， which provides a theoretical basis and technical support for innovating HCC treatment regimens and improving the prognosis of patients through TACE interventions.
- Microspheres /
- Nanospheres /
- Carcinoma， Hepatocellular /
- Chemoembolization， Therapeutic

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参考文献(55)

[1]	LIU ZL, SUN YZ, ZHEN HF, et al. Network pharmacology integrated with transcriptomics deciphered the potential mechanism of Codonopsis pilosula against hepatocellular carcinoma[J]. Evid Based Complement Alternat Med, 2022, 2022: 1340194. DOI: 10.1155/2022/1340194.
[2]	ABOUGHALEB IH, MATBOLI M, SHAWKY SM, et al. Integration of transcriptomes analysis with spectral signature of total RNA for generation of affordable remote sensing of Hepatocellular carcinoma in serum clinical specimens[J]. Heliyon, 2021, 7( 3): e06388. DOI: 10.1016/j.heliyon.2021.e06388.
[3]	KIRSTEIN MM, WIRTH TC. Multimodal treatment of hepatocellular carcinoma[J]. Internist(Berl), 2020, 61( 2): 164- 169. DOI: 10.1007/s00108-019-00722-x.
[4]	HELLER M, PARIKH ND, FIDELMAN N, et al. Frontiers of therapy for hepatocellular carcinoma[J]. Abdom Radiol(NY), 2021, 46( 8): 3648- 3659. DOI: 10.1007/s00261-021-03065-0.
[5]	TAN DJH, WONG C, NG CH, et al. A meta-analysis on the rate of hepatocellular carcinoma recurrence after liver transplant and associations to etiology, alpha-fetoprotein, income and ethnicity[J]. J Clin Med, 2021, 10( 2): 238. DOI: 10.3390/jcm10020238.
[6]	SANTOPAOLO F, LENCI I, MILANA M, et al. Liver transplantation for hepatocellular carcinoma: Where do we stand?[J]. World J Gastroenterol, 2019, 25( 21): 2591- 2602. DOI: 10.3748/wjg.v25.i21.2591.
[7]	SINGAL AG, LLOVET JM, YARCHOAN M, et al. AASLD practice guidance on prevention, diagnosis, and treatment of hepatocellular carcinoma[J]. Hepatology, 2023, 78( 6): 1922- 1965. DOI: 10.1097/HEP.0000000000000466.
[8]	NEVOLA R, RUOCCO R, CRISCUOLO L, et al. Predictors of early and late hepatocellular carcinoma recurrence[J]. World J Gastroenterol, 2023, 29( 8): 1243- 1260. DOI: 10.3748/wjg.v29.i8.1243.
[9]	YU ZY, YANG SY, LI JQ, et al. Current developmental status of non-surgical treatment of hepatocellular carcinoma[J]. J Clin Hepatol, 2021, 37( 5): 1205- 1207. DOI: 10.3969/j.issn.1001-5256.2021.05.048. 于志远, 杨诗语, 李佳启, 等. 肝细胞癌非手术治疗的发展现状[J]. 临床肝胆病杂志, 2021, 37( 5): 1205- 1207. DOI: 10.3969/j.issn.1001-5256.2021.05.048.
[10]	LENCIONI R, DE BAERE T, SOULEN MC, et al. Lipiodol transarterial chemoembolization for hepatocellular carcinoma: A systematic review of efficacy and safety data[J]. Hepatology, 2016, 64( 1): 106- 116. DOI: 10.1002/hep.28453.
[11]	PENG QJ, DAI T, XIE GB, et al. Research advances in transcatheter arterial chemoembolization combined with targeted agents or anti-PD-1/PD-L1 monoclonal antibody in treatment of patients with unresectable hepatocellular carcinoma[J]. J Clin Hepatol, 2023, 39( 7): 1740- 1746. DOI: 10.3969/j.issn.1001-5256.2023.07.033. 彭秋菊, 戴涛, 谢贵波, 等. 不可切除肝细胞癌的经肝动脉化疗栓塞术联合靶向药物或程序性死亡受体1及其配体单抗治疗进展[J]. 临床肝胆病杂志, 2023, 39( 7): 1740- 1746. DOI: 10.3969/j.issn.1001-5256.2023.07.033.
[12]	XU JS, CHENG XQ, TAN LF, et al. Microwave responsive nanoplatform via P-selectin mediated drug delivery for treatment of hepatocellular carcinoma with distant metastasis[J]. Nano Lett, 2019, 19( 5): 2914- 2927. DOI: 10.1021/acs.nanolett.8b05202.
[13]	LADJU RB, ULHAQ ZS, SORAYA GV. Nanotheranostics: A powerful next-generation solution to tackle hepatocellular carcinoma[J]. World J Gastroenterol, 2022, 28( 2): 176- 187. DOI: 10.3748/wjg.v28.i2.176.
[14]	REN ZG, CHEN XM, HONG LJ, et al. Nanoparticle conjugation of ginsenoside Rg3 inhibits hepatocellular carcinoma development and metastasis[J]. Small, 2020, 16( 2): e1905233. DOI: 10.1002/smll.201905233.
[15]	KANG T, ZHU QQ, WEI D, et al. Nanoparticles coated with neutrophil membranes can effectively treat cancer metastasis[J]. ACS Nano, 2017, 11( 2): 1397- 1411. DOI: 10.1021/acsnano.6b06477.
[16]	MIN YZ, ROCHE KC, TIAN SM, et al. Antigen-capturing nanoparticles improve the abscopal effect and cancer immunotherapy[J]. Nat Nanotechnol, 2017, 12( 9): 877- 882. DOI: 10.1038/nnano.2017.113.
[17]	WANG DW, WU QR, GUO R, et al. Magnetic liquid metal loaded nano-in-micro spheres as fully flexible theranostic agents for SMART embolization[J]. Nanoscale, 2021, 13( 19): 8817- 8836. DOI: 10.1039/d1nr01268a.
[18]	ZHANG YC, WANG MZ, HAN XW, et al. Safety and efficacy of camrelizumab added to second-line therapy after drug-eluting bead transarterial chemoembolization combined with apatinib for unresectable hepatocellular carcinoma[J]. J Clin Hepatol, 2023, 39( 4): 834- 842. DOI: 10.3969/j.issn.1001-5256.2023.04.014. 张延藏, 王满周, 韩新巍, 等. 载药栓塞微球经肝动脉化疗栓塞术联合阿帕替尼治疗不可切除肝癌后二线追加卡瑞利珠单抗的安全性和有效性分析[J]. 临床肝胆病杂志, 2023, 39( 4): 834- 842. DOI: 10.3969/j.issn.1001-5256.2023.04.014.
[19]	BAKRANIA A, ZHENG G, BHAT M. Nanomedicine in hepatocellular carcinoma: A new frontier in targeted cancer treatment[J]. Pharmaceutics, 2021, 14( 1): 41. DOI: 10.3390/pharmaceutics14010041.
[20]	JIA GR, van VALKENBURGH J, CHEN AZ, et al. Recent advances and applications of microspheres and nanoparticles in transarterial chemoembolization for hepatocellular carcinoma[J]. Wiley Interdiscip Rev Nanomed Nanobiotechnol, 2022, 14( 2): e1749. DOI: 10.1002/wnan.1749.
[21]	LAMMER J, MALAGARI K, VOGL T, et al. Prospective randomized study of doxorubicin-eluting-bead embolization in the treatment of hepatocellular carcinoma: Results of the PRECISION V study[J]. Cardiovasc Intervent Radiol, 2010, 33( 1): 41- 52. DOI: 10.1007/s00270-009-9711-7.
[22]	GOLFIERI R, GIAMPALMA E, RENZULLI M, et al. Randomised controlled trial of doxorubicin-eluting beads vs conventional chemoembolisation for hepatocellular carcinoma[J]. Br J Cancer, 2014, 111( 2): 255- 264. DOI: 10.1038/bjc.2014.199.
[23]	ZHANG ZS, LI HZ, MA C, et al. Conventional versus drug-eluting beads chemoembolization for infiltrative hepatocellular carcinoma: A comparison of efficacy and safety[J]. BMC Cancer, 2019, 19( 1): 1162. DOI: 10.1186/s12885-019-6386-6.
[24]	LE BQG, DOAN TLH. Trend in biodegradable porous nanomaterials for anticancer drug delivery[J]. Wiley Interdiscip Rev Nanomed Nanobiotechnol, 2023, 15( 4): e1874. DOI: 10.1002/wnan.1874.
[25]	WU G, HUI XD, HU LH, et al. Recent advancement of bioinspired nanomaterials and their applications: A review[J]. Front Bioeng Biotechnol, 2022, 10: 952523. DOI: 10.3389/fbioe.2022.952523.
[26]	GIRI TK, CHOUDHARY C, AJAZUDDIN, et al. Prospects of pharmaceuticals and biopharmaceuticals loaded microparticles prepared by double emulsion technique for controlled delivery[J]. Saudi Pharm J, 2013, 21( 2): 125- 141. DOI: 10.1016/j.jsps.2012.05.009.
[27]	DELICQUE J, GUIU B, BOULIN M, et al. Liver chemoembolization of hepatocellular carcinoma using TANDEM^® microspheres[J]. Future Oncol, 2018, 14( 26): 2761- 2772. DOI: 10.2217/fon-2018-0237.
[28]	LEWIS AL, HALL B. Toward a better understanding of the mechanism of action for intra-arterial delivery of irinotecan from DC Bead^(TM)(DEBIRI)[J]. Future Oncol, 2019, 15( 17): 2053- 2068. DOI: 10.2217/fon-2019-0071.
[29]	LEI Q, ZHAO J, HE F, et al. Preparation of poly(ionic liquid) microbeads via cooling-assisted phase separation method[J]. Macromol Rapid Commun, 2021, 42( 17): e2100275. DOI: 10.1002/marc.202100275.
[30]	WANG JM, JANSEN JA, YANG F. Electrospraying: Possibilities and challenges of engineering carriers for biomedical applications-a mini review[J]. Front Chem, 2019, 7: 258. DOI: 10.3389/fchem.2019.00258.
[31]	ISHIKAWA T. Prevention of post-embolization syndrome after transarterial chemoembolization for hepatocellular carcinoma-is prophylactic dexamethasone useful, or not?[J]. Hepatobiliary Surg Nutr, 2018, 7( 3): 214- 216. DOI: 10.21037/hbsn.2018.03.08.
[32]	IDÉE JM, GUIU B. Use of Lipiodol as a drug-delivery system for transcatheter arterial chemoembolization of hepatocellular carcinoma: A review[J]. Crit Rev Oncol Hematol, 2013, 88( 3): 530- 549. DOI: 10.1016/j.critrevonc.2013.07.003.
[33]	XIE Y, QI X, XU K, et al. Transarterial infusion of iRGD-modified ZrO₂ nanoparticles with lipiodol improves the tissue distribution of doxorubicin and its antitumor efficacy[J]. J Vasc Interv Radiol, 2019, 30( 12): 2026- 2035.e2. DOI: 10.1016/j.jvir.2019.04.014.
[34]	XUE HY, YU ZY, LIU Y, et al. Delivery of miR-375 and doxorubicin hydrochloride by lipid-coated hollow mesoporous silica nanoparticles to overcome multiple drug resistance in hepatocellular carcinoma[J]. Int J Nanomedicine, 2017, 12: 5271- 5287. DOI: 10.2147/IJN.S135306.
[35]	LEE SY, CHOI JW, LEE JY, et al. Hyaluronic acid/doxorubicin nanoassembly-releasing microspheres for the transarterial chemoembolization of a liver tumor[J]. Drug Deliv, 2018, 25( 1): 1472- 1483. DOI: 10.1080/10717544.2018.1480673.
[36]	LI GP, YE L, PAN JS, et al. Antitumoural hydroxyapatite nanoparticles-mediated hepatoma-targeted trans-arterial embolization gene therapy: in vitro and in vivo studies[J]. Liver Int, 2012, 32( 6): 998- 1007. DOI: 10.1111/j.1478-3231.2012.02761.x.
[37]	FANG Y, ZHENG GF, YANG JP, et al. Dual-pore mesoporous carbon@silica composite core-shell nanospheres for multidrug delivery[J]. Angew Chem Int Ed Engl, 2014, 53( 21): 5366- 5370. DOI: 10.1002/anie.201402002.
[38]	WHITESIDES GM. The origins and the future of microfluidics[J]. Nature, 2006, 442( 7101): 368- 373. DOI: 10.1038/nature05058.
[39]	ROZYNEK Z, BIELAS R, JÓZEFCZAK A. Correction: Efficient formation of oil-in-oil Pickering emulsions with narrow size distributions by using electric fields[J]. Soft Matter, 2019, 15( 7): 1692. DOI: 10.1039/c9sm90016k.
[40]	WU ST, FAN K, YANG Q, et al. Smart nanoparticles and microbeads for interventional embolization therapy of liver cancer: State of the art[J]. J Nanobiotechnology, 2023, 21( 1): 42. DOI: 10.1186/s12951-023-01804-7.
[41]	FACCIORUSSO A. Drug-eluting beads transarterial chemoembolization for hepatocellular carcinoma: Current state of the art[J]. World J Gastroenterol, 2018, 24( 2): 161- 169. DOI: 10.3748/wjg.v24.i2.161.
[42]	GANGLOFF N, ULBRICHT J, LORSON T, et al. Peptoids and polypeptoids at the frontier of supra- and macromolecular engineering[J]. Chem Rev, 2016, 116( 4): 1753- 1802. DOI: 10.1021/acs.chemrev.5b00201.
[43]	LEE Y, THOMPSON DH. Stimuli-responsive liposomes for drug delivery[J]. Wiley Interdiscip Rev Nanomed Nanobiotechnol, 2017, 9( 5): 10.1002/wnan. 1450. DOI: 10.1002/wnan.1450.
[44]	MURA S, NICOLAS J, COUVREUR P. Stimuli-responsive nanocarriers for drug delivery[J]. Nat Mater, 2013, 12( 11): 991- 1003. DOI: 10.1038/nmat3776.
[45]	WU BL, ZHOU J, LING GH, et al. CalliSpheres drug-eluting beads versus lipiodol transarterial chemoembolization in the treatment of hepatocellular carcinoma: A short-term efficacy and safety study[J]. World J Surg Oncol, 2018, 16( 1): 69. DOI: 10.1186/s12957-018-1368-8.
[46]	BZEIZI KI, ARABI M, JAMSHIDI N, et al. Conventional transarterial chemoembolization versus drug-eluting beads in patients with hepatocellular carcinoma: A systematic review and meta-analysis[J]. Cancers, 2021, 13( 24): 6172. DOI: 10.3390/cancers13246172.
[47]	ZENG J, LI L, ZHANG HS, et al. Radiopaque and uniform alginate microspheres loaded with tantalum nanoparticles for real-time imaging during transcatheter arterial embolization[J]. Theranostics, 2018, 8( 17): 4591- 4600. DOI: 10.7150/thno.27379.
[48]	HU JJ, ALBADAWI H, CHONG BW, et al. Advances in biomaterials and technologies for vascular embolization[J]. Adv Mater, 2019, 31( 33): e1901071. DOI: 10.1002/adma.201901071.
[49]	TACHER V, DURAN R, LIN MD, et al. Multimodality imaging of ethiodized oil-loaded radiopaque microspheres during transarterial embolization of rabbits with VX2 liver tumors[J]. Radiology, 2016, 279( 3): 741- 753. DOI: 10.1148/radiol.2015141624.
[50]	MONDINI M, LEVY A, MEZIANI L, et al. Radiotherapy-immunotherapy combinations-perspectives and challenges[J]. Mol Oncol, 2020, 14( 7): 1529- 1537. DOI: 10.1002/1878-0261.12658.
[51]	DHONDT E, LAMBERT B, HERMIE L, et al. ⁹⁰Y radioembolization versus drug-eluting bead chemoembolization for unresectable hepatocellular carcinoma: Results from the TRACE phase II randomized controlled trial[J]. Radiology, 2022, 303( 3): 699- 710. DOI: 10.1148/radiol.211806.
[52]	FAN WZ, WU YQ, LU MJ, et al. A meta-analysis of the efficacy and safety of iodine[¹³¹I]metuximab infusion combined with TACE for treatment of hepatocellular carcinoma[J]. Clin Res Hepatol Gastroenterol, 2019, 43( 4): 451- 459. DOI: 10.1016/j.clinre.2018.09.006.
[53]	LEE KH, LIAPI E, VOSSEN JA, et al. Distribution of iron oxide-containing Embosphere particles after transcatheter arterial embolization in an animal model of liver cancer: Evaluation with MR imaging and implication for therapy[J]. J Vasc Interv Radiol, 2008, 19( 10): 1490- 1496. DOI: 10.1016/j.jvir.2008.06.008.
[54]	VAN ELK M, OZBAKIR B, BARTEN-RIJBROEK AD, et al. Alginate microspheres containing temperature sensitive liposomes(TSL) for MR-guided embolization and triggered release of doxorubicin[J]. PLoS One, 2015, 10( 11): e0141626. DOI: 10.1371/journal.pone.0141626.
[55]	DASH A, PILLAI MRA, KNAPP FF JR. Production of(177)Lu for targeted radionuclide therapy: Available options[J]. Nucl Med Mol Imaging, 2015, 49( 2): 85- 107. DOI: 10.1007/s13139-014-0315-z.