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Research Article

The enhanced protective effects of salvianic acid A: A functionalized nanoparticles against ischemic stroke through increasing the permeability of the blood-brain barrier

Yaru Li1,2, Xiaojie Zhang1, Zhifeng Qi3( ), Xueling Guo1,2, Xiaopeng Liu4, Wenjuan Shi3, Yang Liu1,2( ), Libo Du1,2( )
State Key Laboratory for Structural Chemistry of Unstable and Stable Species, Center for Molecular Science, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China
Graduate School, University of Chinese Academy of Sciences, Beijing 100049, China
Cerebrovascular Diseases Research Institute, Xuanwu Hospital of Captital Medical University, Beijing 100053, China
Department of Neurosurgery, The Second Hospital of Hebei Medical University, Shijiazhuang 050051, China
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Abstract

Ischemic stroke is the leading cause of disability and death worldwide. Currently, the only proven treatment for ischemic stroke is restoring the cerebral blood supply. In addition, some of the tissue is damaged during the subsequent reperfusion because of the overproduction of reactive oxygen species (ROS). Furthermore, antioxidant therapies have shown promise in preclinical studies for the treatment of ischemia-reperfusion injury. However, their therapeutic efficacy has been limited because of their low bioavailability in brain. To resolve this issue, we synthesized ROS-responsive, fan-shaped dendrimer nanoparticles (NPs) and conjugated them with a blood-brain barrier (BBB)-targeting peptide, COG1410, and salvianic acid A (SA), which is an effective antioxidant in ischemic stroke. The BBB targeting peptide acts as a ligand of the nanocarrier system and penetrates the BBB through the endocytosis of the ligand receptor. The results showed that T-SA-NPs not only target and accumulate in the infarct area, they also reduce over 2 times of the infarct area and reverse the behavioral deficits in MCAO mice, which illustrates that these NPs have an effective therapeutic effect on the ischemic stroke. In addition, these NPs had no toxicity in any organs of the body. Importantly, the present study provides an alternative strategy for delivering antioxidants to the brain and achieving targeted therapy of ischemic stroke.

Keywords

ischemic strokeblood-brain barriermitophagysalvianic acid ACOG1410reactive oxygen species (ROS)-responsive nanocarrier

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References

[1]
Donnan, G. A.; Fisher, M.; Macleod, M.; Davis, S. M. Stroke. Lancet 2008, 371, 1612-1623.
Google Scholar
[2]
Campbell, B. C. V.; Ma, H.; Ringleb, P. A.; Parsons, M. W.; Churilov, L.; Bendszus, M.; Levi, C. R.; Hsu, C.; Kleinig, T. J.; Fatar, M. et al. Extending thrombolysis to 4·5-9 h and wake-up stroke using perfusion imaging: A systematic review and meta-analysis of individual patient data. Lancet 2019, 394, 139-147.
Google Scholar
[3]
Coutts, S. B.; Menon, B. K. Late thrombolysis for stroke works, but how do we do it? Lancet 2019, 394, 97-98.
Google Scholar
[4]
Chouchani, E. T.; Pell, V. R.; Gaude, E.; Aksentijević, D.; Sundier, S. Y.; Robb, E. L.; Logan, A.; Nadtochiy, S. M.; Ord, E. N. J.; Smith, A. C. et al. Ischemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature 2014, 515, 431-435.
Google Scholar
[5]
Yamato, M.; Egashira, T.; Utsumi, H. Application of in vivo ESR spectroscopy to measurement of cerebrovascular ROS generation in stroke. Free Radic. Biol. Med. 2003, 35, 1619-1631.
Google Scholar
[6]
Kim, C. K.; Kim, T.; Choi, I. Y.; Soh, M.; Kim, D.; Kim, Y. J.; Jang, H.; Yang, H. S.; Kim, J. Y.; Park, H. K. et al. Ceria nanoparticles that can protect against ischemic stroke. Angew. Chem., Int. Ed. Engl. 2012, 51, 11039-11043.
Google Scholar
[7]
Parikh, N. S.; Elkind, M. S. V. Divergent effects of lipids on stroke. Nat. Med. 2019, 25, 543-544.
Google Scholar
[8]
Liu, X. J.; Yan, L.; Xue, F. Z. The associations of lipids and lipid ratios with stroke: A prospective cohort study. J. Clin. Hypertens. 2019, 21, 127-135.
Google Scholar
[9]
Holmes, M. V.; Millwood, I. Y.; Kartsonaki, C.; Hill, M. R.; Bennett, D. A.; Boxall, R.; Guo, Y.; Xu, X.; Bian, Z.; Hu, R. Y. et al. Lipids, lipoproteins, and metabolites and risk of myocardial infarction and stroke. J. Am. Coll. Cardiol. 2018, 71, 620-632.
Google Scholar
[10]
Ding, W.; Hudson, L. G.; Liu, K. J. Inorganic arsenic compounds cause oxidative damage to DNA and protein by inducing ROS and RNS generation in human keratinocytes. Mol. Cell. Biochem. 2005, 279, 105-112.
Google Scholar
[11]
Liu, L.; Zhang, K.; Sandoval, H.; Yamamoto, S.; Jaiswal, M.; Sanz, E.; Li, Z. H.; Hui, J.; Graham, B. H.; Quintana, A. et al. Glial lipid droplets and ROS induced by mitochondrial defects promote neurodegeneration. Cell 2015, 160, 177-190.
Google Scholar
[12]
Melo, A.; Monteiro, L.; Lima, R. M. F.; De Oliveira, D. M.; De Cerqueira, M. D.; El-Bachá, R. S. Oxidative stress in neurodegenerative diseases: Mechanisms and therapeutic perspectives. Oxid. Med. Cell. Longev. 2011, 2011, 467180.
Google Scholar
[13]
Reed, T. T. Lipid peroxidation and neurodegenerative disease. Free Radic Biol. Med. 2011, 51, 1302-1319.
Google Scholar
[14]
Rajendran, P.; Nandakumar, N.; Rengarajan, T.; Palaniswami, R.; Gnanadhas, E. N.; Lakshminarasaiah, U.; Gopas, J.; Nishigaki, I. Antioxidants and human diseases. Clin. Chim. Acta 2014, 436, 332-347.
Google Scholar
[15]
Fan, Y.; Luo, Q. P.; Wei, J. J.; Lin, R. H.; Lin, L. L.; Li, Y. K.; Chen, Z. R.; Lin, W.; Chen, Q. Mechanism of salvianolic acid B neuroprotection against ischemia/reperfusion induced cerebral injury. Brain Res. 2018, 1679, 125-133.
Google Scholar
[16]
Chang, Y.; Hsieh, C. Y.; Peng, Z. A.; Yen, T. L.; Hsiao, G.; Chou, D. S.; Chen, C. M.; Sheu, J. R. Neuroprotective mechanisms of puerarin in middle cerebral artery occlusion-induced brain infarction in rats. J. Biomed. Sci. 2009, 16, 9.
Google Scholar
[17]
Yan, R. Y.; Wang, S. J.; Yao, G. T.; Liu, Z. G.; Xiao, N. The protective effect and its mechanism of 3-n-butylphthalide pretreatment on cerebral ischemia reperfusion injury in rats. Eur. Rev. Med. Pharmacol. Sci. 2017, 21, 5275-5282.
Google Scholar
[18]
Yang, Y. J.; Su, Y. J.; Wang, D. T.; Chen, Y. H.; Wu, T.; Li, G.; Sun, X. G.; Cui, L. Tanshinol attenuates the deleterious effects of oxidative stress on osteoblastic differentiation via Wnt/FoxO3a signaling. Oxid. Med. Cell. Longev. 2013, 2013, 351895.
Google Scholar
[19]
Song, W.; Pu, J.; He, B. Tanshinol protects human umbilical vein endothelial cells against hydrogen peroxide-induced apoptosis. Mol. Med. Rep. 2014, 10, 2764-2770.
Google Scholar
[20]
Chong, C. M.; Zhou, Z. Y.; Razmovski-Naumovski, V.; Cui, G. Z.; Zhang, L. Q.; Sa, F.; Hoi, P. M.; Chan, K.; Lee, S. M. Y. Danshensu protects against 6-hydroxydopamine-induced damage of PC12 cells in vitro and dopaminergic neurons in zebrafish. Neurosci. Lett., 2013, 543, 121-125.
Google Scholar
[21]
Wei, Y.; Zhang, L.; Yu, Z. P.; Lin, K. S.; Yang, S. F.; Dai, L.; Liu, J. F.; Mao, L. K.; Yuan, F.; Gao, Y. X. Enhanced stability, structural characterization and simulated gastrointestinal digestion of coenzyme Q10 loaded ternary nanoparticles. Food Hydr. 2019, 94, 333-344.
Google Scholar
[22]
Liu, C. Z.; Zhang, S. Z.; McClements, D. J.; Wang, D. F.; Xu, Y. Design of Astaxanthin-loaded core-shell nanoparticles consisting of chitosan oligosaccharides and poly (lactic-co-glycolic acid): Enhancement of water solubility, stability, and bioavailability. J. Agric. Food Chem. 2019, 67, 5113-5121.
Google Scholar
[23]
Esposito, E.; Drechsler, M.; Puglia, C.; Cortesi, R. New strategies for the delivery of some natural anti-oxidants with therapeutic properties. Mini-Rev. Med. Chem. 2019, 19, 1030-1039.
Google Scholar
[24]
Chen, C. T.; Duan, Z. Q.; Yuan, Y.; Li, R. X.; Pang, L.; Liang, J. M.; Xu, X. C.; Wang, J. X. Peptide-22 and cyclic RGD functionalized liposomes for glioma targeting drug delivery overcoming BBB and BBTB. ACS Appl. Mater. Interfaces 2017, 9, 5864-5873.
Google Scholar
[25]
Yin, T. T.; Xie, W. J.; Sun, J.; Yang, L. C.; Liu, J. Penetratin peptide-functionalized gold nanostars: Enhanced BBB permeability and NIR photothermal treatment of alzheimer’s disease using ultralow irradiance. ACS Appl. Mater. Interfaces 2016, 8, 19291-19302.
Google Scholar
[26]
Yang, J. T.; Kuo, Y. C.; Chen, I. Y.; Rajesh, R.; Lou, Y. I.; Hsu, J. P. Protection against neurodegeneration in the hippocampus using sialic acid- and 5-HT-moduline-conjugated lipopolymer nanoparticles. ACS Biomater. Sci. Eng. 2019, 5, 1311-1320.
Google Scholar
[27]
Malvajerd, S. S.; Azadi, A.; Izadi, Z.; Kurd, M.; Dara, T.; Dibaei, M.; Zadeh, M. S.; Javar, H. A.; Hamidi, M. Brain delivery of curcumin using solid lipid nanoparticles and nanostructured lipid carriers: Preparation, optimization, and pharmacokinetic evaluation. ACS Chem. Neurosci. 2019, 10, 728-739.
Google Scholar
[28]
Zhang, P.; Omaye, S. T. DNA strand breakage and oxygen tension: Effects of β-carotene, α-tocopherol and ascorbic acid. Food Chem. Toxicol. 2001, 39, 239-246.
Google Scholar
[29]
Ekladious, I.; Colson, Y. L.; Grinstaff, M. W. Polymer-drug conjugate therapeutics: Advances, insights and prospects. Nat. Rev. Drug. Discov. 2019, 18, 273-294.
Google Scholar
[30]
Mohammed, F.; Ke, W. D.; Mukerabigwi, J. F.; Japir A. A. W. M.; Ibrahim, A.; Wang, Y. H.; Zha, Z. S.; Lu, N. N.; Zhou, M.; Ge, Z. S. ROS-responsive polymeric nanocarriers with photoinduced exposure of cell-penetrating moieties for specific intracellular drug delivery. ACS Appl. Mater. Interfaces 2019, 11, 31681-31692.
Google Scholar
[31]
Xiang, J. J.; Liu, X.; Zhou, Z. X.; Zhu, D. C.; Zhou, Q.; Piao, Y.; Jiang, L. M.; Tang, J. B.; Liu, X. R.; Shen, Y. Q. Reactive oxygen species (ROS)-responsive charge-switchable nanocarriers for gene therapy of metastatic cancer. ACS Appl. Mater. Interfaces 2018, 10, 43352-43362.
Google Scholar
[32]
Zhang, M.; Song, C. C.; Su, S.; Du, F. S.; Li, Z. C. ROS-activated ratiometric fluorescent polymeric nanoparticles for self-reporting drug delivery. ACS Appl. Mater. Interfaces 2018, 10, 7798-7810.
Google Scholar
[33]
Qiao, Y. T.; Wan, J. Q.; Zhou, L. Q.; Ma, W.; Yang, Y. Y.; Luo, W. X.; Yu, Z. Q.; Wang, H. X. Stimuli-responsive nanotherapeutics for precision drug delivery and cancer therapy. Wires Nanomed. Nanobi. 2019, 11, e1527.
Google Scholar
[34]
Kalhapure, R. S.; Renukuntla, J. Thermo- and pH dual responsive polymeric micelles and nanoparticles. Chem. Biol. Int. 2018, 295, 20-37.
Google Scholar
[35]
Xu, X. D.; Saw, P. E.; Tao, W.; Li, Y. J.; Ji, X. Y.; Bhasin, S.; Liu, Y. L.; Ayyash, D.; Rasmussen, J.; Huo, M. et al. ROS-responsive polyprodrug nanoparticles for triggered drug delivery and effective cancer therapy. Adv. Mater. 2017, 29, 1700141.
Google Scholar
[36]
Zhang, X. Q.; Li, L. H.; Li, C. F.; Zheng, H.; Song, H. Y.; Xiong, F. L.; Qiu, T.; Yang, J. Cisplatin-crosslinked glutathione-sensitive micelles loaded with doxorubicin for combination and targeted therapy of tumors. Carbohydr. Polym. 2017, 155, 407-415.
Google Scholar
[37]
Sharma, A. K.; Gothwal, A.; Kesharwani, P.; Alsaab, H.; Iyer, A. K.; Gupta, U. Dendrimer nanoarchitectures for cancer diagnosis and anticancer drug delivery. Drug Dis. Today 2017, 22, 314-326.
Google Scholar
[38]
Luong, D.; Kesharwani, P.; Deshmukh, R.; Amin, M. C. I. M.; Gupta, U.; Greish, K.; Iyer, A. K. PEGylated PAMAM dendrimers: Enhancing efficacy and mitigating toxicity for effective anticancer drug and gene delivery. Acta Biomater. 2016, 43, 14-29.
Google Scholar
[39]
Lu, Y. P.; Han, S. P.; Zheng, H. Y.; Ma, R.; Ping, Y. T.; Zou, J. F.; Tang, H. X.; Zhang, Y. P.; Xu, X. L.; Li, F. Z. A novel RGDyC/PEG co-modified PAMAM dendrimer-loaded arsenic trioxide of glioma targeting delivery system. Int. J. Nanomedicine 2018, 13, 5937-5952.
Google Scholar
[40]
Gothwal, A.; Nakhate, K. T.; Alexander, A.; Ajazuddin; Gupta, U. Boosted memory and improved brain bioavailability of rivastigmine: Targeting effort to the brain using covalently tethered lower generation PAMAM dendrimers with lactoferrin. Mol. Pharmaceutics 2018, 15, 4538-4549.
Google Scholar
[41]
Sharma, A.; Liaw, K.; Sharma, R.; Zhang, Z.; Kannan, S.; Kannan, R. M. Targeting mitochondrial dysfunction and oxidative stress in activated microglia using dendrimer-based therapeutics. Theranostics 2018, 8, 5529-5547.
Google Scholar
[42]
Guo, X. L.; Kang, X. X.; Wang, Y. Q.; Zhang, X. J.; Li, C. J.; Liu, Y.; Du, L. B. Co-delivery of cisplatin and doxorubicin by covalently conjugating with polyamidoamine dendrimer for enhanced synergistic cancer therapy. Acta Biomater. 2019, 84, 367-377.
Google Scholar
[43]
Chiou, S. H.; Wu, W. T. Immobilization of Candida rugosa lipase on chitosan with activation of the hydroxyl groups. Biomaterials 2004, 25, 197-204.
Google Scholar
[44]
Guo, X. L.; Kang, X. X.; Wang, Y. Q.; Zhang, X. J.; Li, C. J.; Liu, Y.; Du, L. B. Co-delivery of cisplatin and doxorubicin by covalently conjugating with polyamidoamine dendrimer for enhanced synergistic cancer therapy. Acta Biomater. 2019, 84, 367-377.
Google Scholar
[45]
Jiang, X. C.; Xiang, J. J.; Wu, H. H.; Zhang, T. Y.; Zhang, D. P.; Xu, Q. H.; Huang, X. L.; Kong, X. L.; Sun, J. H.; Hu, Y. L. et al. Neural stem cells transfected with reactive oxygen species-responsive polyplexes for effective treatment of ischemic stroke. Adv. Mater. 2019, 31, 1807591.
Google Scholar
[46]
Lu, Y. F.; Li, C.; Chen, Q. J.; Liu, P. X.; Guo, Q.; Zhang, Y.; Chen, X. L.; Zhang, Y. J.; Zhou, W. X.; Liang, D. H. et al. Microthrombus- targeting micelles for neurovascular remodeling and enhanced microcirculatory perfusion in acute ischemic stroke. Adv. Mater. 2019, 31, 1808361.
Google Scholar
[47]
Fan, Q.; Chen, M. L.; Fang, X. Y.; Lau, W. B.; Xue, L.; Zhao, L. N.; Zhang, H.; Liang, Y. H.; Bai, X.; Niu, H. Y. et al. Aging might augment reactive oxygen species (ROS) formation and affect reactive nitrogen species (RNS) level after myocardial ischemia/reperfusion in both humans and rats. AGE 2013, 35, 1017-1026.
Google Scholar
[48]
Moloney, J. N.; Cotter, T. G. ROS signalling in the biology of cancer. Semin. Cell Develop. Biol. 2018, 80, 50-64.
Google Scholar
[49]
El-Kenawi, A.; Ruffell, B. Inflammation, ROS, and mutagenesis. Cancer Cell 2017, 32, 727-729.
Google Scholar
[50]
Manton, K. G.; Volovik, S.; Kulminski, A. ROS effects on neurodegeneration in Alzheimer’s disease and related disorders: On environmental stresses of ionizing radiation. Curr. Alzheimer Res. 2004, 1, 277-293.
Google Scholar
[51]
Lan, A. P.; Chen, J.; Chai, Z. F.; Hu, Y. The neurotoxicity of iron, copper and cobalt in Parkinson’s disease through ROS-mediated mechanisms. BioMetals 2016, 29, 665-678.
Google Scholar
[52]
Li, P. Y.; Stetler, R. A.; Leak, R. K.; Shi, Y. J.; Li, Y.; Yu, W. F.; Bennett, M. V. L.; Chen, J. Oxidative stress and DNA damage after cerebral ischemia: Potential therapeutic targets to repair the genome and improve stroke recovery. Neuropharmacology 2018, 134, 208-217.
Google Scholar
[53]
Hatefi, Y. ATP synthesis in mitochondria. Eur. J. Biochem. 1993, 218, 759-767.
Google Scholar
[54]
Nicholls, D. G. Mitochondrial membrane potential and aging. Aging Cell 2004, 3, 35-40.
Google Scholar
[55]
Hüttemann, M.; Lee, I.; Pecinova, A.; Pecina, P.; Przyklenk, K.; Doan, J. W. Regulation of oxidative phosphorylation, the mitochondrial membrane potential, and their role in human disease. J. Bioenerg. Biomembr. 2008, 40, 445.
Google Scholar
[56]
Susin, S. A.; Zamzami, N.; Castedo, M.; Daugas, E.; Wang, H. G.; Geley, S.; Fassy, F.; Reed, J. C.; Kroemer, G. The central executioner of apoptosis: Multiple connections between protease activation and mitochondria in Fas/APO-1/CD95- and ceramide-induced apoptosis. J. Exp. Med. 1997, 186, 25-37.
Google Scholar
[57]
Kubli, D. A.; Gustafsson, A. B. Mitochondria and mitophagy: The yin and yang of cell death control. Circ. Res. 2012, 111, 1208-1221.
Google Scholar
[58]
Kolosowska, N.; Keuters, M. H.; Wojciechowski, S.; Keksa- Goldsteine, V.; Laine, M.; Malm, T.; Goldsteins, G.; Koistinaho, J.; Dhungana, H. Peripheral administration of IL-13 induces anti- inflammatory microglial/macrophage responses and provides neuroprotection in ischemic stroke. Neurotherapeutics 2019, 16, 1304-1319.
Google Scholar
[59]
Subramaniam, S. R.; Chesselet, M. F. Mitochondrial dysfunction and oxidative stress in Parkinson’s disease. Prog. Neurobiol. 2013, 106-107, 17-32.
Google Scholar
[60]
Hauser, D. N.; Hastings, T. G. Mitochondrial dysfunction and oxidative stress in Parkinson’s disease and monogenic parkinsonism. Neurobiol. Dis. 2013, 51, 35-42.
Google Scholar
[61]
Mondragón-Rodríguez, S.; Perry, G.; Zhu, X. W.; Moreira, P. I.; Acevedo-Aquino, M. C.; Williams, S. Phosphorylation of tau protein as the link between oxidative stress, mitochondrial dysfunction, and connectivity failure: Implications for Alzheimer’s disease. Oxid. Med. Cell. Longev. 2013, 2013, 940603.
Google Scholar
Nano Research
Volume 13 Issue 10,
October 2020
Pages 2791-2802
DOI: 10.1007/s12274-020-2930-6
Cite this article:
Li Y, Zhang X, Qi Z, et al. The enhanced protective effects of salvianic acid A: A functionalized nanoparticles against ischemic stroke through increasing the permeability of the blood-brain barrier. Nano Research, 2020, 13(10): 2791-2802. https://doi.org/10.1007/s12274-020-2930-6
Topics:
Biochemistry BloodLigands MammalsMolecular biologyNanoparticlesPeptidesSynthesis (chemical)

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Received: 03 May 2020
Revised: 07 June 2020
Accepted: 08 June 2020
Published: 05 October 2020
© Tsinghua University Press and Springer-Verlag GmbH Germany, part of Springer Nature 2020
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