Skip to main content

Advertisement

SpringerLink
Log in

Targeted Intravenous Nanoparticle Delivery: Role of Flow and Endothelial Glycocalyx Integrity

  • Biomaterials - Engineering Cell Behavior
  • Published:
Annals of Biomedical Engineering Aims and scope Submit manuscript

Abstract

Therapies for atherosclerotic cardiovascular disease should target early disease stages and specific vascular sites where disease occurs. Endothelial glycocalyx (GCX) degradation compromises endothelial barrier function and increases vascular permeability. This initiates pro-atherosclerotic lipids and inflammatory cells to penetrate vessel walls, and at the same time this can be leveraged for targeted drug delivery. In prior cell culture studies, GCX degradation significantly increased endothelial cell uptake of nanoparticle vehicles that are designed for drug delivery, compared to the effects of intact GCX. The present study assessed if the cell culture findings translate to selective nanoparticle uptake in animal vessels. In mice, the left carotid artery (LCA) was partially ligated to disturb blood flow, which induces GCX degradation, endothelial dysfunction, and atherosclerosis. After ligation, the LCA vessel wall exhibited a loss of continuity of the GCX layer on the intima. 10-nm gold nanospheres (GNS) coated with polyethylene glycol (PEG) were delivered intravenously. GCX degradation in the ligated LCA correlated to increased GNS infiltration of the ligated LCA wall. This suggests that GCX dysfunction, which coincides with atherosclerosis, can indeed be targeted for enhanced drug delivery, offering a new approach in cardiovascular disease therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8

Similar content being viewed by others

Abbreviations

ANOVA:

Analysis of variance

BSA:

Bovine serum albumin

DAPI:

4′,6-diamidino-2-phenylindole

DLS:

Dynamic light scattering

ECA:

External carotid artery

EGM-2:

Endothelial cell growth medium-2

GCX:

Glycocalyx

GNS:

Gold nanospheres

HepIII:

Heparinase III

HS:

Heparan sulfate

HUVEC:

Human umbilical vein endothelial cells

IACUC:

Institutional Animal Care and Use Committee

ICA:

Internal carotid artery

LCA:

Left carotid artery

NHS:

N-Hydroxysuccinimide

OA:

Occipital artery

OCT:

Optimal cutting temperatire

PBS:

Phosphate buffered saline

PEG:

Polyethylene glycol

RCA:

Right carotid artery

SEM:

Standard error of the mean

SH–PEG–COOH:

PEG with a thiol (SH) group and a carboxyl (COOH) group

SH–PEG–NH2 :

PEG with a thiol (SH) group and an amide (NH2) group

SH–PEG–OCH3 :

PEG with a thiol (SH) group and a methoxy (OCH3) group

TEM:

Transmission electron microscopy

THPC:

Tetrakis-(hydroxymethyl)-phosphonium chloride

TSA:

Tyramide signal amplification

WGA:

Wheat germ agglutinin

References

  1. Alexis, F., E. Pridgen, L. K. Molnar, and O. C. Farokhzad. Factors affecting the clearance and biodistribution of polymeric nanoparticles. Mol. Pharm. 5:505–515, 2008.

    Article  CAS  Google Scholar 

  2. Becker, B. F., M. Jacob, S. Leipert, A. H. Salmon, and D. Chappell. Degradation of the endothelial glycocalyx in clinical settings: searching for the sheddases. Br. J. Clin. Pharmacol. 80:389–402, 2015.

    Article  CAS  Google Scholar 

  3. Bennett, K. M., K. C. Kent, J. Schumacher, C. C. Greenberg, and J. E. Scarborough. Targeting the most important complications in vascular surgery. J. Vasc. Surg. 65:793–803, 2017.

    Article  Google Scholar 

  4. Bhadra, D., S. Bhadra, P. Jain, and N. K. Jain. Pegnology: a review of PEG-ylated systems. Pharmazie 57:5–29, 2002.

    CAS  PubMed  Google Scholar 

  5. Cheng, M. J., N. N. Bal, P. Prabakaran, R. Kumar, T. J. Webster, S. Sridhar, and E. E. Ebong. Ultrasmall gold nanorods: synthesis and glycocalyx-related permeability in human endothelial cells. Int. J. Nanomed. 319–333:2019, 2019.

    Google Scholar 

  6. Cheng, M. J., R. Kumar, S. Sridhar, T. J. Webster, and E. E. Ebong. Endothelial glycocalyx conditions influence nanoparticle uptake for passive targeting. Int. J. Nanomed. 11:3305–3315, 2016.

    Article  CAS  Google Scholar 

  7. Cheng, M. J., P. Prabakaran, R. Kumar, S. Sridhar, and E. E. Ebong. Synthesis of functionalized 10-nm polymer-coated gold particles for endothelium targeting and drug delivery. J. Vis. Exp. 313:56760, 2018.

    Google Scholar 

  8. DeBakey, M. E. Surgical treatment of atherosclerotic heart disease. Am. J. Cardiol. 63:9H–11H, 1989.

    Article  CAS  Google Scholar 

  9. Duwayri, Y., J. Goss, W. Knechtle, R. K. Veeraswamy, S. Arya, R. R. Rajani, L. P. Brewster, T. F. Dodson, and J. F. Sweeney. The readmission event after vascular surgery: causes and costs. Ann. Vasc. Surg. 36:7–12, 2016.

    Article  Google Scholar 

  10. Ebong, E. E., S. Kim, and N. DePaola. Flow regulates intercellular communication in HAEC by assembling functional Cx40 and Cx37 gap junctional channels. Am. J. Physiol. Heart Circ. Physiol. 290:H2015–2023, 2006.

    Article  CAS  Google Scholar 

  11. Ebong, E. E., F. P. Macaluso, D. C. Spray, and J. M. Tarbell. Imaging the endothelial glycocalyx in vitro by rapid freezing/freeze substitution transmission electron microscopy. Arterioscler. Thromb. Vasc. Biol. 31:1908–1915, 2011.

    Article  CAS  Google Scholar 

  12. Galyfos, G., K. Filis, F. Sigala, and G. Geropapas. Beta-blockers in vascular surgery patients: is the debate still going on? J. Anesth. 30:1031–1036, 2016.

    Article  Google Scholar 

  13. Gomez-Garcia, M. J., A. L. Doiron, R. R. M. Steele, H. I. Labouta, B. Vafadar, R. D. Shepherd, I. D. Gates, D. T. Cramb, S. J. Childs, and K. D. Rinker. Nanoparticle localization in blood vessels: dependence on fluid shear stress, flow disturbances, and flow-induced changes in endothelial physiology. Nanoscale 10:15249–15261, 2018.

    Article  CAS  Google Scholar 

  14. Harding, I. C., R. Mitra, S. A. Mensah, A. Nersesyan, N. N. Bal, and E. E. Ebong. Endothelial barrier reinforcement relies on flow-regulated glycocalyx, a potential therapeutic target. Biorheology 56:131–149, 2019.

    Article  CAS  Google Scholar 

  15. Kumar, S., D.-W. Kang, A. Rezvan, and H. Jo. Accelerated atherosclerosis development in C57Bl6 mice by overexpressing AAV-mediated PCSK9 and partial carotid ligation. Lab. Invest. 97:935, 2017.

    Article  CAS  Google Scholar 

  16. Kumase, F., Y. Morizane, S. Mohri, I. Takasu, A. Ohtsuka, and H. Ohtsuki. Glycocalyx degradation in retinal and choroidal capillary endothelium in rats with diabetes and hypertension. Acta Med. Okayama 64:277–283, 2010.

    PubMed  Google Scholar 

  17. Lewis, J. C., R. G. Taylor, N. D. Jones, R. W. St Clair, and J. F. Cornhill. Endothelial surface characteristics in pigeon coronary artery atherosclerosis. I. Cellular alterations during the initial stages of dietary cholesterol challenge. Lab. Invest. 46:123–138, 1982.

    CAS  PubMed  Google Scholar 

  18. Mathers, C. D., T. Boerma, and D. Ma Fat. Global and regional causes of death. Br. Med. Bull. 92:7–32, 2009.

    Article  Google Scholar 

  19. Mensah, S. A., I. C. Harding, M. Zhang, M. P. Jaeggli, V. P. Torchilin, M. J. Niedre, and E. E. Ebong. Metastatic cancer cell attachment to endothelium is promoted by endothelial glycocalyx sialic acid degradation. AIChE J. 65:e16634, 2019.

    Article  Google Scholar 

  20. Mitra, R., G. L. O’Neil, I. C. Harding, M. J. Cheng, S. A. Mensah, and E. E. Ebong. Glycocalyx in atherosclerosis-relevant endothelium function and as a therapeutic target. Curr. Atheroscler. Rep. 19:63, 2017.

    Article  Google Scholar 

  21. Mitra, R., J. Qiao, S. Madhavan, G. L. O’Neil, B. Ritchie, P. Kulkarni, S. Sridhar, A. L. van de Ven, E. M. C. Kemmerling, C. Ferris, J. A. Hamilton, and E. E. Ebong. The comparative effects of high fat diet or disturbed blood flow on glycocalyx integrity and vascular inflammation. Trans. Med. Commun. 2018. https://doi.org/10.1186/s41231-018-0029-9.

    Article  Google Scholar 

  22. Mockl, L., S. Hirn, A. A. Torrano, B. Uhl, C. Brauchle, and F. Krombach. The glycocalyx regulates the uptake of nanoparticles by human endothelial cells in vitro. Nanomedicine (Lond.) 12:207–217, 2017.

    Article  Google Scholar 

  23. Nam, D., C.-W. Ni, A. Rezvan, J. Suo, K. Budzyn, A. Llanos, D. Harrison, D. Giddens, and H. Jo. Partial carotid ligation is a model of acutely induced disturbed flow, leading to rapid endothelial dysfunction and atherosclerosis. Am. J. Physiol. 297:H1535–H1543, 2009.

    CAS  Google Scholar 

  24. Newman, C. B., D. Preiss, J. A. Tobert, T. A. Jacobson, R. L. Page II, L. B. Goldstein, C. Chin, L. R. Tannock, M. Miller, G. Raghuveer, P. B. Duell, E. A. Brinton, A. Pollak, L. T. Braun, F. K. Welty, et al. Statin safety and associated adverse events: a scientific statement from the American Heart Association. Arterioscler. Thromb. Vasc. Biol. 39:e38–e81, 2019.

    Article  CAS  Google Scholar 

  25. Nieuwdorp, M., M. C. Meuwese, H. Vink, J. B. Hoekstra, J. J. Kastelein, and E. S. Stroes. The endothelial glycocalyx: a potential barrier between health and vascular disease. Curr. Opin. Lipidol. 16:507–511, 2005.

    Article  CAS  Google Scholar 

  26. Oohira, A., T. N. Wight, and P. Bornstein. Sulfated proteoglycans synthesized by vascular endothelial cells in culture. J. Biol. Chem. 258:2014–2021, 1983.

    CAS  PubMed  Google Scholar 

  27. Potteaux, S., H. Ait-Oufella, and Z. Mallat. Mouse models of atherosclerosis. Drug Discov. Today 4:165–170, 2007.

    Article  Google Scholar 

  28. Pries, A. R., T. W. Secomb, and P. Gaehtgens. The endothelial surface layer. Pflugers Arch. 440:653–666, 2000.

    Article  CAS  Google Scholar 

  29. Prydz, K. Determinants of glycosaminoglycan (GAG) structure. Biomolecules 5:2003–2022, 2015.

    Article  CAS  Google Scholar 

  30. Rahbar, E., J. C. Cardenas, G. Baimukanova, B. Usadi, R. Bruhn, S. Pati, S. R. Ostrowski, P. I. Johansson, J. B. Holcomb, and C. E. Wade. Endothelial glycocalyx shedding and vascular permeability in severely injured trauma patients. J. Trans. Med. 13:117, 2015.

    Article  Google Scholar 

  31. Rehm, M., D. Bruegger, F. Christ, P. Conzen, M. Thiel, M. Jacob, D. Chappell, M. Stoeckelhuber, U. Welsch, B. Reichart, K. Peter, and B. F. Becker. Shedding of the endothelial glycocalyx in patients undergoing major vascular surgery with global and regional ischemia. Circulation 116:1896–1906, 2007.

    Article  CAS  Google Scholar 

  32. Reitsma, S., D. W. Slaaf, H. Vink, M. van Zandvoort, and M. G. A. oude Egbrink. The endothelial glycocalyx: composition, functions, and visualization. Pflugers Arch. 454:345–359, 2007.

    Article  CAS  Google Scholar 

  33. Singh, A., S. C. Satchell, C. R. Neal, E. A. McKenzie, J. E. Tooke, and P. W. Mathieson. Glomerular endothelial glycocalyx constitutes a barrier to protein permeability. J. Am. Soc. Nephrol. 18:2885–2893, 2007.

    Article  CAS  Google Scholar 

  34. Tarbell, J. M., and L. M. Cancel. The glycocalyx and its significance in human medicine. J. Intern. Med. 280:97–113, 2016.

    Article  CAS  Google Scholar 

  35. Tarbell, J. M., Z. D. Shi, J. Dunn, and H. Jo. Fluid mechanics, arterial disease, and gene expression. Annu. Rev. Fluid Mech. 46:591–614, 2014.

    Article  Google Scholar 

  36. Uhl, B., S. Hirn, R. Immler, K. Mildner, L. Mockl, M. Sperandio, C. Brauchle, C. A. Reichel, D. Zeuschner, and F. Krombach. The endothelial glycocalyx controls interactions of quantum dots with the endothelium and their translocation across the blood-tissue border. ACS Nano 11:1498–1508, 2017.

    Article  CAS  Google Scholar 

  37. Ushiyama, A., H. Kataoka, and T. Iijima. Glycocalyx and its involvement in clinical pathophysiologies. J. Intensive Care 4:59, 2016.

    Article  Google Scholar 

  38. Wang, H., Y. Lin, K. Nienhaus, and G. U. Nienhaus. The protein corona on nanoparticles as viewed from a nanoparticle-sizing perspective. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 10:e1500, 2018.

    Article  Google Scholar 

  39. You, J., J. Zhou, M. Zhou, Y. Liu, J. D. Robertson, D. Liang, C. Van Pelt, and C. Li. Pharmacokinetics, clearance, and biosafety of polyethylene glycol-coated hollow gold nanospheres. Part Fibre Toxicol. 11:26, 2014.

    Article  Google Scholar 

Download references

Acknowledgements

Solomon Mensah, Bijay Singh, Maeve X Enright, Paige Baldwin, Bailey L Ritchie, and James Lister of Northeastern University provided technical assistance and feedback. Northeastern University’s Professor Thomas Webster, Professor Heather Clark, Assistant Professor Adam Ekenseair, the Department of Physics, and the Electronic Materials Research Institute shared equipment.

Author Contributions

All authors contributed to data analysis, drafted and revised the article, and gave final approval of the version to be published. Specifically: M.J.C. and E.E.E. designed the experiments. M.J.C, R.M., C.C.O., A.A.N., I.C.H, and R.K. performed the experiments and analyzed the data. M.J.C. and E.E.E. interpreted the results of the experiments. M.J.C., R.M., N.N.B, and E.E.E drafted the figures and manuscript. M.J.C., R.M., C.C.O., A.A.N., I.C.H, N.N.B, R.K., H.J., S.S., and E.E.E. edited, revised, and approved the final manuscript. H.J., S.S., and E.E.E. supervised the project. All authors agree to be accountable for all aspects of the work.

Funding

This work was funded by the National Institutes of Health (K01 HL125499 granted to EEE), the National Science Foundation (DGE-0965843 granted to SS and CMMI-1846962 granted to EEE), and the American Heart Association (18PRE33960461 granted to ICH). The funders had no role in data or information collection and analysis, decision to publish, or preparation of the manuscript.

Conflict of interest

Ming Cheng, Chinedu Okorafor, Alina Nersesyan, Ian Harding, Nandita Bal, Rajiv Kumar, Hanjoong Jo, Srinivas Sridhar, and Eno Ebong declare that they have no conflict of interest.

Research Involving Human and Animal Rights

No human studies were carried out by the authors for this article. All institutional and national guidelines for the care and use of laboratory animals were followed and approved by the appropriate institutional committees.

Author information

Authors and Affiliations

  1. Department of Chemical Engineering, Northeastern University, 360 Huntington Avenue, 313 Snell Engineering Building, Boston, MA, 02115, USA

    Ming J. Cheng, Ronodeep Mitra, Chinedu C. Okorafor, Nandita N. Bal & Eno E. Ebong

  2. Department of Bioengineering, Northeastern University, Boston, MA, USA

    Alina A. Nersesyan, Ian C. Harding & Eno E. Ebong

  3. Department of Physics, Northeastern University, Boston, MA, USA

    Rajiv Kumar & Srinivas Sridhar

  4. Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, GA, USA

    Hanjoong Jo

  5. Department of Neuroscience, Albert Einstein College of Medicine, New York, NY, USA

    Eno E. Ebong

  6. Department of Neurology, The Massachusetts General Hospital, Boston, MA, USA

    Ming J. Cheng

  7. The NeuroDiscovery Center, Harvard Medical School, Boston, MA, USA

    Ming J. Cheng

  8. R&D Biomedical Materials, Millipore Sigma (A Business of Merck KGaA, Darmstadt, Germany), Milwaukee, WI, USA

    Rajiv Kumar

Authors
  1. Ming J. Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ronodeep Mitra
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chinedu C. Okorafor
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Alina A. Nersesyan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ian C. Harding
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nandita N. Bal
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Rajiv Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hanjoong Jo
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Srinivas Sridhar
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Eno E. Ebong
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eno E. Ebong.

Additional information

Associate Editor Debra T. Auguste oversaw the review of this article.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 130 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cheng, M.J., Mitra, R., Okorafor, C.C. et al. Targeted Intravenous Nanoparticle Delivery: Role of Flow and Endothelial Glycocalyx Integrity. Ann Biomed Eng 48, 1941–1954 (2020). https://doi.org/10.1007/s10439-020-02474-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10439-020-02474-4

Keywords

Search

Navigation