Calcium-Binding Nanoparticles for Vascular Disease

  • Deborah D. Chin
  • Sampreeti Chowdhuri
  • Eun Ji ChungEmail author


Cardiovascular disease (CVD) including atherosclerosis is the leading cause of death worldwide. As CVDs and atherosclerosis develop, plaques begin to form in the blood vessels and become calcified. Calcification within the vasculature and atherosclerotic plaques have been correlated with rupture and consequently, acute myocardial infarction. However, current imaging methods to identify vascular calcification have limitations in determining plaque composition and structure. Nanoparticles can overcome these limitations due to their versatility and ability to incorporate a wide range of targeting and contrast agents. In this review, we summarize the current understanding of calcification in atherosclerosis, their role in instigating plaque instability, and clinical methodologies to detect and analyze vascular calcification. In addition, we highlight the potential of calcium-targeting ligands and nanoparticles to create novel calcium-detecting tools.

Lay Summary

Atherosclerosis is one of the major contributors of ischemic heart disease and stroke, which remain the world’s leading cause of death. Atherosclerosis is characterized by the chronic buildup of plaque and occlusion of the arteries. Over time, blood vessels become calcified, losing the elasticity and compliance that is critical to vascular health. Current diagnostic methods to detect calcification are limited to invasive imaging procedures with potentially fatal complications or methods with inadequate sensitivity in identifying plaque composition. Notably, recent work in calcium-detecting nanoparticles show promise as useful diagnostic tools for cardiovascular disease. In this review, we discuss the role of calcification in cardiovascular diseases, current imaging technologies for the detection of calcification, and the potential of nanoparticles as diagnostic and therapeutic agents.


Nanoparticle Cardiovascular disease Vascular calcification Imaging Drug delivery Peptides 


Funding Information

The authors would like to acknowledge the financial support from the Women in Science and Engineering Program at University of Southern California (USC) for undergraduate research awarded to SC and Gabilan Assistant Professorship awarded to EJC. In addition, we acknowledge the financial support from the L. K. Whittier Foundation and the National Heart, Lung, and Blood Institute (NHLBI), R00HL124279, awarded to EJC.


  1. 1.
    Leopold JA. Vascular calcification: mechanisms of vascular smooth muscle cell calcification. Trends Cardiovasc Med. 2015;25(4):267–74. Scholar
  2. 2.
    Benjamin EJ, Virani SS, Callaway CW, Chamberlain AM, Chang AR, Cheng S, et al. Heart disease and stroke statistics—2018 update: a report from the American Heart Association. Circulation. 2018;137(12):e67–e492. Scholar
  3. 3.
    Naghavi M, Libby P, Falk E, Casscells SW, Litovsky S, Rumberger J, et al. From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: part II. Circulation. 2003;108(15):1772–8. Scholar
  4. 4.
    Falk E, Nakano M, Bentzon JF, Finn AV, Virmani R. Update on acute coronary syndromes: the pathologists’ view. Eur Heart J. 2013;34(10):719–28. Scholar
  5. 5.
    Libby P, Pasterkamp G. Requiem for the ‘vulnerable plaque’. Eur Heart J. 2015;36(43):2984–7. Scholar
  6. 6.
    Stone GW, Maehara A, Lansky AJ, de Bruyne B, Cristea E, Mintz GS, et al. A prospective natural-history study of coronary atherosclerosis. N Engl J Med. 2011;364(3):226–35. Scholar
  7. 7.
    Pasterkamp G, Schoneveld AH, van der Wal AC, Haudenschild CC, Clarijs RJ, Becker AE, et al. Relation of arterial geometry to luminal narrowing and histologic markers for plaque vulnerability: the remodeling paradox. J Am Coll Cardiol. 1998;32(3):655–62.Google Scholar
  8. 8.
    Zhu D, Mackenzie NC, Farquharson C, Macrae VE. Mechanisms and clinical consequences of vascular calcification. Front Endocrinol (Lausanne). 2012;3:95. Scholar
  9. 9.
    Abedin M, Tintut Y, Demer LL. Vascular calcification: mechanisms and clinical ramifications. Arterioscler Thromb Vasc Biol. 2004;24(7):1161–70. Scholar
  10. 10.
    Yu PJ, Skolnick A, Ferrari G, Heretis K, Mignatti P, Pintucci G, et al. Correlation between plasma osteopontin levels and aortic valve calcification: potential insights into the pathogenesis of aortic valve calcification and stenosis. J Thorac Cardiovasc Surg. 2009;138(1):196–9. Scholar
  11. 11.
    Sangiorgi G, Rumberger JA, Severson A, Edwards WD, Gregoire J, Fitzpatrick LA, et al. Arterial calcification and not lumen stenosis is highly correlated with atherosclerotic plaque burden in humans: a histologic study of 723 coronary artery segments using nondecalcifying methodology. J Am Coll Cardiol. 1998;31(1):126–33.Google Scholar
  12. 12.
    Ehara S, Kobayashi Y, Yoshiyama M, Shimada K, Shimada Y, Fukuda D, et al. Spotty calcification typifies the culprit plaque in patients with acute myocardial infarction: an intravascular ultrasound study. Circulation. 2004;110(22):3424–9. Scholar
  13. 13.
    Hoshino T, Chow LA, Hsu JJ, Perlowski AA, Abedin M, Tobis J, et al. Mechanical stress analysis of a rigid inclusion in distensible material: a model of atherosclerotic calcification and plaque vulnerability. Am J Physiol Heart Circ Physiol. 2009;297(2):H802–10. Scholar
  14. 14.
    Lutgens E, van Suylen RJ, Faber BC, Gijbels MJ, Eurlings PM, Bijnens AP, et al. Atherosclerotic plaque rupture: local or systemic process? Arterioscler Thromb Vasc Biol. 2003;23(12):2123–30. Scholar
  15. 15.
    Sage AP, Tintut Y, Demer LL. Regulatory mechanisms in vascular calcification. Nat Rev Cardiol. 2010;7(9):528–36. Scholar
  16. 16.
    Mintz GS. Intravascular imaging of coronary calcification and its clinical implications. JACC Cardiovasc Imaging. 2015;8(4):461–71. Scholar
  17. 17.
    Motro M, Shemesh J. Calcium channel blocker nifedipine slows down progression of coronary calcification in hypertensive patients compared with diuretics. Hypertension. 2001;37(6):1410–3.Google Scholar
  18. 18.
    Manson JE, Allison MA, Rossouw JE, Carr JJ, Langer RD, Hsia J, et al. Estrogen therapy and coronary-artery calcification. N Engl J Med. 2007;356(25):2591–602. Scholar
  19. 19.
    de Costa R Jr, Mintz GS, Carlier SG, Mehran R, Teirstein P, Sano K, et al. Nonrandomized comparison of coronary stenting under intravascular ultrasound guidance of direct stenting without predilation versus conventional predilation with a semi-compliant balloon versus predilation with a new scoring balloon. Am J Cardiol. 2007;100(5):812–7. Scholar
  20. 20.
    Seo A, Fujii T, Inoue T, Onoda S, Koga A, Tanaka Y, et al. Initial and long-term outcomes of sirolimus-eluting stents for calcified lesions compared with bare-metal stents. Int Heart J. 2007;48(2):137–47.Google Scholar
  21. 21.
    Khattab AA, Otto A, Hochadel M, Toelg R, Geist V, Richardt G. Drug-eluting stents versus bare metal stents following rotational atherectomy for heavily calcified coronary lesions: late angiographic and clinical follow-up results. J Interv Cardiol. 2007;20(2):100–6. Scholar
  22. 22.
    Madhavan MV, Tarigopula M, Mintz GS, Maehara A, Stone GW, Genereux P. Coronary artery calcification: pathogenesis and prognostic implications. J Am Coll Cardiol. 2014;63(17):1703–14. Scholar
  23. 23.
    Biju V. Chemical modifications and bioconjugate reactions of nanomaterials for sensing, imaging, drug delivery and therapy. Chem Soc Rev. 2014;43(3):744–64. Scholar
  24. 24.
    Sperling RA, Parak WJ. Surface modification, functionalization and bioconjugation of colloidal inorganic nanoparticles. Philos Trans A Math Phys Eng Sci. 2010;368(1915):1333–83. Scholar
  25. 25.
    Chen J, Saeki F, Wiley BJ, Cang H, Cobb MJ, Li ZY, et al. Gold nanocages: bioconjugation and their potential use as optical imaging contrast agents. Nano Lett. 2005;5(3):473–7. Scholar
  26. 26.
    Bogart LK, Pourroy G, Murphy CJ, Puntes V, Pellegrino T, Rosenblum D, et al. Nanoparticles for imaging, sensing, and therapeutic intervention. ACS Nano. 2014;8(4):3107–22. Scholar
  27. 27.
    Blanco E, Shen H, Ferrari M. Principles of nanoparticle design for overcoming biological barriers to drug delivery. Nat Biotechnol. 2015;33(9):941–51. Scholar
  28. 28.
    Sharma G, She ZG, Valenta DT, Stallcup WB, Smith JW. Targeting of macrophage foam cells in atherosclerotic plaque using oligonucleotide-functionalized nanoparticles. Nano Life. 2010;1(3–4):207–14. Google Scholar
  29. 29.
    Yilmaz A, Dengler MA, van der Kuip H, Yildiz H, Rosch S, Klumpp S, et al. Imaging of myocardial infarction using ultrasmall superparamagnetic iron oxide nanoparticles: a human study using a multi-parametric cardiovascular magnetic resonance imaging approach. Eur Heart J. 2013;34(6):462–75. Scholar
  30. 30.
    Sanchez-Gaytan BL, Fay F, Lobatto ME, Tang J, Ouimet M, Kim Y, et al. HDL-mimetic PLGA nanoparticle to target atherosclerosis plaque macrophages. Bioconjug Chem. 2015;26(3):443–51. Scholar
  31. 31.
    Niu M, Naguib YW, Aldayel AM, Shi YC, Hursting SD, Hersh MA, et al. Biodistribution and in vivo activities of tumor-associated macrophage-targeting nanoparticles incorporated with doxorubicin. Mol Pharm. 2014;11(12):4425–36. Google Scholar
  32. 32.
    Yoo SP, Pineda F, Barrett JC, Poon C, Tirrell M, Chung EJ. Gadolinium-functionalized peptide amphiphile micelles for multimodal imaging of atherosclerotic lesions. ACS Omega. 2016;1(5):996–1003. Scholar
  33. 33.
    Anselmo AC, Modery-Pawlowski CL, Menegatti S, Kumar S, Vogus DR, Tian LL, et al. Platelet-like nanoparticles: mimicking shape, flexibility, and surface biology of platelets to target vascular injuries. ACS Nano. 2014;8(11):11243–53. Scholar
  34. 34.
    Charoenphol P, Huang RB, Eniola-Adefeso O. Potential role of size and hemodynamics in the efficacy of vascular-targeted spherical drug carriers. Biomaterials. 2010;31(6):1392–402. Scholar
  35. 35.
    Dahlman JE, Barnes C, Khan O, Thiriot A, Jhunjunwala S, Shaw TE, et al. In vivo endothelial siRNA delivery using polymeric nanoparticles with low molecular weight. Nat Nanotechnol. 2014;9(8):648–55. Scholar
  36. 36.
    Tsourkas A, Shinde-Patil VR, Kelly KA, Patel P, Wolley A, Allport JR, et al. In vivo imaging of activated endothelium using an anti-VCAM-1 magnetooptical probe. Bioconjug Chem. 2005;16(3):576–81. Scholar
  37. 37.
    Bruckman MA, Jiang K, Simpson EJ, Randolph LN, Luyt LG, Yu X, et al. Dual-modal magnetic resonance and fluorescence imaging of atherosclerotic plaques in vivo using VCAM-1 targeted tobacco mosaic virus. Nano Lett. 2014;14(3):1551–8. Scholar
  38. 38.
    Nahrendorf M, Zhang H, Hembrador S, Panizzi P, Sosnovik DE, Aikawa E, et al. Nanoparticle PET-CT imaging of macrophages in inflammatory atherosclerosis. Circulation. 2008;117(3):379–87. Scholar
  39. 39.
    Chung EJ, Tirrell M. Recent advances in targeted, self-assembling nanoparticles to address vascular damage due to atherosclerosis. Adv Healthc Mater. 2015;4(16):2408–22. Scholar
  40. 40.
    Khodabandehlou K, Masehi-Lano JJ, Poon C, Wang J, Chung EJ. Targeting cell adhesion molecules with nanoparticles using in vivo and flow-based in vitro models of atherosclerosis. Exp Biol Med (Maywood). 2017;242(8):799–812. Scholar
  41. 41.
    Kumar S, Kim CW, Simmons RD, Jo H. Role of flow-sensitive microRNAs in endothelial dysfunction and atherosclerosis: mechanosensitive athero-miRs. Arterioscler Thromb Vasc Biol. 2014;34(10):2206–16. Scholar
  42. 42.
    Tsigkas N, Kidambi S, Tawakol A, Chatzizisis YS. Drug-loaded particles: “Trojan horses” in the therapy of atherosclerosis. Atherosclerosis. 2016;251:528–30. Scholar
  43. 43.
    Ross RD, Roeder RK. Binding affinity of surface functionalized gold nanoparticles to hydroxyapatite. J Biomed Mater Res A. 2011;99(1):58–66. Scholar
  44. 44.
    de Miguel L, Popa I, Noiray M, Caudron E, Arpinati L, Desmaele D, et al. Osteotropic polypeptide nanoparticles with dual hydroxyapatite binding properties and controlled cisplatin delivery. Pharm Res. 2015;32(5):1794–803. Scholar
  45. 45.
    Lee JS, Tung CH. Osteocalcin biomimic recognizes bone hydroxyapatite. Chembiochem. 2011;12(11):1669–73. Scholar
  46. 46.
    Gilbert M, Shaw WJ, Long JR, Nelson K, Drobny GP, Giachelli CM, et al. Chimeric peptides of statherin and osteopontin that bind hydroxyapatite and mediate cell adhesion. J Biol Chem. 2000;275(21):16213–8. Scholar
  47. 47.
    Fujisawa R, Kuboki Y. Preferential adsorption of dentin and bone acidic proteins on the (100) face of hydroxyapatite crystals. Biochim Biophys Acta. 1991;1075(1):56–60.Google Scholar
  48. 48.
    Fujisawa R, Wada Y, Nodasaka Y, Kuboki Y. Acidic amino acid-rich sequences as binding sites of osteonectin to hydroxyapatite crystals. Biochim Biophys Acta. 1996;1292(1):53–60.Google Scholar
  49. 49.
    Johnsson M, Levine MJ, Nancollas GH. Hydroxyapatite binding domains in salivary proteins. Crit Rev Oral Biol Med. 1993;4(3–4):371–8.Google Scholar
  50. 50.
    Boskey AL. Osteopontin and related phosphorylated sialoproteins: effects on mineralization. Ann N Y Acad Sci. 1995;760:249–56.Google Scholar
  51. 51.
    Chen NX, O'Neill KD, Chen X, Moe SM. Annexin-mediated matrix vesicle calcification in vascular smooth muscle cells. J Bone Miner Res. 2008;23(11):1798–805. Scholar
  52. 52.
    Demer LL, Watson KE, Bostrom K. Mechanism of calcification in atherosclerosis. Trends Cardiovasc Med. 1994;4(1):45–9. Scholar
  53. 53.
    Hsu JJ, Lim J, Tintut Y, Demer LL. Cell-matrix mechanics and pattern formation in inflammatory cardiovascular calcification. Heart. 2016;102(21):1710–5. Scholar
  54. 54.
    Kapustin AN, Davies JD, Reynolds JL, McNair R, Jones GT, Sidibe A, et al. Calcium regulates key components of vascular smooth muscle cell-derived matrix vesicles to enhance mineralization. Circ Res. 2011;109(1):e1–12. Google Scholar
  55. 55.
    Bostrom KI, Rajamannan NM, Towler DA. The regulation of valvular and vascular sclerosis by osteogenic morphogens. Circ Res. 2011;109(5):564–77. Scholar
  56. 56.
    Hunt JL, Fairman R, Mitchell ME, Carpenter JP, Golden M, Khalapyan T, et al. Bone formation in carotid plaques: a clinicopathological study. Stroke. 2002;33(5):1214–9.Google Scholar
  57. 57.
    Schlieper G, Schurgers L, Brandenburg V, Reutelingsperger C, Floege J. Vascular calcification in chronic kidney disease: an update. Nephrol Dial Transplant. 2016;31(1):31–9. Scholar
  58. 58.
    Al-Aly Z, Shao JS, Lai CF, Huang E, Cai J, Behrmann A, et al. Aortic Msx2-Wnt calcification cascade is regulated by TNF-alpha-dependent signals in diabetic Ldlr−/− mice. Arterioscler Thromb Vasc Biol. 2007;27(12):2589–96. Scholar
  59. 59.
    Yang X, Meng X, Su X, Mauchley DC, Ao L, Cleveland JC Jr, et al. Bone morphogenic protein 2 induces Runx2 and osteopontin expression in human aortic valve interstitial cells: role of Smad1 and extracellular signal-regulated kinase 1/2. J Thorac Cardiovasc Surg. 2009;138(4):1008–15. Scholar
  60. 60.
    Choi ST, Kim JH, Kang EJ, Lee SW, Park MC, Park YB, et al. Osteopontin might be involved in bone remodelling rather than in inflammation in ankylosing spondylitis. Rheumatology (Oxford). 2008;47(12):1775–9. Scholar
  61. 61.
    Lomashvili KA, Wang X, Wallin R, O'Neill WC. Matrix Gla protein metabolism in vascular smooth muscle and role in uremic vascular calcification. J Biol Chem. 2011;286(33):28715–22. Scholar
  62. 62.
    Speer MY, Yang HY, Brabb T, Leaf E, Look A, Lin WL, et al. Smooth muscle cells give rise to osteochondrogenic precursors and chondrocytes in calcifying arteries. Circ Res. 2009;104(6):733–41. Scholar
  63. 63.
    Hutcheson JD, Goettsch C, Bertazzo S, Maldonado N, Ruiz JL, Goh W, et al. Genesis and growth of extracellular-vesicle-derived microcalcification in atherosclerotic plaques. Nat Mater. 2016;15(3):335–43. Scholar
  64. 64.
    Demer LL, Tintut Y. Inflammatory, metabolic, and genetic mechanisms of vascular calcification. Arterioscler Thromb Vasc Biol. 2014;34(4):715–23. Scholar
  65. 65.
    Genge BR, Wu LNY, Wuthier RE. Differential fractionation of matrix vesicle proteins—further characterization of the acidic phospholipid-dependent Ca2+-binding proteins. J Biol Chem. 1990;265(8):4703–10.Google Scholar
  66. 66.
    Kapustin AN, Shanahan CM. Calcium regulation of vascular smooth muscle cell-derived matrix vesicles. Trends Cardiovas Med. 2012;22(5):133–7. Scholar
  67. 67.
    Krohn JB, Hutcheson JD, Martinez-Martinez E, Aikawa E. Extracellular vesicles in cardiovascular calcification: expanding current paradigms. J Physiol. 2016;594(11):2895–903. Scholar
  68. 68.
    Persy V, D'Haese P. Vascular calcification and bone disease: the calcification paradox. Trends Mol Med. 2009;15(9):405–16. Scholar
  69. 69.
    Patrick F, Ross JC, Alvarez JI, Sander D, Butler WT, Farach-Carson MC, et al. Interactions between the bone matrix proteins osteopontin and bone sialoprotein and the osteoclast integration potentiate bone resorption. J Biol Chem. 1993;268:9901–7.Google Scholar
  70. 70.
    Guiqian Chen CD, Li Y-P. TGF-beta and BMP signaling in osteoblastt differentiation and bone formation. Int J Biol Sci. 2012;8(2):272–88.Google Scholar
  71. 71.
    Hutcheson JD, Maldonado N, Aikawa E. Small entities with large impact: microcalcifications and atherosclerotic plaque vulnerability. Curr Opin Lipidol. 2014;25(5):327–32. Scholar
  72. 72.
    Richardson PD, Davies MJ, Born GV. Influence of plaque configuration and stress distribution on fissuring of coronary atherosclerotic plaques. Lancet. 1989;2(8669):941–4.Google Scholar
  73. 73.
    Calvert PA, Liew TV, Gorenne I, Clarke M, Costopoulos C, Obaid DR, et al. Leukocyte telomere length is associated with high-risk plaques on virtual histology intravascular ultrasound and increased proinflammatory activity. Arterioscler Thromb Vasc Biol. 2011;31(9):2157–64. Scholar
  74. 74.
    Kelly-Arnold A, Maldonado N, Laudier D, Aikawa E, Cardoso L, Weinbaum S. Revised microcalcification hypothesis for fibrous cap rupture in human coronary arteries. Proc Natl Acad Sci U S A. 2013;110(26):10741–6. Scholar
  75. 75.
    Maldonado N, Kelly-Arnold A, Vengrenyuk Y, Laudier D, Fallon JT, Virmani R, et al. A mechanistic analysis of the role of microcalcifications in atherosclerotic plaque stability: potential implications for plaque rupture. Am J Physiol Heart Circ Physiol. 2012;303(5):H619–28. Scholar
  76. 76.
    Demer LL, Tintut Y, Nguyen KL, Hsiai T, Lee JT. Rigor and reproducibility in analysis of vascular calcification. Circ Res. 2017;120(8):1240–2. Scholar
  77. 77.
    Bittencourt MS, Cerci RJ. Statin effects on atherosclerotic plaques: regression or healing? BMC Med. 2015;13:260. Scholar
  78. 78.
    Imoto K, Hiro T, Fujii T, Murashige A, Fukumoto Y, Hashimoto G, et al. Longitudinal structural determinants of atherosclerotic plaque vulnerability: a computational analysis of stress distribution using vessel models and three-dimensional intravascular ultrasound imaging. J Am Coll Cardiol. 2005;46(8):1507–15. Scholar
  79. 79.
    Messika-Zeitoun D, Aubry MC, Detaint D, Bielak LF, Peyser PA, Sheedy PF, et al. Evaluation and clinical implications of aortic valve calcification measured by electron-beam computed tomography. Circulation. 2004;110(3):356–62. Scholar
  80. 80.
    Hecht HS, Budoff MJ, Berman DS, Ehrlich J, Rumberger JA. Coronary artery calcium scanning: clinical paradigms for cardiac risk assessment and treatment. Am Heart J. 2006;151(6):1139–46. Scholar
  81. 81.
    Greenland P, Alpert JS, Beller GA, Benjamin EJ, Budoff MJ, Fayad ZA, et al. 2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2010;56(25):e50–103. Scholar
  82. 82.
    Rumberger JA, Kaufman L. A rosetta stone for coronary calcium risk stratification: agatston, volume, and mass scores in 11,490 individuals. AJR Am J Roentgenol. 2003;181(3):743–8. Scholar
  83. 83.
    Callister TQ, Cooil B, Raya SP, Lippolis NJ, Russo DJ, Raggi P. Coronary artery disease: improved reproducibility of calcium scoring with an electron-beam CT volumetric method. Radiology. 1998;208(3):807–14. Scholar
  84. 84.
    Sanz J, Fayad ZA. Imaging of atherosclerotic cardiovascular disease. Nature. 2008;451(7181):953–7. Scholar
  85. 85.
    Saam T, Ferguson MS, Yarnykh VL, Takaya N, Xu D, Polissar NL, et al. Quantitative evaluation of carotid plaque composition by in vivo MRI. Arterioscler Thromb Vasc Biol. 2005;25(1):234–9. Scholar
  86. 86.
    Kramer CM, Anderson JD. MRI of atherosclerosis: diagnosis and monitoring therapy. Expert Rev Cardiovasc Ther. 2007;5(1):69–80. Scholar
  87. 87.
    Friedrich GJ, Moes NY, Muhlberger VA, Gabl C, Mikuz G, Hausmann D, et al. Detection of intralesional calcium by intracoronary ultrasound depends on the histologic pattern. Am Heart J. 1994;128(3):435–41.Google Scholar
  88. 88.
    Johnson RC, Leopold JA, Loscalzo J. Vascular calcification: pathobiological mechanisms and clinical implications. Circ Res. 2006;99(10):1044–59. Scholar
  89. 89.
    Prati F, Regar E, Mintz GS, Arbustini E, Di Mario C, Jang IK, et al. Expert review document on methodology, terminology, and clinical applications of optical coherence tomography: physical principles, methodology of image acquisition, and clinical application for assessment of coronary arteries and atherosclerosis. Eur Heart J. 2010;31(4):401–15. Scholar
  90. 90.
    Yabushita H, Bouma BE, Houser SL, Aretz HT, Jang IK, Schlendorf KH, et al. Characterization of human atherosclerosis by optical coherence tomography. Circulation. 2002;106(13):1640–5.Google Scholar
  91. 91.
    Jang IK, Bouma BE, Kang DH, Park SJ, Park SW, Seung KB, et al. Visualization of coronary atherosclerotic plaques in patients using optical coherence tomography: comparison with intravascular ultrasound. J Am Coll Cardiol. 2002;39(4):604–9.Google Scholar
  92. 92.
    Orbay H, Hong H, Zhang Y, Cai W. Positron emission tomography imaging of atherosclerosis. Theranostics. 2013;3(11):894–902. Scholar
  93. 93.
    Derlin T, Richter U, Bannas P, Begemann P, Buchert R, Mester J, et al. Feasibility of 18F-sodium fluoride PET/CT for imaging of atherosclerotic plaque. J Nucl Med. 2010;51(6):862–5. Scholar
  94. 94.
    Dweck MR, Jones C, Joshi NV, Fletcher AM, Richardson H, White A, et al. Assessment of valvular calcification and inflammation by positron emission tomography in patients with aortic stenosis. Circulation. 2012;125(1):76–86. Scholar
  95. 95.
    Beheshti M, Saboury B, Mehta NN, Torigian DA, Werner T, Mohler E, et al. Detection and global quantification of cardiovascular molecular calcification by fluoro18-fluoride positron emission tomography/computed tomography—a novel concept. Hell J Nucl Med. 2011;14(2):114–20.Google Scholar
  96. 96.
    Allen S, Liu YG, Scott E. Engineering nanomaterials to address cell-mediated inflammation in atherosclerosis. Regen Eng Transl Med. 2016;2(1):37–50. Scholar
  97. 97.
    Christopher AF, Kaur RP, Kaur G, Kaur A, Gupta V, Bansal P. MicroRNA therapeutics: discovering novel targets and developing specific therapy. Perspect Clin Res. 2016;7(2):68–74. Scholar
  98. 98.
    Kheirolomoom A, Kim CW, Seo JW, Kumar S, Son DJ, Gagnon MK, et al. Multifunctional nanoparticles facilitate molecular targeting and miRNA delivery to inhibit atherosclerosis in ApoE(−/−) mice. ACS Nano. 2015;9(9):8885–97. Scholar
  99. 99.
    Lee JS, Morrisett JD, Tung CH. Detection of hydroxyapatite in calcified cardiovascular tissues. Atherosclerosis. 2012;224(2):340–7. Scholar
  100. 100.
    Schulz RB, Semmler W. Fundamentals of optical imaging. Handb Exp Pharmacol. 2008;185 Pt 1:3–22. Scholar
  101. 101.
    Aikawa E, Nahrendorf M, Sosnovik D, Lok VM, Jaffer FA, Aikawa M, et al. Multimodality molecular imaging identifies proteolytic and osteogenic activities in early aortic valve disease. Circulation. 2007;115(3):377–86. Scholar
  102. 102.
    Pellicoab J, AVL-V M, Benitoa JM, García-Segurab V, Fusterc J, Ruiz-Cabelloab, et al. Microwave-driven synthesis of bisphosphonate nanoparticles allows in vivo visualisation of atherosclerotic plaque. RSC Adv. 2014;5:1661–5. Google Scholar
  103. 103.
    Ho AM, Johnson MD, Kingsley DM. Role of the mouse ank gene in control of tissue calcification and arthritis. Science. 2000;289(5477):265–70.Google Scholar
  104. 104.
    Lei Y, Nosoudi N, Vyavahare N. Targeted chelation therapy with EDTA-loaded albumin nanoparticles regresses arterial calcification without causing systemic side effects. J Control Release. 2014;196:79–86. Scholar
  105. 105.
    Li N, Song J, Zhu G, Shi X, Wang Y. Alendronate conjugated nanoparticles for calcification targeting. Colloids Surf B Biointerfaces. 2016;142:344–50. Scholar
  106. 106.
    Choi SW, Kim JH. Design of surface-modified poly(D,L-lactide-co-glycolide) nanoparticles for targeted drug delivery to bone. J Control Release. 2007;122(1):24–30. Scholar
  107. 107.
    Thamake SI, Raut SL, Gryczynski Z, Ranjan AP, Vishwanatha JK. Alendronate coated poly-lactic-co-glycolic acid (PLGA) nanoparticles for active targeting of metastatic breast cancer. Biomaterials. 2012;33(29):7164–73. Scholar
  108. 108.
    Swami A, Reagan MR, Basto P, Mishima Y, Kamaly N, Glavey S, et al. Engineered nanomedicine for myeloma and bone microenvironment targeting. Proc Natl Acad Sci U S A. 2014;111(28):10287–92. Scholar
  109. 109.
    Hengst V, Oussoren C, Kissel T, Storm G. Bone targeting potential of bisphosphonate-targeted liposomes. Preparation, characterization and hydroxyapatite binding in vitro. Int J Pharm. 2007;331(2):224–7. Scholar
  110. 110.
    Sanchez F, Zhang L. Molecular dynamics modeling of the interface between surface functionalized graphitic structures and calcium-silicate-hydrate: interaction energies, structure, and dynamics. J Colloid Interface Sci. 2008;323(2):349–58. Scholar
  111. 111.
    Murphy MB, Hartgerink JD, Goepferich A, Mikos AG. Synthesis and in vitro hydroxyapatite binding of peptides conjugated to calcium-binding moieties. Biomacromolecules. 2007;8(7):2237–43. Scholar
  112. 112.
    Torchilin VP. Multifunctional nanocarriers. Adv Drug Deliv Rev. 2006;58(14):1532–55. Scholar
  113. 113.
    Mao J, Shi X, Wu YB, Gong SQ. Identification of specific hydroxyapatite {001} binding heptapeptide by phage display and its nucleation effect. Materials (Basel) 2016;9(8).
  114. 114.
    Roy MD, Amis EJ, Becker ML. Identification of a highly specific hydroxyapatite-binding peptide using phage display. Adv Mater. 2008;20(10):1830–6.Google Scholar
  115. 115.
    Weiger MC, Park JJ, Roy MD, Stafford CM, Karim A, Becker ML. Quantification of the binding affinity of a specific hydroxyapatite binding peptide. Biomaterials. 2010;31(11):2955–63. Scholar
  116. 116.
    Hauschka PV, Carr SA. Calcium-dependent alpha-helical structure in osteocalcin. Biochemistry. 1982;21(10):2538–47.Google Scholar
  117. 117.
    Meisel CL, Bainbridge P, Mitsouras D, Wong JY. Targeted nanoparticle binding to hydroxyapatite in a high serum environment for early detection of heart disease. ACS Appl Nano Mater. 2018;1:4927–39. Scholar
  118. 118.
    Bain JL, Culpepper BK, Reddy MS, Bellis SL. Comparing variable-length polyglutamate domains to anchor an osteoinductive collagen-mimetic peptide to diverse bone grafting materials. Int J Oral Maxillofac Implants. 2014;29(6):1437–45. Scholar
  119. 119.
    Bain JL, Bonvallet PP, Abou-Arraj RV, Schupbach P, Reddy MS, Bellis SL. Enhancement of the regenerative potential of anorganic bovine bone graft utilizing a polyglutamate-modified BMP2 peptide with improved binding to calcium-containing materials. Tissue Eng A. 2015;21(17–18):2426–36. Scholar
  120. 120.
    Culpepper BK, Bonvallet PP, Reddy MS, Ponnazhagan S, Bellis SL. Polyglutamate directed coupling of bioactive peptides for the delivery of osteoinductive signals on allograft bone. Biomaterials. 2013;34(5):1506–13. Scholar

Copyright information

© The Regenerative Engineering Society 2018

Authors and Affiliations

  1. 1.Department of Biomedical EngineeringUniversity of Southern CaliforniaLos AngelesUSA
  2. 2.Department of Chemical Engineering and Materials ScienceUniversity of Southern CaliforniaLos AngelesUSA
  3. 3.Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of MedicineUniversity of Southern CaliforniaLos AngelesUSA
  4. 4.Division of Nephrology and Hypertension, Department of Medicine, Keck School of MedicineUniversity of Southern CaliforniaLos AngelesUSA
  5. 5.Division of Vascular Surgery and Endovascular Therapy, Department of Surgery, Keck School of MedicineUniversity of Southern CaliforniaLos AngelesUSA
  6. 6.Norris Comprehensive Cancer Center, Keck School of MedicineUniversity of Southern CaliforniaLos AngelesUSA

Personalised recommendations