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Identification of a peptide that crosses the blood-cerebrospinal fluid barrier by phage display technology

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Abstract

Treatments of brain diseases are heavily limited by the existence of the blood–brain barrier (BBB), which precludes efficient drug delivery to the brain. Compared with the BBB, drugs may have a better likelihood of reaching the brain via the cerebrospinal fluid (CSF) because of the lack of a barrier between the CSF and the brain. In this study, phage display technology was effectively applied to screen novel peptides as targeting motifs to transport drugs across the blood-cerebrospinal fluid barrier (BCSFB). We applied a phage seven-mer cyclic peptide library (Ph.D.-C7C™) intravenously to rats and later recovered phages from the CSF. After several rounds of screening, the candidate phages that could cross the BCSFB were enriched. Several bacteriophage clones from the final round were randomly selected and sequenced. A peptide sequence denoted as PMK, which was demonstrated to be able to cross the BCSFB via in vivo optical imaging analysis, could be used in the future for the construction of targeted drug delivery systems.

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References

  • Alexander JJ (2018) Blood-brain barrier (BBB) and the complement landscape. Mol Immunol 102:26–31

    Article  CAS  Google Scholar 

  • Backen A, Lamarca A, Hubner RA et al (2021) HPB cancers in older patients|inclusion of older/senior patients in clinical trials. Eur J Surg Oncol 47(3 Pt A):597–602

    Article  Google Scholar 

  • Bakhshinejad B, Zade HM, Shekarabi HS et al (2016) Phage display biopanning and isolation of target-unrelated peptides: in search of nonspecific binders hidden in a combinatorial library. Amino Acids 48:2699–2716

    Article  CAS  Google Scholar 

  • Gao H, Yang Z, Zhang S et al (2018) Internalization and subcellular fate of aptamer and peptide dual-functioned nanoparticles. J Drug Target 22:450–459

    Article  CAS  Google Scholar 

  • Haley MJ, Lawrence CB (2017) The blood-brain barrier after stroke: structural studies and the role of transcytotic vesicles. J Cereb Blood Flow Metab 37:456–470

    Article  Google Scholar 

  • Householder KT, Dharmaraj S, Sandberg DI et al (2019) Fate of nanoparticles in the central nervous system after intrathecal injection in healthy mice. Sci Rep 9:12587

    Article  CAS  Google Scholar 

  • Keaney J, Campbell M (2015) The dynamic blood-brain barrier. FEBS J 282:4067–4079

    Article  CAS  Google Scholar 

  • Kim H, Na DL, Lee NK et al (2020) Intrathecal injection in a rat model: a potential route to deliver human Wharton’s jelly-derived mesenchymal stem cells into the brain. Int J Mol 21:1272–1284

    Article  CAS  Google Scholar 

  • Koivunen E, Gay DA, Ruoslahti (1993) Selection of peptides binding to the alpha 5 beta 1 integrin from phage display library. J Biol Chem 268(27):20205–20210

  • Li J, Feng L, Jiang X (2015) In vivo phage display screen for peptide sequences that cross the blood-cerebrospinal-fluid barrier. Amino Acids 47:401–405

    Article  CAS  Google Scholar 

  • Luo Z, He Y, Ma G et al (2020) Years of life lost due to premature death and their trends in people with malignant neoplasm of female genital organs in Shanghai, China during 1995–2018: a population-based study. BMC Public Health 20(1):1489–1498

    Article  Google Scholar 

  • Majerova P, Hanes J, Olesova D et al (2020) Novel blood–brain barrier ShuttlePeptides discovered through the phage display method. Molecules 25:874–890

    Article  CAS  Google Scholar 

  • Méndez-Gómez HR, Galera-Prat A, Meyers C et al (2015) Transcytosis in the blood-cerebrospinal fluid barrier of the mouse brain with an engineered receptor/ligand system. Mol Ther Methods Clin Dev 2:15037

    Article  CAS  Google Scholar 

  • Miller L, Michel J, Vogt G et al (2014) Identification and characterization of a phage display-derived peptide for orthopoxvirus detection. Anal Bioanal Chem 406:7611–7621

    Article  CAS  Google Scholar 

  • Reynolds JL, Mahato RI (2017) Nanomedicines for the treatment of CNS diseases. J Neuroimmune Pharmacol 12:1–5

    Article  Google Scholar 

  • Scheltens P, Blennow K, Breteler MM et al (2016) Alzheimer’s disease. Lancet 388:505–517

    Article  CAS  Google Scholar 

  • Smith GP (1985) Filamentous fusion phage: novel expression vectors that display cloned antigens on the virion surface. Science 228:1315–1317

    Article  CAS  Google Scholar 

  • Sun C, Xu B, Lu Z et al (2009) Analysis of curative effect of intracranial infections after craniotomy treated with intrathecal vancomycin. J Jilin Univ 35:735–737

    Google Scholar 

  • Tang B, Li Z, Huang D et al (2013) Screening of a specific peptide binding to VPAC1 receptor from a phage display peptide library. PLoS ONE 8:e54264

    Article  CAS  Google Scholar 

  • Tietz S, Engelhardt B (2015) Brain barriers: crosstalk between complex tight junctions and adherens junctions. J Cell Biol 209:493–506

    Article  CAS  Google Scholar 

  • Van Rooy I, Hennink WE, Storm G, Mastrobattista E et al (2012) Attaching the phage display-selected GLA peptide to liposomes: factors influencing target binding. Eur J Pharm Sci 45:330–335

    Article  CAS  Google Scholar 

  • Verma A, Hesterman J, Chazen J et al (2020) Intrathecal 99mTc-DTPA imaging of molecular passage from lumbar cerebrospinal fluid to brain and periphery in humans. Alzheimer’s Dement 12:e12030

    Google Scholar 

  • Wang P, Zheng X, Guo Q et al (2018) Systemic delivery of BACE1 siRNA through neuron-targeted nanocomplexes for treatment of Alzheimer’s disease. J Control Release 279:220–233

    Article  CAS  Google Scholar 

  • Wright P, Nogueira G, Levin E (1971) Role of the pia mater in the transfer of substances in and out of the cerebrospinal fluid. Exp Brain Res 113:294–305

    PubMed  CAS  Google Scholar 

  • Wu LP, Ahmadvand D, Su J et al (2019) Crossing the blood–brain-barrier with nanoligand drug carriers self-assembled from a phage display peptide. Nat Commun 10:4635–4651

    Article  CAS  Google Scholar 

  • Yang S, Emelyanov A, You MS et al (2020) Camel regulates development of the brain ventricular system. Cell Tissue Res 383:835–852

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Natural Science Foundation of China (Grant No. 81641130 and 81760636) and the Applied Basic Research Programs of Yunnan Province (Grant No. 2017FB140).

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Authors and Affiliations

  1. College of Pharmacy (School of Pharmacy), Dali University, Xueren Rd, Dali, 671000, People’s Republic of China

    Xi Yang, Yongjie Li, Zhanzhan Zhu, Xufang Huang, Tianlong Wang, Jinjin Yuan & Jingwei Li

  2. Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, Dali University, Dali, 671000, People’s Republic of China

    Jingwei Li

  3. National-Local Joint Engineering Research Center of Entomoceutics, Dali, 671000, People’s Republic of China

    Jingwei Li

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  1. Xi Yang
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  2. Yongjie Li
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  3. Zhanzhan Zhu
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  4. Xufang Huang
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  5. Tianlong Wang
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  6. Jinjin Yuan
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  7. Jingwei Li
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Correspondence to Jingwei Li.

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This study was approved by the Institutional Animal Care and Use Committee of Dali University.

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This study does not contain any studies with human participants performed by any of the authors.

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Handling editor: E. I. Closs.

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Yang, X., Li, Y., Zhu, Z. et al. Identification of a peptide that crosses the blood-cerebrospinal fluid barrier by phage display technology. Amino Acids 53, 1181–1186 (2021). https://doi.org/10.1007/s00726-021-03016-5

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  • DOI: https://doi.org/10.1007/s00726-021-03016-5

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