Skip to main content

Nano- and Microscale Delivery Systems for Cardiovascular Therapy

  • Chapter
Microscale Technologies for Cell Engineering
  • 1317 Accesses

Abstract

Cardiovascular disease is still a major healthcare concern as it continues to be the leading cause of death in developed countries. Recent advancement in bioengineering technologies to generate micro- and nanoscale materials as biotransporters and therapeutics has led to a variety of new approaches to treat cardiovascular diseases. Although these strategies are still in their initial stage of research, developing effective alternate therapies to treat life-threatening diseases such as myocardial infarction and atherosclerosis can potentially improve patient outcomes and long-term economic costs imposed on the healthcare system. Over the last decade, a wide array of materials with tunable biophysical and chemical properties has been developed to successfully deliver therapeutic agents such as nucleic acids, proteins, and small molecules, and even stem cells in combination with nanomaterials for advanced cardiovascular treatments. This mainly includes polymeric nanoparticles and nanohybrid materials, microparticles, carbon nanotubes, graphene oxide, liposomes, microgels, nanofibers, and nanoscaffolds. In addition, these materials also find application as multifunctional theranostic nanoagents which combine in vivo diagnostic properties along with therapeutic capabilities. This chapter discusses the emerging therapeutic delivery systems for biomedical research and highlights the recent developments in this highly interdisciplinary field along with examples of strategies that hold promise for the future of cardiovascular medicine.

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

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

AcDex:

Acetylated dextran

Ang-1:

Angiopoietin-1

bFGF:

Fibroblast growth factor

CLIOs:

Crosslinked dextran-coated iron oxide nanoparticles

CVD:

Cardiovascular diseases

ECM:

Extracellular matrix

H2O2 :

Hydrogen peroxide

IMPs:

Immune-modulating microparticles

MI:

Myocardial infarction

miR-1:

microRNA-1

miRNAs:

micro-RNA

MSCs:

Mesenchymal stem cells

O2 :

Oxygen

PEG:

Polyethylene glycol

PLGA:

Poly(lactic-co-glycolic acid)

SMCs:

Smooth muscle cells

TF:

Tissue factor

tPA:

Tissue plasminogen activator

VEGF:

Vascular endothelial growth factor

References

  1. Heidenreich P, Trogdon J, Khavjou O et al (2011) Forecasting the future of cardiovascular disease in the United States: a policy statement from the American Heart Association. Circulation 8:933–944

    Article  Google Scholar 

  2. Libby P, Ridker P, Hansson G (2011) Progress and challenges in translating the biology of atherosclerosis. Nature 473:317–325

    Article  Google Scholar 

  3. Park H, Larson B, Kolewe M et al (2014) Biomimetic scaffold combined with electrical stimulation and growth factor promotes tissue engineered cardiac development. Exp Cell Res 321:297–306

    Article  Google Scholar 

  4. Thygesen K, Alpert J, Jaffe A et al (2012) Third universal definition of myocardial infarction. J Am Coll Cardiol 60:1581–1598

    Article  Google Scholar 

  5. Krijnen P, Nijmeijer R, Meijer C et al (2002) Apoptosis in myocardial ischaemia and infarction. J Clin Pathol 55:801–811

    Article  Google Scholar 

  6. Cam C, Segura T (2013) Matrix-based gene delivery for tissue repair. Curr Opin Biotechnol 24:855–863

    Article  Google Scholar 

  7. Jaffe A (2006) Chasing troponin: how low can you go if you can see the rise? J Am Coll Cardiol 48:1763–1764

    Article  Google Scholar 

  8. Melo L, Pachori A, Kong D et al (2004) Molecular and cell-based therapies for protection, rescue, and repair of ischemic myocardium: reasons for cautious optimism. Circulation 109:2386–2393

    Article  Google Scholar 

  9. Melo L, Pachori A, Kong D et al (2004) Gene and cell-based therapies for heart disease. FASEB J 18:648–663

    Article  Google Scholar 

  10. Chen C, Jamaluddin M, Kougias P et al (2011) miRNAs: roles and clinical applications in vascular disease. Expert Rev Mol Diagn 11:79–89

    Article  Google Scholar 

  11. Dorn I, Gerald W (2011) MicroRNAs in cardiac disease. Transl Res 157:226–235

    Article  Google Scholar 

  12. Pucéat M (2008) Pharmacological approaches to regenerative strategies for the treatment of cardiovascular diseases. Curr Opin Pharmacol 8:189–192

    Article  Google Scholar 

  13. Traverse J, Henry T, Ellis S et al (2011) Effect of intracoronary delivery of autologous bone marrow mononuclear cells 2 to 3 weeks following acute myocardial infarction on left ventricular function: the LateTIME randomized trial. JAMA 306:2110–2119

    Article  Google Scholar 

  14. Traverse J, Henry T, Pepine C et al (2012) Effect of the use and timing of bone marrow mononuclear cell delivery on left ventricular function after acute myocardial infarction: the time randomized trial. JAMA 308:2380–2389

    Article  Google Scholar 

  15. Schächinger V, Erbs S, Elsässer A et al (2006) Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction. N Engl J Med 355:1210–1221

    Article  Google Scholar 

  16. Traverse J, Henry T, Vaughn D et al (2009) Rationale and design for TIME: a phase II, randomized, double-blind, placebo-controlled pilot trial evaluating the safety and effect of timing of administration of bone marrow mononuclear cells after acute myocardial infarction. Am Heart J 158:356–363

    Article  Google Scholar 

  17. Huang X-P, Sun Z, Miyagi Y et al (2010) Differentiation of allogeneic mesenchymal stem cells induces immunogenicity and limits their long-term benefits for myocardial repair. Circulation 122:2419–2429

    Article  Google Scholar 

  18. Hare J, Fishman J, Gerstenblith G et al (2012) Comparison of allogeneic vs. autologous bone marrow-derived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: the Poseidon randomized trial. JAMA 308:2369–2379

    Article  Google Scholar 

  19. Perin E, Mei T, Marini F III et al (2011) Imaging long-term fate of intramyocardially implanted mesenchymal stem cells in a porcine myocardial infarction model. PLoS One 6:1–13

    Article  Google Scholar 

  20. Blum B, Benvenisty N (2009) The tumorigenicity of diploid and aneuploid human pluripotent stem cells. Cell Cycle 8:3822–3830

    Article  Google Scholar 

  21. Godin B, Ferrari M (2012) Cardiovascular nanomedicine: a posse ad esse. Methodist Debakey Cardiovasc J 8:2–5

    Article  Google Scholar 

  22. Cheng Z, Al Zaki A, Hui J et al (2012) Multifunctional nanoparticles: cost versus benefit of adding targeting and imaging capabilities. Science 338:903–910

    Article  Google Scholar 

  23. Shi J, Xiao Z, Kamaly N et al (2011) Self-assembled targeted nanoparticles: evolution of technologies and bench to bedside translation. Acc Chem Res 44:1123–1134

    Article  Google Scholar 

  24. Christian P, Von der Kammer F, Baalousha M et al (2008) Nanoparticles: structure, properties, preparation and behaviour in environmental media. Ecotoxicology 17:326–343

    Article  Google Scholar 

  25. Sahoo S, Parveen S, Panda JJ (2007) The present and future of nanotechnology in human health care. Nanomedicine 3:20–31

    Article  Google Scholar 

  26. Gupta A (2011) Nanomedicine approaches in vascular disease: a review. Nanomedicine 6:763–779

    Article  Google Scholar 

  27. Lukyanov A, Torchilin V (2004) Micelles from lipid derivatives of water-soluble polymers as delivery systems for poorly soluble drugs. Adv Drug Deliv Rev 56:1273–1289

    Article  Google Scholar 

  28. Torchilin V (2007) Micellar nanocarriers: pharmaceutical perspectives. Pharm Res 24:1–16

    Article  Google Scholar 

  29. Liu YT, Thomas A, Ou-Yang D et al (2012) The shape of things to come: importance of design in nanotechnology for drug delivery. Ther Deliv 3:181–194

    Article  Google Scholar 

  30. Alzaraa A, Gravante G, Chung W et al (2012) Targeted microbubbles in the experimental and clinical setting. Am J Surg 204:355–366

    Article  Google Scholar 

  31. Kang S, Yeh C (2012) Ultrasound microbubble contrast agents for diagnostic and therapeutic applications: current status and future design. Chang Gung Med J 35:125–139

    Google Scholar 

  32. Kircher M, Willmann J (2012) Molecular body imaging: MR imaging, CT, and US. Part I. Principles. Radiology 263:633–643

    Article  Google Scholar 

  33. Unnikrishnan S, Klibanov A (2012) Microbubbles as ultrasound contrast agents for molecular imaging: preparation and application. Am J Roentgenol 199:292–299

    Article  Google Scholar 

  34. Colombo M, Carregal-Romero S, Casula M et al (2012) Biological applications of magnetic nanoparticles. Chem Soc Rev 41:4306–4334

    Article  Google Scholar 

  35. Sosnovik D, Nahrendorf M, Weissleder R (2008) Magnetic nanoparticles for MR imaging: agents, techniques and cardiovascular applications. Basic Res Cardiol 103:122–130

    Article  Google Scholar 

  36. Tomczak N, Jańczewski D, Dorokhin D et al (2012) Enabling biomedical research with designer quantum dots. In: Navarro M, Planell JA (eds) Nanotechnology in regenerative medicine, vol 811, Methods in molecular biology. Humana Press, New York, pp 245–265

    Chapter  Google Scholar 

  37. Obonyo O, Fisher E, Edwards M et al (2010) Quantum dots synthesis and biological applications as imaging and drug delivery systems. Crit Rev Biotechnol 30:283–301

    Article  Google Scholar 

  38. Paul A, Nayan M, Khan A et al (2012) Angiopoietin-1-expressing adipose stem cells genetically modified with baculovirus nanocomplex: investigation in rat heart with acute infarction. Int J Nanomedicine 7:663–682

    Article  Google Scholar 

  39. Paul A, Shao W, Abbasi S et al (2012) PAMAM dendrimer-baculovirus nanocomplex for microencapsulated adipose stem cell-gene therapy: in vitro and in vivo functional assessment. Mol Pharm 9:2479–2488

    Article  Google Scholar 

  40. Paul A, Binsalamah Z, Khan A et al (2011) A nanobiohybrid complex of recombinant baculovirus and Tat/DNA nanoparticles for delivery of Ang-1 transgene in myocardial infarction therapy. Biomaterials 32:8304–8318

    Article  Google Scholar 

  41. T-I K, Rothmund T, Kissel T et al (2011) Bioreducible polymers with cell penetrating and endosome buffering functionality for gene delivery systems. J Control Release 152:110–119

    Article  Google Scholar 

  42. Won Y-W, Bull D, Kim S (2014) Functional polymers of gene delivery for treatment of myocardial infarct. J Control Release 195:110–119

    Article  Google Scholar 

  43. Liu M, Li M, Sun S et al (2014) The use of antibody modified liposomes loaded with AMO-1 to deliver oligonucleotides to ischemic myocardium for arrhythmia therapy. Biomaterials 35:3697–3707

    Article  MathSciNet  Google Scholar 

  44. Park H-J, Yang F, Cho S-W (2012) Nonviral delivery of genetic medicine for therapeutic angiogenesis. Adv Drug Deliv Rev 64:40–52

    Article  Google Scholar 

  45. Eulalio A, Mano M, Ferro M et al (2012) Functional screening identifies miRNAs inducing cardiac regeneration. Nature 492:376–381

    Article  Google Scholar 

  46. Tafuro S, Ayuso E, Zacchigna S et al (2009) Inducible adeno-associated virus vectors promote functional angiogenesis in adult organisms via regulated vascular endothelial growth factor expression. Cardiovasc Res 83:663–671

    Article  Google Scholar 

  47. Tao Z, Chen B, Tan X et al (2011) Coexpression of VEGF and angiopoietin-1 promotes angiogenesis and cardiomyocyte proliferation reduces apoptosis in porcine myocardial infarction (MI) heart. Proc Natl Acad Sci U S A 108:2064–2069

    Article  Google Scholar 

  48. Martinelli V, Cellot G, Toma F et al (2013) Carbon nanotubes instruct physiological growth and functionally mature syncytia: nongenetic engineering of cardiac myocytes. ACS Nano 7:5746–5756

    Article  Google Scholar 

  49. Shin S, Jung S, Zalabany M et al (2013) Carbon-nanotube-embedded hydrogel sheets for engineering cardiac constructs and bioactuators. ACS Nano 7:2369–2380

    Article  Google Scholar 

  50. Martinelli V, Cellot G, Fabbro A et al (2013) Improving cardiac myocytes performance by carbon nanotubes platforms. Front Physiol 4:239

    Article  Google Scholar 

  51. Ghasemi-Mobarakeh L, Prabhakaran MP, Nematollahi M et al (2013) Embryonic stem cell differentiation to cardiomyocytes on nanostructured scaffolds for myocardial tissue regeneration. Int J Polym Mater Polym Biomater 63:240–245

    Article  Google Scholar 

  52. Shi C, Li Q, Zhao Y et al (2011) Stem-cell-capturing collagen scaffold promotes cardiac tissue regeneration. Biomaterials 32:2508–2515

    Article  Google Scholar 

  53. Karam J-P, Muscari C, Montero-Menei C (2012) Combining adult stem cells and polymeric devices for tissue engineering in infarcted myocardium. Biomaterials 33:5683–5695

    Article  Google Scholar 

  54. Prabhakaran M, Nair S, Kai D et al (2012) Electrospun composite scaffolds containing poly(octanediol-co-citrate) for cardiac tissue engineering. Biopolymers 97:529–538

    Article  Google Scholar 

  55. Kai D, Prabhakaran M, Jin G et al (2011) Guided orientation of cardiomyocytes on electrospun aligned nanofibers for cardiac tissue engineering. J Biomed Mater Res B Appl Biomater 98B:379–386

    Article  Google Scholar 

  56. Şenel Ayaz H, Perets A, Ayaz H et al (2014) Textile-templated electrospun anisotropic scaffolds for regenerative cardiac tissue engineering. Biomaterials 35:8540–8552

    Article  Google Scholar 

  57. Dvir T, Timko B, Kohane D (2011) Nanotechnological strategies for engineering complex tissues. Nat Nanotechnol 6:13–22

    Article  Google Scholar 

  58. Ravichandran R, Griffith M, Phopase J (2014) Applications of self-assembling peptide scaffolds in regenerative medicine: the way to the clinic. J Mater Chem B 2:8466–8478

    Article  Google Scholar 

  59. Lin Y-D, Luo C-Y, Hu Y-N et al (2012) Instructive nanofiber scaffolds with VEGF create a microenvironment for arteriogenesis and cardiac repair. Sci Transl Med 4:146ra109

    Google Scholar 

  60. Holzwarth J, Ma P (2011) 3D nanofibrous scaffolds for tissue engineering. J Mater Chem 21:10243–10251

    Article  Google Scholar 

  61. Singelyn J, Christman K (2010) Injectable materials for the treatment of myocardial infarction and heart failure: the promise of decellularized matrices. J Cardiovasc Transl Res 3:478–486

    Article  Google Scholar 

  62. Badylak S, Freytes D, Gilbert T (2009) Extracellular matrix as a biological scaffold material: structure and function. Acta Biomater 5:1–13

    Article  Google Scholar 

  63. Lu T-Y, Lin B, Kim J et al (2013) Repopulation of decellularized mouse heart with human induced pluripotent stem cell-derived cardiovascular progenitor cells. Nat Commun 4. doi:10.1038/ncomms3307

    Google Scholar 

  64. Kolios G, Moodley Y (2012) Introduction to stem cells and regenerative medicine. Respiration 85:3–10

    Article  Google Scholar 

  65. Yang F, Cho S-W, Son S et al (2010) Genetic engineering of human stem cells for enhanced angiogenesis using biodegradable polymeric nanoparticles. Proc Natl Acad Sci U S A 107:3317–3322

    Article  Google Scholar 

  66. Tang J, Lobatto M, Read J et al (2012) Nanomedical theranostics in cardiovascular disease. Curr Cardiovasc Imaging Rep 5:19–25

    Article  Google Scholar 

  67. Winter P, Caruthers S, Zhang H et al (2008) Antiangiogenic synergism of integrin-targeted fumagillin nanoparticles and atorvastatin in atherosclerosis. JACC Cardiovasc Imaging 1:624–634

    Article  Google Scholar 

  68. Winter P, Neubauer A, Caruthers S et al (2006) Endothelial alpha(v)beta3 integrin-targeted fumagillin nanoparticles inhibit angiogenesis in atherosclerosis. Arterioscler Thromb Vasc Biol 26:2103–2109

    Article  Google Scholar 

  69. McCarthy J, Korngold E, Weissleder R et al (2010) A light-activated theranostic nanoagent for targeted macrophage ablation in inflammatory atherosclerosis. Small 6:2041–2049

    Article  Google Scholar 

  70. Marsh J, Senpan A, Hu G et al (2007) Fibrin-targeted perfluorocarbon nanoparticles for targeted thrombolysis. Nanomedicine 4:533–543

    Article  Google Scholar 

  71. Erdem S, Sazonova I, Hara T et al (2012) Detection and treatment of intravascular thrombi with magnetofluorescent nanoparticles. Methods Enzymol 508:191–209

    Article  Google Scholar 

  72. McCarthy J, Sazonova I, Erdem S et al (2012) Multifunctional nanoagent for thrombus-targeted fibrinolytic therapy. Nanomedicine 7:1017–1028

    Article  Google Scholar 

  73. Lanza G, Yu X, Winter P et al (2002) Targeted antiproliferative drug delivery to vascular smooth muscle cells with a magnetic resonance imaging nanoparticle contrast agent: implications for rational therapy of restenosis. Circulation 106:2842–2847

    Article  Google Scholar 

  74. Sutton J, Haworth K, Pyne-Geithman G et al (2013) Ultrasound-mediated drug delivery for cardiovascular disease. Expert Opin Drug Deliv 10:573–592

    Article  Google Scholar 

  75. Sy J, Seshadri G, Yang S et al (2008) Sustained release of a p38 inhibitor from non-inflammatory microspheres inhibits cardiac dysfunction. Nat Mater 7:863–868

    Article  Google Scholar 

  76. Formiga F, Pelacho B, Garbayo E et al (2010) Sustained release of VEGF through PLGA microparticles improves vasculogenesis and tissue remodeling in an acute myocardial ischemia-reperfusion model. J Control Release 147:30–37

    Article  Google Scholar 

  77. Simon-Yarza T, Tamayo E, Benavides C et al (2013) Functional benefits of PLGA particulates carrying VEGF and CoQ10 in an animal of myocardial ischemia. Int J Pharm 454:784–790

    Article  Google Scholar 

  78. Suarez S, Grover G, Braden R et al (2013) Tunable protein release from acetalated dextran microparticles: a platform for delivery of protein therapeutics to the heart post-MI. Biomacromolecules 14:3927–3935

    Article  Google Scholar 

  79. Seshadri G, Sy J, Brown M et al (2010) The delivery of superoxide dismutase encapsulated in polyketal microparticles to rat myocardium and protection from myocardial ischemia-reperfusion injury. Biomaterials 31:1372–1379

    Article  Google Scholar 

  80. Formiga F, Garbayo E, Diaz-Herraez P et al (2013) Biodegradation and heart retention of polymeric microparticles in a rat model of myocardial ischemia. Eur J Pharm Biopharm 85:665–672

    Article  Google Scholar 

  81. Simon-Yarza T, Formiga F, Tamayo E et al (2013) PEGylated-PLGA microparticles containing VEGF for long term drug delivery. Int J Pharm 440:13–18

    Article  Google Scholar 

  82. Nelson D, Hashizume R, Yoshizumi T (2014) Intramyocardial injection of a synthetic hydrogel with delivery of bFGF and IGF1 in a rat model of ischemic cardiomyopathy. Biomacromolecules 15:1–11

    Article  Google Scholar 

  83. Li Z, Guo X, Guan J (2012) An oxygen release system to augment cardiac progenitor cell survival and differentiation under hypoxic condition. Biomaterials 33:5914–5923

    Article  Google Scholar 

  84. Ye L, Zhang P, Duval S et al (2013) Thymosin beta4 increases the potency of transplanted mesenchymal stem cells for myocardial repair. Circulation 11(Suppl 128):S32–S41

    Article  Google Scholar 

  85. Tous E, Weber H, Lee M et al (2012) Tunable hydrogel-microsphere composites that modulate local inflammation and collagen bulking. Acta Biomater 8:3218–3227

    Article  Google Scholar 

  86. Do Y, Kao E, Ganaha F et al (2004) In-stent restenosis limitation with stent-based controlled-release nitric oxide: initial results in rabbits. Radiology 230:377–382

    Article  Google Scholar 

  87. Getts D, Terry R, Getts M et al (2014) Therapeutic inflammatory monocyte modulation using immune-modifying microparticles. Sci Transl Med 6:219ra217

    Article  Google Scholar 

  88. Ranganath S, Levy O, Inamdar M et al (2012) Harnessing the mesenchymal stem cell secretome for the treatment of cardiovascular disease. Cell Stem Cell 10:244–258

    Article  Google Scholar 

  89. Paul A, Hasan A, Kindi HA et al (2014) Injectable graphene oxide/hydrogel-based angiogenic gene delivery system for vasculogenesis and cardiac repair. ACS Nano 8:8050–8062

    Article  Google Scholar 

  90. Paul A, Elias CB, Shum-Tim D et al (2013) Bioactive baculovirus nanohybrids for stent based rapid vascular re-endothelialization. Sci Rep 3:2366. doi:10.1038/srep02366

    Article  Google Scholar 

Download references

Acknowledgements

The authors acknowledge the University of Kansas New Faculty General Research Fund for support and assistance with this work. The authors also acknowledge an investigator grant provided by the Institutional Development Award (IDeA) from the National Institute of General Medical Sciences (NIGMS) of the NIH Award Number P20GM103638 (to A.P.). R.W. acknowledges the financial support from NIGMS (NIH) - Biotechnology Predoctoral Research Training Program.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Arghya Paul .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Waters, R., Maloney, R., Ranganath, S.H., Hsieh, HY., Paul, A. (2016). Nano- and Microscale Delivery Systems for Cardiovascular Therapy. In: Singh, A., Gaharwar, A. (eds) Microscale Technologies for Cell Engineering. Springer, Cham. https://doi.org/10.1007/978-3-319-20726-1_13

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-20726-1_13

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-20725-4

  • Online ISBN: 978-3-319-20726-1

  • eBook Packages: EngineeringEngineering (R0)

Publish with us

Policies and ethics