纳米颗粒和外泌体靶向载药系统诊治动脉粥样硬化的机遇与挑战

doi:10.12114/j.issn.1007-9572.2022.0795

摘要/Abstract

摘要： 动脉粥样硬化是一种慢性炎症性疾病，粥样斑块慢性聚集并沉积于大中型动脉内膜，导致严重的狭窄和血运障碍，引发组织器官缺血缺氧。纳米药物相对于传统药物在动脉粥样硬化治疗中因其具有独特的优势而广泛受到关注。本文重点综述几种纳米靶向颗粒（系统）和外泌体靶向载药系统在抗动脉粥样硬化研究中的应用，简述代表性纳米材料的合成过程，对其靶向性进行分析，并概述纳米药物的益处和内在挑战。尽管面临着一些需要解决和完善的挑战，但是纳米颗粒和外泌体靶向载药治疗的前景广阔，并有望将其推广应用于临床实践中。

关键词: 动脉粥样硬化, 心血管疾病, 纳米颗粒, 外泌体, 炎症, 靶向治疗

Abstract:

Atherosclerosis is a chronic inflammatory disease in which atheromatous plaque long-termly accumulates and obstructs the intima of medium and large arteries, causing first severe stenosis and blood flow disorders, and then ischemia and hypoxia in tissues and organs. Nanomedicines have received widespread attention for their unique advantages over conventional drugs in the treatment of atherosclerosis. This article detailedly reviews several nanoparticle- and exosome-based targeted drug delivery systems in anti-atherosclerosis research, briefly describes the synthesis of representative nanomaterials, analyses their targeting properties and outlines the benefits and inherent challenges of nanomedicines. Despite the challenges that need to be addressed and refined, nanoparticles and exosomes used as drug delivery vehiclesin treatments for atherosclerosis hold great promise and are expected to have wider clinical applications.

Key words: Atherosclerosis, Cardiovascular diseases, Nanoparticles, Exosomes, Inflammation, Targeted therapy

刘滔滔,李天容,王雪,等. 纳米颗粒和外泌体靶向载药系统诊治动脉粥样硬化的机遇与挑战[J]. 中国全科医学, 2023, 26(08): 903-910. DOI: 10.12114/j.issn.1007-9572.2022.0795.
LIU Taotao,LI Tianrong,WANG Xue, et al. Nanoparticle- and Exosome-based Targeted Drug Delivery Systems Used in the Diagnosis and Treatment of Atherosclerosis: Opportunities and Challenges[J]. Chinese General Practice, 2023, 26(08): 903-910. DOI: 10.12114/j.issn.1007-9572.2022.0795.

图/表 1

参考文献 61

[1]	ARMITAGE J. The safety of statins in clinical practice[J]. Lancet，2007，370（9601）：1781-1790. DOI：10.1016/S0140-6736(07)60716-8.
[2]	CHEELEY M K, SASEEN J J, AGARWALA A，et al. NLA scientific statement on statin intolerance：a new definition and key considerations for ASCVD risk reduction in the statin intolerant patient[J]. J Clin Lipidol，2022，16（4）：361-375. DOI：10.1016/j.jacl.2022.05.068.
[3]	LEWIS D R, KAMISOGLU K, YORK A W，et al. Polymer-based therapeutics：nanoassemblies and nanoparticles for management of atherosclerosis[J]. Wiley Interdiscip Rev Nanomed Nanobiotechnol，2011，3（4）：400-420. DOI：10.1002/wnan.145.
[4]	YE M, ZHOU J, ZHONG Y X，et al. SR-A-targeted phase-transition nanoparticles for the detection and treatment of atherosclerotic vulnerable plaques[J]. ACS Appl Mater Interfaces，2019，11（10）：9702-9715. DOI：10.1021/acsami.8b18190.
[5]	KHERADMANDI M, ACKERS I, BURDICK M M，et al. Targeting dysfunctional vascular endothelial cells using immunoliposomes under flow conditions[J]. Cell Mol Bioeng，2020，13（3）：189-199. DOI：10.1007/s12195-020-00616-1.
[6]	GAO C, HUANG Q X, LIU C H，et al. Treatment of atherosclerosis by macrophage-biomimetic nanoparticles via targeted pharmacotherapy and sequestration of proinflammatory cytokines[J]. Nat Commun，2020，11（1）：2622. DOI：10.1038/s41467-020-16439-7.
[7]	ZHANG L, TIAN X Y, CHAN C K W，et al. Promoting the delivery of nanoparticles to atherosclerotic plaques by DNA coating[J]. ACS Appl Mater Interfaces，2019，11（15）：13888-13904. DOI：10.1021/acsami.8b17928.
[8]	WANG Y, ZHANG K, QIN X，et al. Biomimetic nanotherapies：red blood cell based core-shell structured nano complexes for atherosclerosis management[J]. Adv Sci （Weinh），2019，6（12）：1900172. DOI：10.1002/advs.201900172.
[9]	PATEL D K, RANA D, ASWAL V K，et al. Influence of graphene on self-assembly of polyurethane and evaluation of its biomedical properties[J]. Polymer，2015，65：183-192. DOI：10.1016/j.polymer.2015.03.076.
[10]	NANDWANA V, RYOO S-R, KANTHALA S，et al. High-density lipoprotein-like magnetic nanostructures （HDL-MNS）：theranostic agents for cardiovascular disease [J]. Chemistry of Materials，2017，29（5）：2276-2282. DOI：10.1021/acs.chemmater.6b05357.
[11]	OUMZIL K, RAMIN M A, LORENZATO C，et al. Solid lipid nanoparticles for image-guided therapy of atherosclerosis[J]. Bioconjug Chem，2016，27（3）：569-575. DOI：10.1021/acs.bioconjchem.5b00590.
[12]	KORCHINSKI D J, TAHA M, YANG R Z，et al. Iron oxide as an MRI contrast agent for cell tracking[J]. Magn Reson Insights，2015，8（Suppl 1）：15-29. DOI：10.4137/MRI.S23557.
[13]	LU K Y, LIN P Y, CHUANG E Y，et al. H₂O₂-depleting and O₂-generating selenium nanoparticles for fluorescence imaging and photodynamic treatment of proinflammatory-activated macrophages[J]. ACS Appl Mater Interfaces，2017，9（6）：5158-5172. DOI：10.1021/acsami.6b15515.
[14]	KOSUGE H, SHERLOCK S P, KITAGAWA T，et al. Near infrared imaging and photothermal ablation of vascular inflammation using single-walled carbon nanotubes[J]. J Am Heart Assoc，2012，1（6）：e002568. DOI：10.1161/JAHA.112.002568.
[15]	CHHOUR P, NAHA P C, O'NEILL S M，et al. Labeling monocytes with gold nanoparticles to track their recruitment in atherosclerosis with computed tomography[J]. Biomaterials，2016，87：93-103. DOI：10.1016/j.biomaterials.2016.02.009.
[16]	QIN J B, PENG Z Y, LI B，et al. Gold nanorods as a theranostic platform for in vitro and in vivo imaging and photothermal therapy of inflammatory macrophages[J]. Nanoscale，2015，7（33）：13991-14001. DOI：10.1039/c5nr02521d.
[17]	SUK J S, XU Q G, KIM N，et al. PEGylation as a strategy for improving nanoparticle-based drug and gene delivery[J]. Adv Drug Deliv Rev，2016，99（Pt A）：28-51. DOI：10.1016/j.addr.2015.09.012.
[18]	LIANG X Y, LI H Y, ZHANG A A，et al. Red blood cell biomimetic nanoparticle with anti-inflammatory，anti-oxidative and hypolipidemia effect ameliorated atherosclerosis therapy[J]. Nanomed-Nanotechnol Biol Med，2022，41：102519. DOI：10.1016/j.nano.2022.102519.
[19]	MEHTA S, BONGCARON V, NGUYEN T K，et al. An ultrasound-responsive theranostic cyclodextrin-loaded nanoparticle for multimodal imaging and therapy for atherosclerosis[J]. Small，2022，18（31）：e2200967. DOI：10.1002/smll.202200967.
[20]	FANG F, NI Y H, YU H C，et al. Inflammatory endothelium-targeted and cathepsin responsive nanoparticles are effective against atherosclerosis[J]. Theranostics，2022，12（9）：4200-4220. DOI：10.7150/thno.70896.
[21]	GAO C, LIU C H, CHEN Q，et al. Cyclodextrin-mediated conjugation of macrophage and liposomes for treatment of atherosclerosis[J]. J Control Release，2022，349：2-15. DOI：10.1016/j.jconrel.2022.06.053.
[22]	PHAM L M, KIM E C, OU W Q，et al. Targeting and clearance of senescent foamy macrophages and senescent endothelial cells by antibody-functionalized mesoporous silica nanoparticles for alleviating aorta atherosclerosis[J]. Biomaterials，2021，269：120677. DOI：10.1016/j.biomaterials.2021.120677.
[23]	WANG Y, ZHANG K, LI T H，et al. Macrophage membrane functionalized biomimetic nanoparticles for targeted anti-atherosclerosis applications[J]. Theranostics，2021，11（1）：164-180. DOI：10.7150/thno.47841.
[24]	DHANASEKARA C S, ZHANG J, NIE S F，et al. Nanoparticles target intimal macrophages in atherosclerotic lesions[J]. Nanomed-Nanotechnol Biol Med，2021，32：102346. DOI：10.1016/j.nano.2020.102346.
[25]	HOU X Y, LIN H, ZHOU X D，et al. Novel dual ROS-sensitive and CD44 receptor targeting nanomicelles based on oligomeric hyaluronic acid for the efficient therapy of atherosclerosis[J]. Carbohydr Polym，2020，232：115787. DOI：10.1016/j.carbpol.2019.115787.
[26]	KIM H, KUMAR S, KANG D W，et al. Affinity-driven design of cargo-switching nanoparticles to leverage a cholesterol-rich microenvironment for atherosclerosis therapy[J]. ACS Nano，2020，14（6）：6519-6531. DOI：10.1021/acsnano.9b08216.
[27]	BOADA C, ZINGER A, TSAO C，et al. Rapamycin-loaded biomimetic nanoparticles reverse vascular inflammation[J]. Circ Res，2020，126（1）：25-37. DOI：10.1161/CIRCRESAHA.119.315185.
[28]	BELDMAN T J, MALINOVA T S, DESCLOS E，et al. Nanoparticle-aided characterization of arterial endothelial architecture during atherosclerosis progression and metabolic therapy[J]. ACS Nano，2019，13（12）：13759-13774. DOI：10.1021/acsnano.8b08875.
[29]	KIM M, SAHU A, HWANG Y，et al. Targeted delivery of anti-inflammatory cytokine by nanocarrier reduces atherosclerosis in Apo E^-/- mice[J]. Biomaterials，2020，226：119550. DOI：10.1016/j.biomaterials.2019.119550.
[30]	WANG Y Q, LI L L, ZHAO W B，et al. Targeted therapy of atherosclerosis by a broad-spectrum reactive oxygen species scavenging nanoparticle with intrinsic anti-inflammatory activity[J]. ACS Nano，2018，12（9）：8943-8960. DOI：10.1021/acsnano.8b02037.
[31]	CHMIELOWSKI R A, ABDELHAMID D S, FAIG J J，et al. Athero-inflammatory nanotherapeutics：ferulic acid-based poly（anhydride-ester） nanoparticles attenuate foam cell formation by regulating macrophage lipogenesis and reactive oxygen species generation[J]. Acta Biomater，2017，57：85-94. DOI：10.1016/j.actbio.2017.05.029.
[32]	SONG Y N, HUANG Z Y, LIU X，et al. Platelet membrane-coated nanoparticle-mediated targeting delivery of Rapamycin blocks atherosclerotic plaque development and stabilizes plaque in apolipoprotein E-deficient （ApoE^-/-） mice[J]. Nanomed-Nanotechnol Biol Med，2019，15（1）：13-24. DOI：10.1016/j.nano.2018.08.002.
[33]	FAVARI E, THOMAS M J, SORCI-THOMAS M G. High-density lipoprotein functionality as a new pharmacological target on cardiovascular disease：unifying mechanism that explains high-density lipoprotein protection toward the progression of atherosclerosis[J]. J Cardiovasc Pharmacol，2018，71（6）：325-331. DOI：10.1097/FJC.0000000000000573.
[34]	MANSUKHANI N A, PETERS E B, SO M M，et al. Peptide amphiphile supramolecular nanostructures as a targeted therapy for atherosclerosis[J]. Macromol Biosci，2019，19（6）：e1900066. DOI：10.1002/mabi.201900066.
[35]	CHIN D D, POON C, TRAC N，et al. Collagenase-cleavable peptide amphiphile micelles as a novel theranostic strategy in atherosclerosis[J]. Adv Ther （Weinh），2020，3（3）：1900196. DOI：10.1002/adtp.201900196.
[36]	AHERN R J, HANRAHAN J P, TOBIN J M，et al. Comparison of fenofibrate-mesoporous silica drug-loading processes for enhanced drug delivery[J]. Eur J Pharm Sci，2013，50（3/4）：400-409. DOI：10.1016/j.ejps.2013.08.026.
[37]	HU Y C, ZHI Z Z, WANG T Y，et al. Incorporation of indomethacin nanoparticles into 3-D ordered macroporous silica for enhanced dissolution and reduced gastric irritancy[J]. Eur J Pharm Biopharm，2011，79（3）：544-551. DOI：10.1016/j.ejpb.2011.07.001.
[38]	MELLAERTS R, MOLS R, JAMMAER J A，et al. Increasing the oral bioavailability of the poorly water soluble drug itraconazole with ordered mesoporous silica[J]. Eur J Pharm Biopharm，2008，69（1）：223-230. DOI：10.1016/j.ejpb.2007.11.006.
[39]	WANG Y Z, SUN L Z, JIANG T Y，et al. The investigation of MCM-48-type and MCM-41-type mesoporous silica as oral solid dispersion carriers for water insoluble cilostazol[J]. Drug Dev Ind Pharm，2014，40（6）：819-828. DOI：10.3109/03639045.2013.788013.
[40]	HU Y C. 3D cubic mesoporous silica microsphere as a carrier for poorly soluble drug carvedilol[J]. Microporous Mesoporous Mater，2012，147（1）：94-101. DOI：10.1016/j.micromeso.2011.06.001.
[41]	ZHANG Y Z, ZHI Z Z, JIANG T Y，et al. Spherical mesoporous silica nanoparticles for loading and release of the poorly water-soluble drug telmisartan[J]. J Control Release，2010，145（3）：257-263. DOI：10.1016/j.jconrel.2010.04.029.
[42]	WU M L, LI X, GUO Q，et al. Magnetic mesoporous silica nanoparticles-aided dual MR/NIRF imaging to identify macrophage enrichment in atherosclerotic plaques[J]. Nanomed-Nanotechnol Biol Med，2021，32：102330. DOI：10.1016/j.nano.2020.102330.
[43]	BELDMAN T J, SENDERS M L, ALAARG A，et al. Hyaluronan nanoparticles selectively target plaque-associated macrophages and improve plaque stability in atherosclerosis[J]. ACS Nano，2017，11（6）：5785-5799. DOI：10.1021/acsnano.7b01385.
[44]	LEWIS D R, PETERSEN L K, YORK A W，et al. Sugar-based amphiphilic nanoparticles arrest atherosclerosis in vivo[J]. Proc Natl Acad Sci USA，2015，112（9）：2693-2698. DOI：10.1073/pnas.1424594112.
[45]	QIE Y Q, YUAN H F, VON ROEMELING C A，et al. Surface modification of nanoparticles enables selective evasion of phagocytic clearance by distinct macrophage phenotypes[J]. Sci Rep，2016，6：26269. DOI：10.1038/srep26269.
[46]	VOLPE C M O, VILLAR-DELFINO P H, DOS ANJOS P M F，et al. Cellular death，reactive oxygen species （ROS） and diabetic complications[J]. Cell Death Dis，2018，9（2）：119. DOI：10.1038/s41419-017-0135-z.
[47]	LI J M, NEWBURGER P E, GOUNIS M J，et al. Local arterial nanoparticle delivery of siRNA for NOX2 knockdown to prevent restenosis in an atherosclerotic rat model[J]. Gene Ther，2010，17（10）：1279-1287. DOI：10.1038/gt.2010.69.
[48]	MOORE K J, TABAS I. Macrophages in the pathogenesis of atherosclerosis[J]. Cell，2011，145（3）：341-355. DOI：10.1016/j.cell.2011.04.005.
[49]	POON C, GALLO J, JOO J，et al. Hybrid，metal oxide-peptide amphiphile micelles for molecular magnetic resonance imaging of atherosclerosis[J]. J Nanobiotechnology，2018，16（1）：92. DOI：10.1186/s12951-018-0420-8.
[50]	GURUNATHAN S, KANG M H, KIM J H. A comprehensive review on factors influences biogenesis，functions，therapeutic and clinical implications of exosomes[J]. Int J Nanomedicine，2021，16：1281-1312. DOI：10.2147/IJN.S291956.
[51]	MA X T, WANG J J, LI J，et al. Loading miR-210 in endothelial progenitor cells derived exosomes boosts their beneficial effects on hypoxia/reoxygeneation-injured human endothelial cells via protecting mitochondrial function[J]. Cell Physiol Biochem，2018，46（2）：664-675. DOI：10.1159/000488635.
[52]	CHEN A Q, GAO X F, WANG Z M，et al. Therapeutic exosomes in prognosis and developments of coronary artery disease[J]. Front Cardiovasc Med，2021，8：691548. DOI：10.3389/fcvm.2021.691548.
[53]	BANIZS A B, HUANG T, DRYDEN K，et al. In vitro evaluation of endothelial exosomes as carriers for small interfering ribonucleic acid delivery[J]. Int J Nanomedicine，2014，9：4223-4230. DOI：10.2147/IJN.S64267.
[54]	HERGENREIDER E, HEYDT S, TRÉGUER K，et al. Atheroprotective communication between endothelial cells and smooth muscle cells through miRNAs[J]. Nat Cell Biol，2012，14（3）：249-256. DOI：10.1038/ncb2441.
[55]	WU G H, ZHANG J F, ZHAO Q R，et al. Molecularly engineered macrophage-derived exosomes with inflammation tropism and intrinsic heme biosynthesis for atherosclerosis treatment[J]. Angew Chem Int Ed Engl，2020，59（10）：4068-4074. DOI：10.1002/anie.201913700.
[56]	MOGHIMI S M, SIMBERG D. Complement activation turnover on surfaces of nanoparticles[J]. Nano Today，2017，15：8-10. DOI：10.1016/j.nantod.2017.03.001.
[57]	CHEN F F, WANG G K, GRIFFIN J I，et al. Complement proteins bind to nanoparticle protein Corona and undergo dynamic exchange in vivo[J]. Nat Nanotechnol，2017，12（4）：387-393. DOI：10.1038/nnano.2016.269.
[58]	SZEBENI J, BEDOCS P, ROZSNYAY Z，et al. Liposome-induced complement activation and related cardiopulmonary distress in pigs：factors promoting reactogenicity of Doxil and AmBisome[J]. Nanomed-Nanotechnol Biol Med，2012，8（2）：176-184. DOI：10.1016/j.nano.2011.06.003.
[59]	WANG G K, CHEN F F, BANDA N K，et al. Activation of human complement system by dextran-coated iron oxide nanoparticles is not affected by dextran/Fe ratio，hydroxyl modifications，and crosslinking[J]. Front Immunol，2016，7：418. DOI：10.3389/fimmu.2016.00418.
[60]	BANDA N K, MEHTA G, CHAO Y，et al. Mechanisms of complement activation by dextran-coated superparamagnetic iron oxide （SPIO） nanoworms in mouse versus human serum[J]. Part Fibre Toxicol，2014，11：64. DOI：10.1186/s12989-014-0064-2.
[61]	NORDIN J Z, LEE Y, VADER P，et al. Ultrafiltration with size-exclusion liquid chromatography for high yield isolation of extracellular vesicles preserving intact biophysical and functional properties[J]. Nanomed-Nanotechnol Biol Med，2015，11（4）：879-883. DOI：10.1016/j.nano.2015.01.003.

纳米粒子	类型	粒径（nm）	药物	实验模型	靶点	报道时间（年）
RP-PU	膜包裹纳米颗粒	239.2±5.40	普罗布考	ApoE^-/-小鼠	斑块内ROS	2022^[18]
CDNPs	金属纳米粒子	388±34	2-羟丙基-β-环糊精	ApoE^-/-小鼠	动脉粥样硬化斑块	2022^[19]
RAP@T/R NPs	复合纳米粒子	274.9	雷帕霉素	ApoE^-/-小鼠	变中组织蛋白酶K酶	2022^[20]
MP-QT-NP	脂质体	105	槲皮素	ApoE^-/-小鼠		2022^[21]
CD9-HMSN@RSV	介孔二氧化硅纳米颗粒	100~150	瑞舒伐他汀	ApoE^-/-小鼠	CD9高表达的衰老细胞	2021^[22]
MM/RAPNPs	膜包裹纳米颗粒	90	雷帕霉素	ApoE^-/-小鼠	动脉粥样硬化斑块	2021^[23]
L-NPs	脂质体	88.7±1.4	—	LDLR^-/-小鼠	巨噬细胞内膜上CD36受体	2021^[24]
HASF@CUR	纳米胶束	150.8	姜黄素	HFD大鼠	巨噬细胞内的活性氧	2020^[25]
argo-switching nanoparticles （CSNP）	核-壳结构纳米颗粒	104±13	甲基-β-环糊精和辛伐他汀	ApoE^-/-小鼠和HFD小鼠	动脉粥样斑块胆固醇	2020^[26]
Leuko-Rapa	"Leukosomes"	108±2.3	雷帕霉素	ApoE^-/-小鼠	动脉粥样斑块下内皮细胞	2020^[27]
HA-NPs	复合纳米粒子	90	—	ApoE^-/-小鼠	动脉粥样斑块下内皮细胞	2019^[28]
IL10-NC	金属纳米粒子	81±16	IL-10	ApoE^-/-小鼠	斑块新生血管中过表达的αvβ3整合素	2020^[29]
TPCD NP	复合纳米粒子	128±1	Tempol	ApoE^-/-小鼠	巨噬细胞	2018^[30]
1cM-PFAG	复合纳米粒子	215±31	阿魏酸	HMDMs	巨噬细胞	2017^[31]

纳米粒子	类型	粒径（nm）	药物	实验模型	靶点	报道时间（年）
RP-PU	膜包裹纳米颗粒	239.2±5.40	普罗布考	ApoE^-/-小鼠	斑块内ROS	2022^[18]
CDNPs	金属纳米粒子	388±34	2-羟丙基-β-环糊精	ApoE^-/-小鼠	动脉粥样硬化斑块	2022^[19]
RAP@T/R NPs	复合纳米粒子	274.9	雷帕霉素	ApoE^-/-小鼠	变中组织蛋白酶K酶	2022^[20]
MP-QT-NP	脂质体	105	槲皮素	ApoE^-/-小鼠		2022^[21]
CD9-HMSN@RSV	介孔二氧化硅纳米颗粒	100~150	瑞舒伐他汀	ApoE^-/-小鼠	CD9高表达的衰老细胞	2021^[22]
MM/RAPNPs	膜包裹纳米颗粒	90	雷帕霉素	ApoE^-/-小鼠	动脉粥样硬化斑块	2021^[23]
L-NPs	脂质体	88.7±1.4	—	LDLR^-/-小鼠	巨噬细胞内膜上CD36受体	2021^[24]
HASF@CUR	纳米胶束	150.8	姜黄素	HFD大鼠	巨噬细胞内的活性氧	2020^[25]
argo-switching nanoparticles （CSNP）	核-壳结构纳米颗粒	104±13	甲基-β-环糊精和辛伐他汀	ApoE^-/-小鼠和HFD小鼠	动脉粥样斑块胆固醇	2020^[26]
Leuko-Rapa	"Leukosomes"	108±2.3	雷帕霉素	ApoE^-/-小鼠	动脉粥样斑块下内皮细胞	2020^[27]
HA-NPs	复合纳米粒子	90	—	ApoE^-/-小鼠	动脉粥样斑块下内皮细胞	2019^[28]
IL10-NC	金属纳米粒子	81±16	IL-10	ApoE^-/-小鼠	斑块新生血管中过表达的αvβ3整合素	2020^[29]
TPCD NP	复合纳米粒子	128±1	Tempol	ApoE^-/-小鼠	巨噬细胞	2018^[30]
1cM-PFAG	复合纳米粒子	215±31	阿魏酸	HMDMs	巨噬细胞	2017^[31]