Generic placeholder image

Current Nanoscience

Editor-in-Chief

ISSN (Print): 1573-4137
ISSN (Online): 1875-6786

Research Article

Strategy for Targeting Medical Diagnosis of Cerebral Ischemia Regions by Linking Gsk-3β Antibody and RVG29 to Magnetosomes

In Press, (this is not the final "Version of Record"). Available online 16 November, 2023
Author(s): Qing Wang and Xianyu Li*
Published on: 16 November, 2023

DOI: 10.2174/0115734137259242231109174821

open access plus

Abstract

Background: In our previous studies, we have identified Gsk-3β as a crucial target molecule in response to Danhong injection for cerebral ischemia intervention. Furthermore, it can serve as a molecular imaging probe for medical diagnosis. Bacterial magnetic particles (BMPs), synthesized by magnetotactic bacteria, are regarded as excellent natural nanocarriers.

Methods: In this study, we utilized biological modification and chemical crosslinking techniques to produce a multifunctional BMP known as "RVG29-BMP-FA-Gsk-3β-Ab", which exhibits both magnetic properties and brain-targeting capabilities. Then, a combination of analytical techniques was used to characterize the properties of the multifunctional BMPs. Finally, we evaluated the cell targeting ability of the RVG29-BMP-FA-Gsk-3β-Ab.

Results: The multifunctional BMPs were observed to possess uniform size and shape using TEM analysis, with a particle size of 70.1±7.33 nm. Zeta potential analysis revealed that the nanoparticles exhibited a regular and non-aggregative distribution of particle sizes. Relative fluorescence intensity results demonstrated that the complex of 1mg of RVG29-BMP-FA-Gsk- 3β-Ab could bind to FITC-RVG29 polypeptide at a concentration of 2189.5 nM. Cell viability analysis indicated its high biocompatibility and minimal cytotoxicity. The RVG29-BMP-FAGsk- 3β-Ab was observed to possess active targeting towards neuronal cells and fluorescence imaging capabilities in vitro, as evidenced by fluorescence imaging assays. The complex of RVG29-BMP-FA-Gsk-3β-Ab exhibited favourable properties for early diagnosis and efficacy evaluation of traditional Chinese medicine in treating cerebral ischemia.

Conclusion: This study establishes a fundamental basis for the prospective implementation of multimodal imaging in traditional Chinese medicine for cerebral ischemia.

[1]
Lloyd-Jones, D.; Adams, R.; Carnethon, M.; De Simone, G.; Ferguson, T.B.; Flegal, K.; Ford, E.; Furie, K.; Go, A.; Greenlund, K.; Haase, N.; Hailpern, S.; Ho, M.; Howard, V.; Kissela, B.; Kittner, S.; Lackland, D.; Lisabeth, L.; Marelli, A.; McDermott, M.; Meigs, J.; Mozaffarian, D.; Nichol, G.; O’Donnell, C.; Roger, V.; Rosamond, W.; Sacco, R.; Sorlie, P.; Stafford, R.; Steinberger, J.; Thom, T.; Wasserthiel-Smoller, S.; Wong, N.; Wylie-Rosett, J.; Hong, Y. Heart disease and stroke statistics--2009 update: A report from the american heart association statistics committee and stroke statistics subcommittee. Circulation, 2009, 119(3), 480-486.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.108.191259] [PMID: 19171871]
[2]
Kim, A.S.; Johnston, S.C. Temporal and geographic trends in the global stroke epidemic. Stroke, 2013, 44(6_suppl_1), S123-S125.
[http://dx.doi.org/10.1161/STROKEAHA.111.000067] [PMID: 23709707]
[3]
World Health Organization (WHO). Global Status Report on Alcohol., 2004. Available from: http://www.who.int/substance_abuse/publications/global_status_report_2004_overview.pdf
[4]
Maida, C.D.; Norrito, R.L.; Daidone, M.; Tuttolomondo, A.; Pinto, A. Neuroinflammatory mechanisms in ischemic stroke: Focus on cardioembolic stroke, background, and therapeutic approaches. Int. J. Mol. Sci., 2020, 21(18), 6454.
[http://dx.doi.org/10.3390/ijms21186454] [PMID: 32899616]
[5]
Carota, A.; Neufeld, H.; Calabrese, P. Memory profiles after unilateral paramedian thalamic stroke infarction: A comparative study. Case Rep. Med., 2015, 2015, 1-5.
[http://dx.doi.org/10.1155/2015/430869] [PMID: 26587026]
[6]
Moskowitz, M.A.; Lo, E.H.; Iadecola, C. The science of stroke: Mechanisms in search of treatments. Neuron, 2010, 67(2), 181-198.
[http://dx.doi.org/10.1016/j.neuron.2010.07.002] [PMID: 20670828]
[7]
Sun, K.; Fan, J.; Han, J. Ameliorating effects of traditional Chinese medicine preparation, Chinese materia medica and active compounds on ischemia/reperfusion-induced cerebral microcirculatory disturbances and neuron damage. Acta Pharm. Sin. B, 2015, 5(1), 8-24.
[http://dx.doi.org/10.1016/j.apsb.2014.11.002] [PMID: 26579420]
[8]
Guo, H.; Li, M.; Liu, Q.; Guo, L.; Ma, M.; Wang, S.; Yu, B.; Hu, L.M. Danhong injection attenuates ischemia/reperfusion-induced brain damage which is associating with Nrf2 levels in vivo and in vitro. Neurochem. Res., 2014, 39(9), 1817-1824.
[http://dx.doi.org/10.1007/s11064-014-1384-1] [PMID: 25069640]
[9]
Liu, H.; Wang, S.; Sun, A.; Huang, D.; Wang, W.; Zhang, C.; Shi, D.; Chen, K.; Zou, Y.; Ge, J. Danhong inhibits oxidized low-density lipoprotein-induced immune maturation of dentritic cells via a peroxisome proliferator activated receptor γ-mediated pathway. J. Pharmacol. Sci., 2012, 119(1), 1-9.
[http://dx.doi.org/10.1254/jphs.11226FP] [PMID: 22739234]
[10]
Cui, Y.; Liu, X.; Li, X.; Yang, H. In-depth proteomic analysis of the hippocampus in a rat model after cerebral ischaemic injury and repair by Danhong injection (DHI). Int. J. Mol. Sci., 2017, 18(7), 1355.
[http://dx.doi.org/10.3390/ijms18071355] [PMID: 28672812]
[11]
Vargas, G.; Cypriano, J.; Correa, T.; Leão, P.; Bazylinski, D.; Abreu, F. Applications of magnetotactic bacteria, magnetosomes and magnetosome crystals in biotechnology and nanotechnology: Mini-Review. Molecules, 2018, 23(10), 2438.
[http://dx.doi.org/10.3390/molecules23102438] [PMID: 30249983]
[12]
Lin, W.; Pan, Y.; Bazylinski, D.A. Diversity and ecology of and biomineralization by magnetotactic bacteria. Environ. Microbiol. Rep., 2017, 9(4), 345-356.
[http://dx.doi.org/10.1111/1758-2229.12550] [PMID: 28557300]
[13]
Lin, W.; Kirschvink, J.L.; Paterson, G.A.; Bazylinski, D.A.; Pan, Y. On the origin of microbial magnetoreception. Natl. Sci. Rev., 2020, 7(2), 472-479.
[http://dx.doi.org/10.1093/nsr/nwz065] [PMID: 34692062]
[14]
Wang, Q.; Liu, J.X.; Zhang, W.J.; Zhang, T.W.; Yang, J.; Li, Y. Expression patterns of key iron and oxygen metabolism genes during magnetosome formation in Magnetospirillum gryphiswaldense MSR-1. FEMS Microbiol. Lett., 2013, 347(2), 163-172.
[PMID: 23937222]
[15]
Murat, D.; Quinlan, A.; Vali, H.; Komeili, A. Comprehensive genetic dissection of the magnetosome gene island reveals the step-wise assembly of a prokaryotic organelle. Proc. Natl. Acad. Sci., 2010, 107(12), 5593-5598.
[http://dx.doi.org/10.1073/pnas.0914439107] [PMID: 20212111]
[16]
Uebe, R.; Junge, K.; Henn, V.; Poxleitner, G.; Katzmann, E.; Plitzko, J.M.; Zarivach, R.; Kasama, T.; Wanner, G.; Pósfai, M.; Böttger, L.; Matzanke, B.; Schüler, D. The cation diffusion facilitator proteins MamB and MamM of Magnetospirillum gryphiswaldense have distinct and complex functions, and are involved in magnetite biomineralization and magnetosome membrane assembly. Mol. Microbiol., 2011, 82(4), 818-835.
[http://dx.doi.org/10.1111/j.1365-2958.2011.07863.x] [PMID: 22007638]
[17]
Draper, O.; Byrne, M.E.; Li, Z.; Keyhani, S.; Barrozo, J.C.; Jensen, G.; Komeili, A. MamK, a bacterial actin, forms dynamic filaments in vivo that are regulated by the acidic proteins MamJ and LimJ. Mol. Microbiol., 2011, 82(2), 342-354.
[http://dx.doi.org/10.1111/j.1365-2958.2011.07815.x] [PMID: 21883528]
[18]
Katzmann, E.; Scheffel, A.; Gruska, M.; Plitzko, J.M.; Schüler, D. Loss of the actin-like protein MamK has pleiotropic effects on magnetosome formation and chain assembly in Magnetospirillum gryphiswaldense. Mol. Microbiol., 2010, 77(1), 208-224.
[http://dx.doi.org/10.1111/j.1365-2958.2010.07202.x] [PMID: 20487281]
[19]
Faivre, D.; Böttger, L.H.; Matzanke, B.F.; Schüler, D. Intracellular magnetite biomineralization in bacteria proceeds by a distinct pathway involving membrane-bound ferritin and an iron(II) species. Angew. Chem. Int. Ed., 2007, 46(44), 8495-8499.
[http://dx.doi.org/10.1002/anie.200700927] [PMID: 17902080]
[20]
Qi, L.; Li, J.; Zhang, W.; Liu, J.; Rong, C.; Li, Y.; Wu, L. Fur in Magnetospirillum gryphiswaldense influences magnetosomes formation and directly regulates the genes involved in iron and oxygen metabolism. PLoS One, 2012, 7(1), e29572.
[http://dx.doi.org/10.1371/journal.pone.0029572] [PMID: 22238623]
[21]
Deng, Z.; Wang, Q.; Liu, Z.; Zhang, M.; Machado, A.C.D.; Chiu, T.P.; Feng, C.; Zhang, Q.; Yu, L.; Qi, L.; Zheng, J.; Wang, X.; Huo, X.; Qi, X.; Li, X.; Wu, W.; Rohs, R.; Li, Y.; Chen, Z. Mechanistic insights into metal ion activation and operator recognition by the ferric uptake regulator. Nat. Commun., 2015, 6(1), 7642.
[http://dx.doi.org/10.1038/ncomms8642] [PMID: 26134419]
[22]
Wang, Q.; Wang, M.; Wang, X.; Guan, G.; Li, Y.; Peng, Y.; Li, J. Iron response regulator protein IrrB in Magnetospirillum gryphiswaldense MSR-1 helps control the iron/oxygen balance, oxidative stress tolerance, and magnetosome formation. Appl. Environ. Microbiol., 2015, 81(23), 8044-8053.
[http://dx.doi.org/10.1128/AEM.02585-15] [PMID: 26386052]
[23]
Rong, C.; Huang, Y.; Zhang, W.; Jiang, W.; Li, Y.; Li, J. Ferrous iron transport protein B gene (feoB1) plays an accessory role in magnetosome formation in Magnetospirillum gryphiswaldense strain MSR-1. Res. Microbiol., 2008, 159(7-8), 530-536.
[http://dx.doi.org/10.1016/j.resmic.2008.06.005] [PMID: 18639631]
[24]
Rong, C.; Zhang, C.; Zhang, Y.; Qi, L.; Yang, J.; Guan, G.; Li, Y.; Li, J. FeoB2 Functions in magnetosome formation and oxidative stress protection in Magnetospirillum gryphiswaldense strain MSR-1. J. Bacteriol., 2012, 194(15), 3972-3976.
[http://dx.doi.org/10.1128/JB.00382-12] [PMID: 22636767]
[25]
Li, Y.; Katzmann, E.; Borg, S.; Schüler, D. The periplasmic nitrate reductase nap is required for anaerobic growth and involved in redox control of magnetite biomineralization in Magnetospirillum gryphiswaldense. J. Bacteriol., 2012, 194(18), 4847-4856.
[http://dx.doi.org/10.1128/JB.00903-12] [PMID: 22730130]
[26]
Li, Y.; Bali, S.; Borg, S.; Katzmann, E.; Ferguson, S.J.; Schüler, D. Cytochrome cd1 nitrite reductase NirS is involved in anaerobic magnetite biomineralization in Magnetospirillum gryphiswaldense and requires NirN for proper d1 heme assembly. J. Bacteriol., 2013, 195(18), 4297-4309.
[http://dx.doi.org/10.1128/JB.00686-13] [PMID: 23893106]
[27]
Rao, C.; Liao, D.; Pan, Y.; Zhong, Y.; Zhang, W.; Ouyang, Q.; Nezamzadeh-Ejhieh, A.; Liu, J. Novel formulations of metal-organic frameworks for controlled drug delivery. Expert Opin. Drug Deliv., 2022, 19(10), 1183-1202.
[http://dx.doi.org/10.1080/17425247.2022.2064450] [PMID: 35426756]
[28]
Chen, J.; Zhang, Z.; Ma, J.; Nezamzadeh-Ejhieh, A.; Lu, C.; Pan, Y.; Liu, J.; Bai, Z. Current status and prospects of MOFs in controlled delivery of Pt anticancer drugs. Dalton Trans., 2023, 52(19), 6226-6238.
[http://dx.doi.org/10.1039/D3DT00413A] [PMID: 37070759]
[29]
Zeng, Y.; Xu, G.; Kong, X.; Ye, G.; Guo, J.; Lu, C.; Nezamzadeh-Ejhieh, A.; Shahnawaz Khan, M.; Liu, J.; Peng, Y. Recent advances of the core–shell MOFs in tumour therapy. Int. J. Pharm., 2022, 627, 122228.
[http://dx.doi.org/10.1016/j.ijpharm.2022.122228] [PMID: 36162610]
[30]
Li, L.; Zou, J.; Han, Y.; Liao, Z.; Lu, P.; Nezamzadeh-Ejhieh, A.; Liu, J.; Peng, Y. Recent advances in Al(III)/In(III)-based MOFs for the detection of pollutants. New J. Chem., 2022, 46(41), 19577-19592.
[http://dx.doi.org/10.1039/D2NJ03419K]
[31]
Zhou, S.; Lu, L.; Liu, D.; Wang, J.; Sakiyama, H.; Muddassir, M.; Nezamzadeh-Ejhieh, A.; Liu, J. Series of highly stable Cd(II)-based MOFs as sensitive and selective sensors for detection of nitrofuran antibiotic. CrystEngComm, 2021, 23(46), 8043-8052.
[http://dx.doi.org/10.1039/D1CE01264A]
[32]
Chen, J.; Cheng, F.; Luo, D.; Huang, J.; Ouyang, J.; Nezamzadeh-Ejhieh, A.; Khan, M.S.; Liu, J.; Peng, Y. Recent advances in Ti-based MOFs in biomedical applications. Dalton Trans., 2022, 51(39), 14817-14832.
[http://dx.doi.org/10.1039/D2DT02470E] [PMID: 36124915]
[33]
Zhang, W.; Ye, G.; Liao, D.; Chen, X.; Lu, C.; Nezamzadeh-Ejhieh, A.; Khan, M.S.; Liu, J.; Pan, Y.; Dai, Z. Recent advances of silver-based coordination polymers on antibacterial applications. Molecules, 2022, 27(21), 7166.
[http://dx.doi.org/10.3390/molecules27217166] [PMID: 36363993]
[34]
Chen, W.; Liu, M.; Yang, H.; Nezamzadeh-Ejhieh, A.; Lu, C.; Pan, Y.; Liu, J.; Bai, Z. Recent advances of Fe(III)/Fe(II)-MPNs in biomedical applications. Pharmaceutics, 2023, 15(5), 1323.
[http://dx.doi.org/10.3390/pharmaceutics15051323] [PMID: 37242566]
[35]
Liao, D.; Huang, J.; Jiang, C.; Zhou, L.; Zheng, M.; Nezamzadeh-Ejhieh, A.; Qi, N.; Lu, C.; Liu, J. A novel platform of mof for sonodynamic therapy advanced therapies. Pharmaceutics, 2023, 15(8), 2071.
[http://dx.doi.org/10.3390/pharmaceutics15082071] [PMID: 37631285]
[36]
Guo, X.; Zhou, L.; Liu, X.; Tan, G.; Yuan, F.; Nezamzadeh-Ejhieh, A.; Qi, N.; Liu, J.; Peng, Y. Fluorescence detection platform of metal-organic frameworks for biomarkers. Colloids Surf. B Biointerfaces, 2023, 229, 113455.
[http://dx.doi.org/10.1016/j.colsurfb.2023.113455] [PMID: 37473653]
[37]
Nezamzadeh-Ejhieh, A.; Tavakoli-Ghinani, S. Effect of a nano-sized natural clinoptilolite modified by the hexadecyltrimethyl ammonium surfactant on cephalexin drug delivery. C. R. Chim., 2014, 17(1), 49-61.
[http://dx.doi.org/10.1016/j.crci.2013.07.009]
[38]
Najafian, N.; Aarabi, A.; Nezamzadeh-Ejhieh, A. Evaluation of physicomechanical properties of gluten-based film incorporated with Persian gum and Guar gum. Int. J. Biol. Macromol., 2022, 233((Part A)), 1257-1267.
[http://dx.doi.org/10.1016/j.ijbiomac.2022.11.056]
[39]
Revathy, T.; Jayasri, M.A.; Suthindhiran, K. Toxicity assessment of magnetosomes in different models. 3 Biotech, 2017, 7(2), 126.
[http://dx.doi.org/10.1007/s13205-017-0780-z] [PMID: 28573396]
[40]
Xiang, Z.; Yang, X.; Xu, J.; Lai, W.; Wang, Z.; Hu, Z.; Tian, J.; Geng, L.; Fang, Q. Tumor detection using magnetosome nanoparticles functionalized with a newly screened EGFR/HER2 targeting peptide. Biomaterials, 2017, 115, 53-64.
[http://dx.doi.org/10.1016/j.biomaterials.2016.11.022] [PMID: 27888699]
[41]
Zhang, Y.; Ni, Q.; Xu, C.; Wan, B.; Geng, Y.; Zheng, G.; Yang, Z.; Tao, J.; Zhao, Y.; Wen, J.; Zhang, J.; Wang, S.; Tang, Y.; Li, Y.; Zhang, Q.; Liu, L.; Teng, Z.; Lu, G. Smart bacterial magnetic nanoparticles for tumor-targeting magnetic resonance imaging of HER2-positive breast cancers. ACS Appl. Mater. Interfaces, 2019, 11(4), 3654-3665.
[http://dx.doi.org/10.1021/acsami.8b15838] [PMID: 30495920]
[42]
Xu, J.; Hu, J.; Liu, L.; Li, L.; Wang, X.; Zhang, H.; Jiang, W.; Tian, J.; Li, Y.; Li, J. Surface expression of protein A on magnetosomes and capture of pathogenic bacteria by magnetosome/antibody complexes. Front. Microbiol., 2014, 5, 136.
[http://dx.doi.org/10.3389/fmicb.2014.00136] [PMID: 24765089]
[43]
Li, A.; Zhang, H.; Zhang, X.; Wang, Q.; Tian, J.; Li, Y.; Li, J. Rapid separation and immunoassay for low levels of Salmonella in foods using magnetosome-antibody complex and real-time fluorescence quantitative PCR. J. Sep. Sci., 2010, 33(21), 3437-3443.
[http://dx.doi.org/10.1002/jssc.201000441] [PMID: 20886524]
[44]
Xu, J.; Liu, L.; He, J.; Ma, S.; Li, S.; Wang, Z.; Xu, T.; Jiang, W.; Wen, Y.; Li, Y.; Tian, J.; Li, F. Engineered magnetosomes fused to functional molecule (protein A) provide a highly effective alternative to commercial immunomagnetic beads. J. Nanobiotechnol., 2019, 17(1), 37.
[http://dx.doi.org/10.1186/s12951-019-0469-z] [PMID: 30841927]
[45]
Geng, Y.; Wang, J.; Wang, X.; Liu, J.; Zhang, Y.; Niu, W.; Basit, A.; Liu, W.; Jiang, W. Growth-inhibitory effects of anthracycline-loaded bacterial magnetosomes against hepatic cancer in vitro and in vivo. Nanomedicine, 2019, 14(13), 1663-1680.
[http://dx.doi.org/10.2217/nnm-2018-0296] [PMID: 31167626]
[46]
Ma, S.; Gu, C.; Xu, J.; He, J.; Li, S.; Zheng, H.; Pang, B.; Wen, Y.; Fang, Q.; Liu, W.; Tian, J. Strategy for avoiding protein corona inhibition of targeted drug delivery by linking recombinant affibody scaffold to magnetosomes. Int. J. Nanomedicine, 2022, 17, 665-680.
[http://dx.doi.org/10.2147/IJN.S338349] [PMID: 35185331]
[47]
Kumar, P.; Wu, H.; McBride, J.L.; Jung, K.E.; Hee Kim, M.; Davidson, B.L.; Kyung Lee, S.; Shankar, P.; Manjunath, N. Transvascular delivery of small interfering RNA to the central nervous system. Nature, 2007, 448(7149), 39-43.
[http://dx.doi.org/10.1038/nature05901] [PMID: 17572664]
[48]
Pinheiro, R.G.R.; Granja, A.; Loureiro, J.A.; Pereira, M.C.; Pinheiro, M.; Neves, A.R.; Reis, S. RVG29-functionalized lipid nanoparticles for quercetin brain delivery and Alzheimer’s Disease. Pharm. Res., 2020, 37(7), 139.
[http://dx.doi.org/10.1007/s11095-020-02865-1] [PMID: 32661727]
[49]
Tanaka, T.; Matsunaga, T. Fully automated chemiluminescence immunoassay of insulin using antibody-protein A-bacterial magnetic particle complexes. Anal. Chem., 2000, 72(15), 3518-3522.
[http://dx.doi.org/10.1021/ac9912505] [PMID: 10952537]
[50]
Juillerat-Jeanneret, L.; Schmitt, F. Chemical modification of therapeutic drugs or drug vector systems to achieve targeted therapy: Looking for the grail. Med. Res. Rev., 2007, 27(4), 574-590.
[http://dx.doi.org/10.1002/med.20086] [PMID: 17022028]
[51]
Zhang, Y.D. Nanopharmacology; Chemical Industry Press, 2006.
[52]
Sun, J.; Tang, T.; Duan, J.; Xu, P.; Wang, Z.; Zhang, Y.; Wu, L.; Li, Y. Biocompatibility of bacterial magnetosomes: Acute toxicity, immunotoxicity and cytotoxicity. Nanotoxicology, 2010, 4(3), 271-283.
[http://dx.doi.org/10.3109/17435391003690531] [PMID: 20795909]
[53]
Xiang, L.; Wei, J.; Jianbo, S.; Guili, W.; Feng, G.; Ying, L. Purified and sterilized magnetosomes from Magnetospirillum gryphiswaldense MSR-1 were not toxic to mouse fibroblasts in vitro. Lett. Appl. Microbiol., 2007, 45(1), 75-81.
[http://dx.doi.org/10.1111/j.1472-765X.2007.02143.x] [PMID: 17594464]
[54]
Wiatrak, B.; Kubis-Kubiak, A.; Piwowar, A.; Barg, E. PC12 cell line: Cell types, coating of culture vessels, differentiation and other culture conditions. Cells, 2020, 9(4), 958.
[http://dx.doi.org/10.3390/cells9040958] [PMID: 32295099]

© 2025 Bentham Science Publishers | Privacy Policy