Skip to main content

Advertisement

SpringerLink
Log in

Multi-Ligand Poly(l-Lactic-co-Glycolic Acid) Nanoparticles Inhibit Activation of Endothelial Cells

  • Published:
Journal of Cardiovascular Translational Research Aims and scope Submit manuscript

Abstract

Endothelial cell (EC) activation and inflammation is a key step in the initiation and progression of many cardiovascular diseases. Targeted delivery of therapeutic reagents to inflamed EC using nanoparticles is challenging as nanoparticles do not arrest on EC efficiently under high shear stress. In this study, we developed a novel polymeric platelet-mimicking nanoparticle for strong particle adhesion onto ECs and enhanced particle internalization by ECs. This nanoparticle was encapsulated with dexamethasone as the anti-inflammatory drug, and conjugated with polyethylene glycol, glycoprotein 1b, and trans-activating transcriptional peptide. The multi-ligand nanoparticle showed significantly greater adhesion on P-selectin, von Willebrand Factor, than the unmodified particles, and activated EC in vitro under both static and flow conditions. Treatment of injured rat carotid arteries with these multi-ligand nanoparticles suppressed neointimal stenosis more than unconjugated nanoparticles did. These results indicate that this novel multi-ligand nanoparticle is efficient to target inflamed EC and inhibit inflammation and subsequent stenosis.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Schillinger, M., & Minar, E. (2005). Restenosis after percutaneous angioplasty: the role of vascular inflammation. Vascular Health and Risk Management, 1, 73–78.

    Article  PubMed  Google Scholar 

  2. Savoia, C., & Schiffrin, E. L. (2007). Vascular inflammation in hypertension and diabetes: molecular mechanisms and therapeutic interventions. Clinical Science (London, England), 112, 375–384.

    Article  CAS  Google Scholar 

  3. Munro, J. M., & Cotran, R. S. (1988). The pathogenesis of atherosclerosis: atherogenesis and inflammation. Laboratory Investigation, 58, 249–261.

    PubMed  CAS  Google Scholar 

  4. Zampolli, A., Basta, G., Lazzerini, G., Feelisch, M., & De Caterina, R. (2000). Inhibition of endothelial cell activation by nitric oxide donors. Journal of Pharmacology and Experimental Therapeutics, 295, 818–823.

    PubMed  CAS  Google Scholar 

  5. Everts, M., Kok, R. J., Asgeirsdottir, S. A., Melgert, B. N., Moolenaar, T. J. M., Koning, G. A., et al. (2002). Selective intracellular delivery of dexamethasone into activated endothelial cells using an e-selectin-directed immunoconjugate. Journal of Immunology, 168, 883–889.

    CAS  Google Scholar 

  6. Versaci, F., Gaspardone, A., Tomai, F., Ribichini, F., Russo, P., Proietti, I., et al. (2002). Immunosuppressive therapy for the prevention of restenosis after coronary artery stent implantation (impress study). Journal of the American College of Cardiology, 40, 1935–1942.

    Article  PubMed  Google Scholar 

  7. Park YM, Han SH, Lee K, Suh SY, Oh PC, Shin EK (2013) Dexamethasone-eluting stents had sustained favorable ischemic driven target lesion revascularization rates over 5 years: a randomized controlled prospective study. International Journal of Cardiology, in press.

  8. Qin, J., Du, R., Yang, Y. Q., Zhang, H. Q., Li, Q., Liu, L., et al. (2013). Dexamethasone-induced skeletal muscle atrophy was associated with upregulation of myostatin promoter activity. Research Veterinary Science, 94, 84–89.

    Article  CAS  Google Scholar 

  9. Kim, M. H., Lee, G. S., Jung, E. M., Choi, K. C., & Jeung, E. B. (2009). The negative effect of dexamethasone on calcium-processing gene expressions is associated with a glucocorticoid-induced calcium-absorbing disorder. Life Sciences, 85, 146–152.

    Article  PubMed  CAS  Google Scholar 

  10. Ranta, F., Avram, D., Berchtold, S., Dufer, M., Drews, G., Lang, F., et al. (2006). Dexamethasone induces cell death in insulin-secreting cells, an effect reversed by exendin-4. Diabetes, 55, 1380–1390.

    Article  PubMed  CAS  Google Scholar 

  11. Davis, M. E., Chen, Z. G., & Shin, D. M. (2008). Nanoparticle therapeutics: an emerging treatment modality for cancer. Nature Reviews. Drug Discovery, 7, 771–782.

    Article  PubMed  CAS  Google Scholar 

  12. Zhang, L., Gu, F. X., Chan, J. M., Wang, A. Z., Langer, R. S., & Farokhzad, O. C. (2008). Nanoparticles in medicine: therapeutic applications and developments. Clinical Pharmacology and Therapeutics, 83, 761–769.

    Article  PubMed  CAS  Google Scholar 

  13. Dickerson, J. B., Blackwell, J. E., Ou, J. J., Shinde Patil, V. R., & Goetz, D. J. (2001). Limited adhesion of biodegradable microspheres to e- and p-selectin under flow. Biotechnology and Bioengineering, 73, 500–509.

    Article  PubMed  CAS  Google Scholar 

  14. Nguyen, K. T., Shukla, K. P., Moctezuma, M., Braden, A. R., Zhou, J., Hu, Z., et al. (2009). Studies of the cellular uptake of hydrogel nanospheres and microspheres by phagocytes, vascular endothelial cells, and smooth muscle cells. Journal of Biomedical Materials Research. Part A, 88, 1022–1030.

    PubMed  Google Scholar 

  15. Lowenberg, E. C., Meijers, J. C., & Levi, M. (2010). Platelet-vessel wall interaction in health and disease. The Netherlands Journal of Medicine, 68, 242–251.

    PubMed  CAS  Google Scholar 

  16. Deshayes, S., Morris, M. C., Divita, G., & Heitz, F. (2005). Cell-penetrating peptides: tools for intracellular delivery of therapeutics. Cellular and Molecular Life Sciences, 62, 1839–1849.

    Article  PubMed  CAS  Google Scholar 

  17. Morris, M. C., Deshayes, S., Heitz, F., & Divita, G. (2008). Cell-penetrating peptides: from molecular mechanisms to therapeutics. Biology of the Cell, 100, 201–217.

    Article  PubMed  CAS  Google Scholar 

  18. Romo, G. M., Dong, J. F., Schade, A. J., Gardiner, E. E., Kansas, G. S., Li, C. Q., et al. (1999). The glycoprotein Ib-IX-V complex is a platelet counterreceptor for p-selectin. The Journal of Experimental Medicine, 190, 803–813.

    Article  PubMed  CAS  Google Scholar 

  19. Kim, D. H., & Martin, D. C. (2006). Sustained release of dexamethasone from hydrophilic matrices using PLGA nanoparticles for neural drug delivery. Biomaterials, 27, 3031–3037.

    Article  PubMed  CAS  Google Scholar 

  20. Xu, H., Deshmukh, R., Timmons, R., & Nguyen, K. T. (2011). Enhanced endothelialization on surface modified poly(l-lactic acid) substrates. Tissue Engineering. Part A, 17, 865–876.

    Article  PubMed  CAS  Google Scholar 

  21. Kona, S., Dong, J. F., Liu, Y. L., Tan, J. F., & Nguyen, K. T. (2012). Biodegradable nanoparticles mimicking platelet binding as a targeted and controlled drug delivery system. International Journal of Pharmaceutical, 423, 516–524.

    Article  CAS  Google Scholar 

  22. Lin, A., Sabnis, A., Kona, S., Nattama, S., Patel, H., Dong, J. F., et al. (2010). Shear-regulated uptake of nanoparticles by endothelial cells and development of endothelial-targeting nanoparticles. Journal of Biomedical Materials Research. Part A, 93, 833–842.

    PubMed  Google Scholar 

  23. Xu, H., Nguyen, K. T., Brilakis, E. S., Yang, J., Fuh, E., & Banerjee, S. (2012). Enhanced endothelialization of a new stent polymer through surface enhancement and incorporation of growth factor-delivering microparticles. Journal of Cardiovascular Translation, 5, 519–527.

    Article  Google Scholar 

  24. Larifla, L., Deprez, I., Pham, I., Rideau, D., Louzier, V., Adam, M., et al. (2012). Inhibition of vascular smooth muscle cell proliferation and migration in vitro and neointimal hyperplasia in vivo by adenoviral-mediated atrial natriuretic peptide delivery. The Journal of Gene Medicine, 14, 459–467.

    Article  PubMed  CAS  Google Scholar 

  25. Kimura, S., Egashira, K., Nakano, K., Iwata, E., Miyagawa, M., Tsujimoto, H., et al. (2008). Local delivery of imatinib mesylate (sti571)-incorporated nanoparticle ex vivo suppresses vein graft neointima formation. Circulation, 118, S65–S70.

    Article  PubMed  CAS  Google Scholar 

  26. Mei, L., Sun, H., Jin, X., Zhu, D., Sun, R., Zhang, M., et al. (2007). Modified paclitaxel-loaded nanoparticles for inhibition of hyperplasia in a rabbit arterial balloon injury model. Pharmaceutical Research, 24, 955–962.

    Article  PubMed  CAS  Google Scholar 

  27. Bonan, R., Paiement, P., Scortichini, D., Cloutier, M. J., & Leung, T. K. (1993). Coronary restenosis: evaluation of a restenosis injury index in a swine model. American Heart Journal, 126, 1334–1340.

    Article  PubMed  CAS  Google Scholar 

  28. Feng, S. S., Zeng, W., Teng Lim, Y., Zhao, L., Yin Win, K., Oakley, R., et al. (2007). Vitamin E TPGS-emulsified poly(lactic-co-glycolic acid) nanoparticles for cardiovascular restenosis treatment. Nanomedicine (London, England), 2, 333–344.

    Article  CAS  Google Scholar 

  29. Westedt, U., Kalinowski, M., Wittmar, M., Merdan, T., Unger, F., Fuchs, J., et al. (2007). Poly(vinyl alcohol)-graft-poly(lactide-co-glycolide) nanoparticles for local delivery of paclitaxel for restenosis treatment. Journal of Controlled Release, 119, 41–51.

    Article  PubMed  CAS  Google Scholar 

  30. Kamath, K. R., Barry, J. J., & Miller, K. M. (2006). The taxus drug-eluting stent: a new paradigm in controlled drug delivery. Advanced Drug Delivery Reviews, 58, 412–436.

    Article  PubMed  CAS  Google Scholar 

  31. Jain, A. K., Das, M., Swarnakar, N. K., & Jain, S. (2011). Engineered PLGA nanoparticles: an emerging delivery tool in cancer therapeutics. Critical Reviews in Therapeutic Drug Carrier Systems, 28, 1–45.

    Article  PubMed  CAS  Google Scholar 

  32. Petros, R. A., & DeSimone, J. M. (2010). Strategies in the design of nanoparticles for therapeutic applications. Nature Reviews. Drug Discovery, 9, 615–627.

    Article  PubMed  CAS  Google Scholar 

  33. Peracchia, M. T., Vauthier, C., Puisieux, F., & Couvreur, P. (1997). Development of sterically stabilized poly(isobutyl 2-cyanoacrylate) nanoparticles by chemical coupling of poly(ethylene glycol). Journal of Biomedical Materials Research, 34, 17–26.

    Article  Google Scholar 

  34. Betancourt, T., Byrne, J. D., Sunaryo, N., Crowder, S. W., Kadapakkam, M., Patel, S., et al. (2009). Pegylation strategies for active targeting of PLA/PLGA nanoparticles. Journal of Biomedical Materials Research. Part A, 91, 263–276.

    Article  PubMed  Google Scholar 

  35. Andrews, R. K., & Berndt, M. C. (2004). Platelet physiology and thrombosis. Thrombosis Research, 114, 447–453.

    Article  PubMed  CAS  Google Scholar 

  36. Ni, H., & Freedman, J. (2003). Platelets in hemostasis and thrombosis: role of integrins and their ligands. Transfusion and Apheresis Science, 28, 257–264.

    Article  PubMed  Google Scholar 

  37. Zou, X. Y., Patil, V. R. S., Dagia, N. M., Smith, L. A., Wargo, M. J., Interliggi, K. A., et al. (2005). Psgl-1 derived from human neutrophils is a high-efficiency ligand for endothelium-expressed e-selectin under flow. American Journal Physiological-Cell Ph, 289, C415–C424.

    Article  CAS  Google Scholar 

  38. Eniola, A. O., & Hammer, D. A. (2005). Characterization of biodegradable drug delivery vehicles with the adhesive properties of leukocytes II: effect of degradation on targeting activity. Biomaterials, 26, 661–670.

    Article  PubMed  CAS  Google Scholar 

  39. Blackwell, J. E., Dagia, N. M., Dickerson, J. B., Berg, E. L., & Goetz, D. J. (2001). Ligand coated nanosphere adhesion to e- and p-selectin under static and flow conditions. Annals of Biomedical Engineering, 29, 523–533.

    Article  PubMed  CAS  Google Scholar 

  40. Smith, C. A., de la Fuente, J., Pelaz, B., Furlani, E. P., Mullin, M., & Berry, C. C. (2010). The effect of static magnetic fields and tat peptides on cellular and nuclear uptake of magnetic nanoparticles. Biomaterials, 31, 4392–4400.

    Article  PubMed  CAS  Google Scholar 

  41. Medintz, I. L., Pons, T., Delehanty, J. B., Susumu, K., Brunel, F. M., Dawson, P. E., et al. (2008). Intracellular delivery of quantum dot-protein cargos mediated by cell penetrating peptides. Bioconjugate Chemistry, 19, 1785–1795.

    Article  PubMed  CAS  Google Scholar 

  42. Zhang, K., Fang, H., Chen, Z., Taylor, J. S., & Wooley, K. L. (2008). Shape effects of nanoparticles conjugated with cell-penetrating peptides (HIV Tat PTD) on CHO cell uptake. Bioconjugate Chemistry, 19, 1880–1887.

    Article  PubMed  CAS  Google Scholar 

  43. Foerg, C., & Merkle, H. P. (2008). On the biomedical promise of cell penetrating peptides: limits versus prospects. Journal of Pharmaceutical Sciences, 97, 144–162.

    Article  PubMed  CAS  Google Scholar 

  44. Torchilin, V. P. (2008). Cell penetrating peptide-modified pharmaceutical nanocarriers for intracellular drug and gene delivery. Biopolymers, 90, 604–610.

    Article  PubMed  CAS  Google Scholar 

  45. Tsourkas, A., Shinde-Patil, V. R., Kelly, K. A., Patel, P., Wolley, A., Allport, J. R., et al. (2005). In vivo imaging of activated endothelium using an anti-VCAM-1 magnetooptical probe. Bioconjugate Chemistry, 16, 576–581.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors would like to acknowledge the assistance provided by members of the Core Imaging Facility at UTSW and the Characterization Center for Materials and Biology at UTA. We also thank Alicia J. Sisemore for her help with the manuscript editing. We acknowledge the financial support from the American Heart Association Scientist Development Award 0735270N (K.N.), NIH grants HL091232 (K.N.) and EB007271 (L.T.).

Author information

Authors and Affiliations

  1. Division of Cardiology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Hao Xu, Emmanouil S. Brilakis & Subhash Banerjee

  2. Department of Bioengineering, University of Texas at Arlington, 500 UTA Blvd, ERB-241, Arlington, TX, 76010, USA

    Soujanya Kona, Lee-Chun Su, Yi-Ting Tsai, Liping Tang & Kytai T. Nguyen

  3. Puget Sound Blood Center and University of Washington, Seattle, WA, USA

    Jing-Fei Dong

Authors
  1. Hao Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Soujanya Kona
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lee-Chun Su
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yi-Ting Tsai
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jing-Fei Dong
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Emmanouil S. Brilakis
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Liping Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Subhash Banerjee
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Kytai T. Nguyen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Subhash Banerjee or Kytai T. Nguyen.

Additional information

Hao Xu and Soujanya Kona equally contributed to this manuscript.

Clinical Relevance

This study was conducted to assess the effect of a novel targeted drug-delivery nanoparticle developed in our laboratories for treatments of complications after transluminal angioplasty and vascular stenting.

Electronic supplementary material

ESM 1

(DOC 41 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Xu, H., Kona, S., Su, LC. et al. Multi-Ligand Poly(l-Lactic-co-Glycolic Acid) Nanoparticles Inhibit Activation of Endothelial Cells. J. of Cardiovasc. Trans. Res. 6, 570–578 (2013). https://doi.org/10.1007/s12265-013-9460-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12265-013-9460-5

Keywords

Search

Navigation