Elastin-like Polypeptide Delivery of Anti-inflammatory Peptides to the Brain Following Ischemic Stroke

Overview

Journal bioRxiv

Date 2023 Mar 30

PMID 36993686

Authors

John Aaron Howell

Nicholas Gaouette

Mariper Lopez

Stephen P Burke

Eddie Perkins

Gene L Bidwell 3rd

Affiliations

Soon will be listed here.

Abstract

Inflammatory processes are activated following ischemic strokes and lead to increased tissue damage for weeks following the ischemic insult, but there are no approved therapies that target this inflammation-induced secondary injury. Here, we report that SynB1-ELP-p50i, a novel protein inhibitor of the nuclear factor kappa B (NF-κB) inflammatory cascade bound to drug carrier elastin-like polypeptide (ELP), is able to enter both neurons and microglia, cross the blood-brain barrier, localize exclusively in the ischemic core and penumbra in Wistar-Kyoto and spontaneously hypertensive rats (SHRs), and reduce infarct volume in male SHRs. Additionally, in male SHRs, SynB1-ELP-p50i treatment improves survival for 14 days following stroke with no effects of toxicity or peripheral organ dysfunction. These results show high potential for ELP-delivered biologics for therapy of ischemic stroke and other central nervous system disorders and further support targeting inflammation in ischemic stroke.

References

McGowan J, Shao Q, Vig P, Bidwell 3rd G . Intranasal administration of elastin-like polypeptide for therapeutic delivery to the central nervous system. Drug Des Devel Ther. 2016; 10:2803-2813. PMC: 5019317. DOI: 10.2147/DDDT.S106216. View

Liang P, Wang G, Liu X, Wang Z, Wang J, Gao W . Spatiotemporal combination of thermosensitive polypeptide fused interferon and temozolomide for post-surgical glioblastoma immunochemotherapy. Biomaterials. 2020; 264:120447. DOI: 10.1016/j.biomaterials.2020.120447. View

Eddy A, Howell J, Chapman H, Taylor E, Mahdi F, George E . Biopolymer-Delivered, Maternally Sequestered NF-κB (Nuclear Factor-κB) Inhibitory Peptide for Treatment of Preeclampsia. Hypertension. 2019; 75(1):193-201. PMC: 7008946. DOI: 10.1161/HYPERTENSIONAHA.119.13368. View

Khoshnam S, Winlow W, Farzaneh M, Farbood Y, Moghaddam H . Pathogenic mechanisms following ischemic stroke. Neurol Sci. 2017; 38(7):1167-1186. DOI: 10.1007/s10072-017-2938-1. View

Bidwell 3rd G, Perkins E, Raucher D . A thermally targeted c-Myc inhibitory polypeptide inhibits breast tumor growth. Cancer Lett. 2012; 319(2):136-143. PMC: 3536021. DOI: 10.1016/j.canlet.2011.12.042. View

Bidwell 3rd G, Mahdi F, Shao Q, Logue O, Waller J, Reese C . A kidney-selective biopolymer for targeted drug delivery. Am J Physiol Renal Physiol. 2016; 312(1):F54-F64. PMC: 5283886. DOI: 10.1152/ajprenal.00143.2016. View

Borlongan C, Glover L, Sanberg P, Hess D . Permeating the blood brain barrier and abrogating the inflammation in stroke: implications for stroke therapy. Curr Pharm Des. 2012; 18(25):3670-6. PMC: 3411920. DOI: 10.2174/138161212802002841. View

Ridder D, Schwaninger M . NF-kappaB signaling in cerebral ischemia. Neuroscience. 2008; 158(3):995-1006. DOI: 10.1016/j.neuroscience.2008.07.007. View

Jayaraj R, Azimullah S, Beiram R, Jalal F, Rosenberg G . Neuroinflammation: friend and foe for ischemic stroke. J Neuroinflammation. 2019; 16(1):142. PMC: 6617684. DOI: 10.1186/s12974-019-1516-2. View

10.

Herson P, Traystman R . Animal models of stroke: translational potential at present and in 2050. Future Neurol. 2014; 9(5):541-551. PMC: 4266275. DOI: 10.2217/fnl.14.44. View

11.

Kohler E, Prentice D, Bates T, Hankey G, Claxton A, van Heerden J . Intravenous minocycline in acute stroke: a randomized, controlled pilot study and meta-analysis. Stroke. 2013; 44(9):2493-9. DOI: 10.1161/STROKEAHA.113.000780. View

12.

Li Z, Cipolla M . Mechanisms of Flow-Mediated Dilation of Pial Collaterals and the Effect of Hypertension. Hypertension. 2021; 79(2):457-467. PMC: 8755599. DOI: 10.1161/HYPERTENSIONAHA.121.18602. View

13.

Elkins J, Veltkamp R, Montaner J, Johnston S, Singhal A, Becker K . Safety and efficacy of natalizumab in patients with acute ischaemic stroke (ACTION): a randomised, placebo-controlled, double-blind phase 2 trial. Lancet Neurol. 2017; 16(3):217-226. DOI: 10.1016/S1474-4422(16)30357-X. View

14.

Longa E, Weinstein P, Carlson S, Cummins R . Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke. 1989; 20(1):84-91. DOI: 10.1161/01.str.20.1.84. View

15.

Lin Y, Yao S, Veach R, Torgerson T, Hawiger J . Inhibition of nuclear translocation of transcription factor NF-kappa B by a synthetic peptide containing a cell membrane-permeable motif and nuclear localization sequence. J Biol Chem. 1995; 270(24):14255-8. DOI: 10.1074/jbc.270.24.14255. View

16.

Bidwell 3rd G, Raucher D . Application of thermally responsive polypeptides directed against c-Myc transcriptional function for cancer therapy. Mol Cancer Ther. 2005; 4(7):1076-85. DOI: 10.1158/1535-7163.MCT-04-0253. View

17.

Seifert H, Hall A, Chapman C, Collier L, Willing A, Pennypacker K . A transient decrease in spleen size following stroke corresponds to splenocyte release into systemic circulation. J Neuroimmune Pharmacol. 2012; 7(4):1017-24. PMC: 3518577. DOI: 10.1007/s11481-012-9406-8. View

18.

Bidwell 3rd G . Novel Protein Therapeutics Created Using the Elastin-Like Polypeptide Platform. Physiology (Bethesda). 2021; 36(6):367-381. PMC: 8560375. DOI: 10.1152/physiol.00026.2021. View

19.

Nian K, Harding I, Herman I, Ebong E . Blood-Brain Barrier Damage in Ischemic Stroke and Its Regulation by Endothelial Mechanotransduction. Front Physiol. 2021; 11:605398. PMC: 7793645. DOI: 10.3389/fphys.2020.605398. View

20.

Bidwell 3rd G, Raucher D . Therapeutic peptides for cancer therapy. Part I - peptide inhibitors of signal transduction cascades. Expert Opin Drug Deliv. 2009; 6(10):1033-47. DOI: 10.1517/17425240903143745. View