An RGD-Conjugated Prodrug Nanoparticle with Blood-Brain-Barrier Penetrability for Neuroprotection Against Cerebral Ischemia-Reperfusion Injury

Overview

Journal Antioxidants (Basel)

Date 2024 Nov 27

PMID 39594481

Authors

Ayijiang Taledaohan

Maer Maer Tuohan

Renbo Jia

Kai Wang

Liujia Chan

Yijiang Jia

Feng Wang

Yuji Wang

Affiliations

Soon will be listed here.

Abstract

Cerebral ischemia-reperfusion injury significantly contributes to global morbidity and mortality. Loganin is a natural product with various neuroprotective effects; however, it lacks targeted specificity for particular cells or receptors, which may result in reduced therapeutic efficacy and an increased risk of side effects. To address the limitations of loganin, we developed LA-1, a novel compound incorporating an Arg-Gly-Asp (RGD) peptide to target integrin receptor αvβ3, enhancing brain-targeting efficacy. LA-1 exhibited optimal nanoscale properties, significantly improved cell viability, reduced ROS production, and enhanced survival rates in vitro. In vivo, LA-1 decreased infarct sizes, improved neurological function, and reduced oxidative stress and neuroinflammation. Proteomic analysis showed LA-1 modulates PI3K/Akt and Nrf2/HO-1 pathways, providing targeted neuroprotection. These findings suggest LA-1's potential for clinical applications in treating cerebral ischemia-reperfusion injury.

References

Bereczki Jr D, Balla J, Bereczki D . Heme Oxygenase-1: Clinical Relevance in Ischemic Stroke. Curr Pharm Des. 2018; 24(20):2229-2235. PMC: 6302555. DOI: 10.2174/1381612824666180717101104. View

Abumiya T, Lucero J, Heo J, Tagaya M, Koziol J, Copeland B . Activated microvessels express vascular endothelial growth factor and integrin alpha(v)beta3 during focal cerebral ischemia. J Cereb Blood Flow Metab. 1999; 19(9):1038-50. DOI: 10.1097/00004647-199909000-00012. View

Hacke W, Donnan G, Fieschi C, Kaste M, von Kummer R, Broderick J . Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet. 2004; 363(9411):768-74. DOI: 10.1016/S0140-6736(04)15692-4. View

Xu H, Yin R, Chen L, Siraj S, Huang X, Wang M . An RGD-modified endostatin-derived synthetic peptide shows antitumor activity in vivo. Bioconjug Chem. 2008; 19(10):1980-6. DOI: 10.1021/bc800132p. View

Xie K, Cai Y, Yang P, Du F, Wu K . Upregulating microRNA-874-3p inhibits CXCL12 expression to promote angiogenesis and suppress inflammatory response in ischemic stroke. Am J Physiol Cell Physiol. 2020; 319(3):C579-C588. DOI: 10.1152/ajpcell.00001.2020. View

Wiendl H, Elger C, Forstl H, Hartung H, Oertel W, Reichmann H . Gaps Between Aims and Achievements in Therapeutic Modification of Neuronal Damage ("Neuroprotection"). Neurotherapeutics. 2015; 12(2):449-54. PMC: 4404462. DOI: 10.1007/s13311-015-0348-8. View

Xia B, Ding J, Li Q, Zheng K, Wu J, Huang C . Loganin protects against myocardial ischemia-reperfusion injury by modulating oxidative stress and cellular apoptosis via activation of JAK2/STAT3 signaling. Int J Cardiol. 2023; 395:131426. DOI: 10.1016/j.ijcard.2023.131426. View

Zhang T, Li C, Jia J, Chi J, Zhou D, Li J . Combination Therapy with LXW7 and Ceria Nanoparticles Protects against Acute Cerebral Ischemia/Reperfusion Injury in Rats. Curr Med Sci. 2018; 38(1):144-152. DOI: 10.1007/s11596-018-1858-5. View

Liang Y, Li S, Wang X, He B, He B, Dai W . A Nanosystem of Amphiphilic Oligopeptide-Drug Conjugate Actualizing Both αvβ3 Targeting and Reduction-Triggered Release for Maytansinoid. Theranostics. 2017; 7(13):3306-3318. PMC: 5595133. DOI: 10.7150/thno.20242. View

10.

Zhou Y, Luo D, Shi J, Yang X, Xu W, Gao W . Loganin alleviated cognitive impairment in 3×Tg-AD mice through promoting mitophagy mediated by optineurin. J Ethnopharmacol. 2023; 312:116455. DOI: 10.1016/j.jep.2023.116455. View

11.

Wen Z, Hou W, Wu W, Zhao Y, Dong X, Bai X . 6'--Galloylpaeoniflorin Attenuates Cerebral Ischemia Reperfusion-Induced Neuroinflammation and Oxidative Stress via PI3K/Akt/Nrf2 Activation. Oxid Med Cell Longev. 2018; 2018:8678267. PMC: 5889897. DOI: 10.1155/2018/8678267. View

12.

Cheng Y, Park J, Manzanero S, Choi Y, Baik S, Okun E . Evidence that collaboration between HIF-1α and Notch-1 promotes neuronal cell death in ischemic stroke. Neurobiol Dis. 2013; 62:286-95. PMC: 3877697. DOI: 10.1016/j.nbd.2013.10.009. View

13.

Lee S, Kim Y, Lim S, Zhu W, Ko H, Shin S . Solution structure and cell selectivity of piscidin 1 and its analogues. Biochemistry. 2007; 46(12):3653-63. DOI: 10.1021/bi062233u. View

14.

Yagi K, Kitazato K, Uno M, Tada Y, Kinouchi T, Shimada K . Edaravone, a free radical scavenger, inhibits MMP-9-related brain hemorrhage in rats treated with tissue plasminogen activator. Stroke. 2008; 40(2):626-31. DOI: 10.1161/STROKEAHA.108.520262. View

15.

Pardridge W . Blood-brain barrier drug targeting: the future of brain drug development. Mol Interv. 2004; 3(2):90-105, 51. DOI: 10.1124/mi.3.2.90. View

16.

Dijkgraaf I, Kruijtzer J, Frielink C, Corstens F, Oyen W, Liskamp R . Alpha v beta 3 integrin-targeting of intraperitoneally growing tumors with a radiolabeled RGD peptide. Int J Cancer. 2006; 120(3):605-10. DOI: 10.1002/ijc.22297. View

17.

Wu M, Wu P, Liu M, Xie H, Jiang Y, Wei X . Iridoids from Gentiana loureirii. Phytochemistry. 2009; 70(6):746-50. DOI: 10.1016/j.phytochem.2009.03.018. View

18.

Jin S, Wang Y, Zhu H, Wang Y, Zhao S, Zhao M . Nanosized aspirin-Arg-Gly-Asp-Val: delivery of aspirin to thrombus by the target carrier Arg-Gly-Asp-Val tetrapeptide. ACS Nano. 2013; 7(9):7664-73. DOI: 10.1021/nn402171v. View

19.

Danhier F, Pourcelle V, Marchand-Brynaert J, Jerome C, Feron O, Preat V . Targeting of tumor endothelium by RGD-grafted PLGA-nanoparticles. Methods Enzymol. 2012; 508:157-75. DOI: 10.1016/B978-0-12-391860-4.00008-2. View

20.

Yin R, Zheng H, Xi T, Xu H . Effect of RGD-4C position is more important than disulfide bonds on antiangiogenic activity of RGD-4C modified endostatin derived synthetic polypeptide. Bioconjug Chem. 2010; 21(7):1142-7. DOI: 10.1021/bc900292y. View