Drug Delivery and Translational Research

, Volume 8, Issue 4, pp 868–882 | Cite as

Monocyte-mediated drug delivery systems for the treatment of cardiovascular diseases

  • Gil Aizik
  • Etty Grad
  • Gershon GolombEmail author
Review Article


Major advances have been achieved in understanding the mechanisms and risk factors leading to cardiovascular disorders and consequently developing new therapies. A strong inflammatory response occurs with a substantial recruitment of innate immunity cells in atherosclerosis, myocardial infarction, and restenosis. Monocytes and macrophages are key players in the healing process that ensues following injury. In the inflamed arterial wall, monocytes, and monocyte-derived macrophages have specific functions in the initiation and resolution of inflammation, principally through phagocytosis, and the release of inflammatory cytokines and reactive oxygen species. In this review, we will focus on delivery systems, mainly nanoparticles, for modulating circulating monocytes/monocyte-derived macrophages. We review the different strategies of depletion or modulation of circulating monocytes and monocyte subtypes, using polymeric nanoparticles and liposomes for the therapy of myocardial infarction and restenosis. We will further discuss the strategies of exploiting circulating monocytes for biological targeting of nanocarrier-based drug delivery systems for therapeutic and diagnostic applications.


Drug delivery systems Liposomes Polymeric nanoparticles Monocytes Monocyte subpopulations Vascular injury 



Alendronate nanoparticles




Coronary heart disease


Classical monocytes


Cardiovascular disease(s)


Drug delivery system(s)


Drug eluting stent


Endothelial cells


Diabetes mellitus


Enhanced permeability and retention effect






Intermediate monocytes


Liposomal alendronate


Liposomal clodronate


Liposomal quantum dots


Myocardial infraction


Mononuclear phagocytic system


Number concentration


Non-classical monocytes




Percutaneous coronary intervention(s)


Polyethylene glycol


Poly(d,l-lactide co-glycolide)


Quantum dots


Quantum yield


siRNA sequence against CCR2


Smooth muscle cells



GG is grateful to the Woll Sisters and Brothers Chair in Cardiovascular Diseases.

Compliance with ethical standards

Conflict of interests

EG and GA declare that they have no conflict of interest. GG has a financial stake in Biorest Ltd.


  1. 1.
    Benjamin. Heart disease and stroke statistics —2017 update: a report from the American Heart Association (vol 135, pg e146, 2017). Circulation. 2017;135(10):E646-E.Google Scholar
  2. 2.
    Faxon DP. Systemic drug therapy for restenosis: “deja vu all over again”. Circulation. 2002;106(18):2296–8.PubMedCrossRefGoogle Scholar
  3. 3.
    Garas SM, Huber P, Scott NA. Overview of therapies for prevention of restenosis after coronary interventions. Pharmacol Ther. 2001;92(2–3):165–78.PubMedCrossRefGoogle Scholar
  4. 4.
    Serruys PW, de Jaegere P, Kiemeneij F, Macaya C, Rutsch W, Heyndrickx G, et al. A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. Benestent study group. N Engl J Med. 1994;331(8):489–95.PubMedCrossRefGoogle Scholar
  5. 5.
    Lowe HC, Oesterle SN, Khachigian LM. Coronary in-stent restenosis: current status and future strategies. J Am Coll Cardiol. 2002;39(2):183–93.PubMedCrossRefGoogle Scholar
  6. 6.
    Packard RR, Lichtman AH, Libby P. Innate and adaptive immunity in atherosclerosis. Semin Immunopathol. 2009;31(1):5–22.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Dangas GD, Claessen BE, Caixeta A, Sanidas EA, Mintz GS, Mehran R. In-stent restenosis in the drug-eluting stent era. J Am Coll Cardiol. 2010;56(23):1897–907.PubMedCrossRefGoogle Scholar
  8. 8.
    Inoue T, Node K. Molecular basis of restenosis and novel issues of drug-eluting stents. Circ J. 2009;73(4):615–21.PubMedCrossRefGoogle Scholar
  9. 9.
    Kastrati A, Mehilli J, Dirschinger J, Pache J, Ulm K, Schuhlen H, et al. Restenosis after coronary placement of various stent types. Am J Cardiol. 2001;87(1):34–9.PubMedCrossRefGoogle Scholar
  10. 10.
    Marx SO, Jayaraman T, Go LO, Marks AR. Rapamycin-FKBP inhibits cell cycle regulators of proliferation in vascular smooth muscle cells. Circ Res. 1995;76(3):412–7.PubMedCrossRefGoogle Scholar
  11. 11.
    Stone GW, Ellis SG, Cox DA, Hermiller J, O'Shaughnessy C, Mann JT, et al. A polymer-based, paclitaxel-eluting stent in patients with coronary artery disease. N Engl J Med. 2004;350(3):221–31.PubMedCrossRefGoogle Scholar
  12. 12.
    Kastrati A, Mehilli J, von Beckerath N, Dibra A, Hausleiter J, Pache J, et al. Sirolimus-eluting stent or paclitaxel-eluting stent vs balloon angioplasty for prevention of recurrences in patients with coronary in-stent restenosis: a randomized controlled trial. JAMA. 2005;293(2):165–71.PubMedCrossRefGoogle Scholar
  13. 13.
    Poder TG, Erraji J, Coulibaly LP, Koffi K. Percutaneous coronary intervention with second-generation drug-eluting stent versus bare-metal stent: systematic review and cost-benefit analysis. PLoS One. 2017;12(5):e0177476.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Arroyo D, Gendre G, Schukraft S, Kallinikou Z, Muller O, Baeriswyl G et al. Comparison of everolimus- and biolimus-eluting coronary stents with everolimus-eluting bioresorbable vascular scaffolds: two-year clinical outcomes of the EVERBIO II trial. Int J Cardiol 2017; 243:121-125.Google Scholar
  15. 15.
    Park SJ, Shim WH, Ho DS, Raizner AE, Park SW, Hong MK, et al. A paclitaxel-eluting stent for the prevention of coronary restenosis. N Engl J Med. 2003;348(16):1537–45.PubMedCrossRefGoogle Scholar
  16. 16.
    Godin B, Sakamoto JH, Serda RE, Grattoni A, Bouamrani A, Ferrari M. Emerging applications of nanomedicine for the diagnosis and treatment of cardiovascular diseases. Trends Pharmacol Sci. 2010;31(5):199–205.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Ruiz-Esparza GU, Flores-Arredondo JH, Segura-Ibarra V, Torre-Amione G, Ferrari M, Blanco E, et al. The physiology of cardiovascular disease and innovative liposomal platforms for therapy. Int J Nanomedicine. 2013;8:629–40.PubMedPubMedCentralGoogle Scholar
  18. 18.
    Singh B, Garg T, Goyal AK, Rath G. Recent advancements in the cardiovascular drug carriers. Artif Cells Nanomed Biotechnol. 2016;44(1):216–25.PubMedCrossRefGoogle Scholar
  19. 19.
    Matoba T, Koga JI, Nakano K, Egashira K, Tsutsui H. Nanoparticle-mediated drug delivery system for atherosclerotic cardiovascular disease. J Cardiol 2017;70(3):206-211.Google Scholar
  20. 20.
    Ta HT, Truong NP, Whittaker AK, Davis TP, Peter K. The effects of particle size, shape, density and flow characteristics on particle margination to vascular walls in cardiovascular diseases. Expert Opin Drug Deliv. 2017:1–13.Google Scholar
  21. 21.
    Banai S, Chorny M, Gertz SD, Fishbein I, Gao J, Perez L, et al. Locally delivered nanoencapsulated tyrphostin (AGL-2043) reduces neointima formation in balloon-injured rat carotid and stented porcine coronary arteries. Biomaterials. 2005;26(4):451–61.PubMedCrossRefGoogle Scholar
  22. 22.
    Yin RX, Yang DZ, Wu JZ. Nanoparticle drug- and gene-eluting stents for the prevention and treatment of coronary restenosis. Theranostics. 2014;4(2):175–200.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Chorny M, Fishbein I, Yellen BB, Alferiev IS, Bakay M, Ganta S, et al. Targeting stents with local delivery of paclitaxel-loaded magnetic nanoparticles using uniform fields. Proc Natl Acad Sci U S A. 2010;107(18):8346–51.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Tsukie N, Nakano K, Matoba T, Masuda S, Iwata E, Miyagawa M, et al. Pitavastatin-incorporated nanoparticle-eluting stents attenuate in-stent stenosis without delayed endothelial healing effects in a porcine coronary artery model. J Atheroscler Thromb. 2013;20(1):32–45.PubMedCrossRefGoogle Scholar
  25. 25.
    Danenberg HD, Fishbein I, Gao J, Monkkonen J, Reich R, Gati I, et al. Macrophage depletion by clodronate-containing liposomes reduces neointimal formation after balloon injury in rats and rabbits. Circulation. 2002;106(5):599–605.PubMedCrossRefGoogle Scholar
  26. 26.
    Gutman D, Golomb G. Liposomal alendronate for the treatment of restenosis. J Control Release. 2012;161(2):619–27.PubMedCrossRefGoogle Scholar
  27. 27.
    Firestein GS. Evolving concepts of rheumatoid arthritis. Nature. 2003;423(6937):356–61.PubMedCrossRefGoogle Scholar
  28. 28.
    Fernandes JV, Cobucci RN, Jatoba CA, Fernandes TA, de Azevedo JW, de Araujo JM. The role of the mediators of inflammation in cancer development. Pathol Oncol Res. 2015;21(3):527–34.PubMedCrossRefGoogle Scholar
  29. 29.
    Toutouzas K, Colombo A, Stefanadis C. Inflammation and restenosis after percutaneous coronary interventions. Eur Heart J. 2004;25(19):1679–87.PubMedCrossRefGoogle Scholar
  30. 30.
    Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med. 1999;340(2):115–26.PubMedCrossRefGoogle Scholar
  31. 31.
    Drachman DE, Simon DI. Inflammation as a mechanism and therapeutic target for in-stent restenosis. Curr Atheroscler Rep. 2005;7(1):44–9.PubMedCrossRefGoogle Scholar
  32. 32.
    Mickelson JK, Lakkis NM, Villarreal-Levy G, Hughes BJ, Smith CW. Leukocyte activation with platelet adhesion after coronary angioplasty: a mechanism for recurrent disease? J Am Coll Cardiol. 1996;28(2):345–53.PubMedCrossRefGoogle Scholar
  33. 33.
    Palabrica T, Lobb R, Furie BC, Aronovitz M, Benjamin C, Hsu YM, et al. Leukocyte accumulation promoting fibrin deposition is mediated in vivo by P-selectin on adherent platelets. Nature. 1992;359(6398):848–51.PubMedCrossRefGoogle Scholar
  34. 34.
    Rinder HM, Bonan JL, Rinder CS, Ault KA, Smith BR. Activated and unactivated platelet adhesion to monocytes and neutrophils. Blood. 1991;78(7):1760–9.PubMedGoogle Scholar
  35. 35.
    Decano JL, Mattson PC, Aikawa M. Macrophages in vascular inflammation: origins and functions. Curr Atheroscler Rep. 2016;18(6):34.PubMedCrossRefGoogle Scholar
  36. 36.
    Welt FG, Edelman ER, Simon DI, Rogers C. Neutrophil, not macrophage, infiltration precedes neointimal thickening in balloon-injured arteries. Arterioscler Thromb Vasc Biol. 2000;20(12):2553–8.PubMedCrossRefGoogle Scholar
  37. 37.
    Kollum M, Kaiser S, Kinscherf R, Metz J, Kubler W, Hehrlein C. Apoptosis after stent implantation compared with balloon angioplasty in rabbits. Role of macrophages. Arterioscler Thromb Vasc Biol. 1997;17(11):2383–8.PubMedCrossRefGoogle Scholar
  38. 38.
    Rogers C, Welt FG, Karnovsky MJ, Edelman ER. Monocyte recruitment and neointimal hyperplasia in rabbits. Coupled inhibitory effects of heparin. Arterioscler Thromb Vasc Biol. 1996;16(10):1312–8.PubMedCrossRefGoogle Scholar
  39. 39.
    Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nat Rev Immunol. 2005;5(12):953–64.PubMedCrossRefGoogle Scholar
  40. 40.
    Nahrendorf M, Swirski FK, Aikawa E, Stangenberg L, Wurdinger T, Figueiredo JL, et al. The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions. J Exp Med. 2007;204(12):3037–47.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Nahrendorf M, Pittet MJ, Swirski FK. Monocytes: protagonists of infarct inflammation and repair. Circulation. 2010;121(22):2437–45.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Ziegler-Heitbrock L. Monocyte subsets in man and other species. Cell Immunol. 2014;289(1–2):135–9.PubMedCrossRefGoogle Scholar
  43. 43.
    Moniuszko M, Bodzenta-Lukaszyk A, Kowal K, Lenczewska D, Dabrowska M. Enhanced frequencies of CD14++CD16+, but not CD14+CD16+, peripheral blood monocytes in severe asthmatic patients. Clin Immunol. 2009;130(3):338–46.PubMedCrossRefGoogle Scholar
  44. 44.
    Sunderkotter C, Nikolic T, Dillon MJ, van Rooijen N, Stehling M, Drevets DA, et al. Subpopulations of mouse blood monocytes differ in maturation stage and inflammatory response. J Immunol. 2004;172(7):4410–7.PubMedCrossRefGoogle Scholar
  45. 45.
    Yrlid U, Jenkins CD, MacPherson GG. Relationships between distinct blood monocyte subsets and migrating intestinal lymph dendritic cells in vivo under steady-state conditions. J Immunol. 2006;176(7):4155–62.PubMedCrossRefGoogle Scholar
  46. 46.
    Grad E, Zolotarevsky K, Danenberg HD, Nordling-David MM, Gutman D, Golomb G. The role of monocyte subpopulations in vascular injury following partial and transient depletion. Drug Deliv Transl Res. 2017.
  47. 47.
    Tsujioka H, Imanishi T, Ikejima H, Kuroi A, Takarada S, Tanimoto T, et al. Impact of heterogeneity of human peripheral blood monocyte subsets on myocardial salvage in patients with primary acute myocardial infarction. J Am Coll Cardiol. 2009;54(2):130–8.PubMedCrossRefGoogle Scholar
  48. 48.
    Liu Y, Imanishi T, Ikejima H, Tsujioka H, Ozaki Y, Kuroi A, et al. Association between circulating monocyte subsets and in-stent restenosis after coronary stent implantation in patients with ST-elevation myocardial infarction. Circ J. 2010;74(12):2585–91.PubMedCrossRefGoogle Scholar
  49. 49.
    Crane MJ, Daley JM, van Houtte O, Brancato SK, Henry WL, Albina JE. The monocyte to macrophage transition in the murine sterile wound. Plos One. 2014;Jan 22;9(1):e86660.Google Scholar
  50. 50.
    Katsuki S, Matoba T, Nakashiro S, Sato K, Koga J, Nakano K, et al. Nanoparticle-mediated delivery of pitavastatin inhibits atherosclerotic plaque destabilization/rupture in mice by regulating the recruitment of inflammatory monocytes. Circulation. 2014;129(8):896–906.PubMedCrossRefGoogle Scholar
  51. 51.
    Moghimi SM, Hunter AC, Andresen TL. Factors controlling nanoparticle pharmacokinetics: an integrated analysis and perspective. Annu Rev Pharmacol Toxicol. 2012;52:481–503.PubMedCrossRefGoogle Scholar
  52. 52.
    Moghimi SM, Hunter AC, Murray JC. Long-circulating and target-specific nanoparticles: theory to practice. Pharmacol Rev. 2001;53(2):283–318.PubMedPubMedCentralGoogle Scholar
  53. 53.
    Moghimi SM, Szebeni J. Stealth liposomes and long circulating nanoparticles: critical issues in pharmacokinetics, opsonization and protein-binding properties. Prog Lipid Res. 2003;42(6):463–78.PubMedCrossRefGoogle Scholar
  54. 54.
    Park K. Targeted vs. non-targeted delivery systems: reduced toxicity over efficacy. J Control Release. 2014;178:126.PubMedCrossRefGoogle Scholar
  55. 55.
    Roth JC, Curiel DT, Pereboeva L. Cell vehicle targeting strategies. Gene Ther. 2008;15(10):716–29.PubMedCrossRefGoogle Scholar
  56. 56.
    Gladue RP, Bright GM, Isaacson RE, Newborg MF. In vitro and in vivo uptake of azithromycin (CP-62,993) by phagocytic cells: possible mechanism of delivery and release at sites of infection. Antimicrob Agents Chemother. 1989;33(3):277–82.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Gray M, Botelho RJ. Phagocytosis: hungry. Hungry Cells Methods Mol Biol. 2017;1519:1–16.PubMedGoogle Scholar
  58. 58.
    Doshi N, Mitragotri S. Macrophages recognize size and shape of their targets. PLoS One. 2010;5(3).Google Scholar
  59. 59.
    Epstein-Barash H, Gutman D, Markovsky E, Mishan-Eisenberg G, Koroukhov N, Szebeni J, et al. Physicochemical parameters affecting liposomal bisphosphonates bioactivity for restenosis therapy: internalization, cell inhibition, activation of cytokines and complement, and mechanism of cell death. J Control Release. 2010;146(2):182–95.PubMedCrossRefGoogle Scholar
  60. 60.
    Moghimi SM, Hunter AC. Recognition by macrophages and liver cells of opsonized phospholipid vesicles and phospholipid headgroups. Pharm Res. 2001;18(1):1–8.PubMedCrossRefGoogle Scholar
  61. 61.
    van Rooijen N, Sanders A. Liposome mediated depletion of macrophages: mechanism of action, preparation of liposomes and applications. J Immunol Methods. 1994;174(1–2):83–93.PubMedCrossRefGoogle Scholar
  62. 62.
    Moghimi SM, Patel HM. Tissue specific opsonins for phagocytic-cells and their different affinity for cholesterol-rich liposomes. FEBS Lett. 1988;233(1):143–7.PubMedCrossRefGoogle Scholar
  63. 63.
    Patel HM, Tuzel NS, Ryman BE. Inhibitory effect of cholesterol on the uptake of liposomes by liver and spleen. Biochim Biophys Acta. 1983;761(2):142–51.PubMedCrossRefGoogle Scholar
  64. 64.
    Epstein H, Afergan E, Moise T, Richter Y, Rudich Y, Golomb G. Number-concentration of nanoparticles in liposomal and polymeric multiparticulate preparations: empirical and calculation methods. Biomaterials. 2006;27(4):651–9.PubMedCrossRefGoogle Scholar
  65. 65.
    Aizik G, Waiskopf N, Agbaria M, Levi-Kalisman Y, Banin U, Golomb G. Delivery of liposomal quantum dots via monocytes for imaging of inflamed tissue. ACS Nano. 2017;11(3):3038–51.PubMedCrossRefGoogle Scholar
  66. 66.
    Matsui M, Shimizu Y, Kodera Y, Kondo E, Ikehara Y, Nakanishi H. Targeted delivery of oligomannose-coated liposome to the omental micrometastasis by peritoneal macrophages from patients with gastric cancer. Cancer Sci. 2010;101(7):1670–7.PubMedCrossRefGoogle Scholar
  67. 67.
    Afergan E, Epstein H, Dahan R, Koroukhov N, Rohekar K, Danenberg HD, et al. Delivery of serotonin to the brain by monocytes following phagocytosis of liposomes. J Control Release. 2008;132(2):84–90.PubMedCrossRefGoogle Scholar
  68. 68.
    Trivedi RA, Mallawarachi C, U-King-Im JM, Graves MJ, Horsley J, Goddard MJ, et al. Identifying inflamed carotid plaques using in vivo USPIO-enhanced MR imaging to label plaque macrophages. Arterioscler Thromb Vasc Biol. 2006;26(7):1601–6.PubMedCrossRefGoogle Scholar
  69. 69.
    Sigovan M, Boussel L, Sulaiman A, Sappey-Marinier D, Alsaid H, Desbleds-Mansard C, et al. Rapid-clearance iron nanoparticles for inflammation imaging of atherosclerotic plaque: initial experience in animal model. Radiology. 2009;252(2):401–9.PubMedCrossRefGoogle Scholar
  70. 70.
    Harel-Adar T, Ben Mordechai T, Amsalem Y, Feinberg MS, Leor J, Cohen S. Modulation of cardiac macrophages by phosphatidylserine-presenting liposomes improves infarct repair. Proc Natl Acad Sci U S A. 2011;108(5):1827–32.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Bae YH, Park K. Targeted drug delivery to tumors: myths, reality and possibility. J Control Release. 2011;153(3):198–205.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Zhu XF, Amir E, Singh G, Clemons M, Addison C. Bone-targeted therapy for metastatic breast cancer—where do we go from here? A commentary from the BONUS 8 meeting. J Bone Oncol. 2014;3(1):1–4.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Koga J, Matoba T, Egashira K. Anti-inflammatory nanoparticle for prevention of atherosclerotic vascular diseases. J Atheroscler Thromb. 2016;23(7):757–65.PubMedCrossRefGoogle Scholar
  74. 74.
    Leuschner F, Dutta P, Gorbatov R, Novobrantseva TI, Donahoe JS, Courties G, et al. Therapeutic siRNA silencing in inflammatory monocytes in mice. Nat Biotechnol. 2011;29(11):1005–10.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Afergan E, Ben David M, Epstein H, Koroukhov N, Gilhar D, Rohekar K, et al. Liposomal simvastatin attenuates neointimal hyperplasia in rats. AAPS J. 2010;12(2):181–7.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Danenberg HD, Golomb G, Groothuis A, Gao J, Epstein H, Swaminathan RV, et al. Liposomal alendronate inhibits systemic innate immunity and reduces in-stent neointimal hyperplasia in rabbits. Circulation. 2003;108(22):2798–804.PubMedCrossRefGoogle Scholar
  77. 77.
    Danenberg HD, Fishbein I, Epstein H, Waltenberger J, Moerman E, Monkkonen J, et al. Systemic depletion of macrophages by liposomal bisphosphonates reduces neointimal formation following balloon-injury in the rat carotid artery. J Cardiovasc Pharmacol. 2003;42(5):671–9.PubMedCrossRefGoogle Scholar
  78. 78.
    Cohen-Sela E, Rosenzweig O, Gao J, Epstein H, Gati I, Reich R, et al. Alendronate-loaded nanoparticles deplete monocytes and attenuate restenosis. J Control Release. 2006;113(1):23–30.PubMedCrossRefGoogle Scholar
  79. 79.
    Markovsky E, Koroukhov N, Golomb G. Additive-free albumin nanoparticles of alendronate for attenuating inflammation through monocyte inhibition. Nanomedicine. 2007;2(4):545–53.PubMedCrossRefGoogle Scholar
  80. 80.
    Epstein H, Berger V, Levi I, Eisenberg G, Koroukhov N, Gao J, et al. Nanosuspensions of alendronate with gallium or gadolinium attenuate neointimal hyperplasia in rats. J Control Release. 2007;117(3):322–32.PubMedCrossRefGoogle Scholar
  81. 81.
    Nakashiro S, Matoba T, Umezu R, Koga J, Tokutome M, Katsuki S, et al. Pioglitazone-incorporated nanoparticles prevent plaque destabilization and rupture by regulating monocyte/macrophage differentiation in ApoE(−/−) mice. Arterioscler Thromb Vasc Biol. 2016;36(3):491–500.PubMedCrossRefGoogle Scholar
  82. 82.
    Liu T, van Rooijen N, Tracey DJ. Depletion of macrophages reduces axonal degeneration and hyperalgesia following nerve injury. Pain. 2000;86(1–2):25–32.PubMedCrossRefGoogle Scholar
  83. 83.
    Hiraoka K, Zenmyo M, Watari K, Iguchi H, Fotovati A, Kimura YN, et al. Inhibition of bone and muscle metastases of lung cancer cells by a decrease in the number of monocytes/macrophages. Cancer Sci. 2008;99(8):1595–602.PubMedCrossRefGoogle Scholar
  84. 84.
    Haber E, Danenberg HD, Koroukhov N, Ron-El R, Golomb G, Schachter M. Peritoneal macrophage depletion by liposomal bisphosphonate attenuates endometriosis in the rat model. Hum Reprod. 2009;24(2):398–407.PubMedCrossRefGoogle Scholar
  85. 85.
    Calin MV, Manduteanu I, Dragomir E, Dragan E, Nicolae M, Gan AM, et al. Effect of depletion of monocytes/macrophages on early aortic valve lesion in experimental hyperlipidemia. Cell Tissue Res. 2009;336(2):237–48.PubMedCrossRefGoogle Scholar
  86. 86.
    Samad A, Sultana Y, Aqil M. Liposomal drug delivery systems: an update review. Curr Drug Deliv. 2007;4(4):297–305.PubMedCrossRefGoogle Scholar
  87. 87.
    Gao W, Langer R, Farokhzad OC. Poly(ethylene glycol) with observable shedding. Angew Chem Int Ed Engl. 2010;49(37):6567–71.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Lasic DD, Martin FJ, Gabizon A, Huang SK, Papahadjopoulos D. Sterically stabilized liposomes: a hypothesis on the molecular origin of the extended circulation times. Biochim Biophys Acta. 1991;1070(1):187–92.PubMedCrossRefGoogle Scholar
  89. 89.
    Kingsley JD, Dou HY, Morehead J, Rabinow B, Gendelman HE, Destache CJ. Nanotechnology: a focus on nanoparticles as a drug delivery system. J NeuroImmune Pharmacol. 2006;1(3):340–50.PubMedCrossRefGoogle Scholar
  90. 90.
    Tirosh B, Khatib N, Barenholz Y, Nissan A, Rubinstein A. Transferrin as a luminal target for negatively charged liposomes in the inflamed colonic mucosa. Mol Pharm. 2009;6(4):1083–91.PubMedCrossRefGoogle Scholar
  91. 91.
    Schroeder A, Turjeman K, Schroeder JE, Leibergall M, Barenholz Y. Using liposomes to target infection and inflammation induced by foreign body injuries or medical implants. Expert Opin Drug Deliv. 2010;7(10):1175–89.PubMedCrossRefGoogle Scholar
  92. 92.
    Barenholz Y, Bombelli C, Bonicelli MG, di Profio P, Giansanti L, Mancini G, et al. Influence of lipid composition on the thermotropic behavior and size distribution of mixed cationic liposomes. J Colloid Interface Sci. 2011;356(1):46–53.PubMedCrossRefGoogle Scholar
  93. 93.
    Gabizon AA, Shmeeda H, Zalipsky S. Pros and cons of the liposome platform in cancer drug targeting. J Liposome Res. 2006;16(3):175–83.PubMedCrossRefGoogle Scholar
  94. 94.
    van Rooijen N, van Nieuwmegen R. Elimination of phagocytic cells in the spleen after intravenous injection of liposome-encapsulated dichloromethylene diphosphonate. An enzyme-histochemical study. Cell Tissue Res. 1984;238(2):355–8.PubMedCrossRefGoogle Scholar
  95. 95.
    van Rooijen N. The liposome-mediated macrophage suicide technique. J Immunol Methods. 1989;124(1):1–6.PubMedCrossRefGoogle Scholar
  96. 96.
    Rodan GA. Mechanisms of action of bisphosphonates. Annu Rev Pharmacol Toxicol. 1998;38:375–88.PubMedCrossRefGoogle Scholar
  97. 97.
    Fleisch H. Development of bisphosphonates. Breast Cancer Res. 2002;4(1):30–4.PubMedCrossRefGoogle Scholar
  98. 98.
    Rogers MJ, Crockett JC, Coxon FP, Monkkonen J. Biochemical and molecular mechanisms of action of bisphosphonates. Bone. 2011;49(1):34–41.PubMedCrossRefGoogle Scholar
  99. 99.
    Feldman LJ, Mazighi M, Scheuble A, Deux JF, De Benedetti E, Badier-Commander C, et al. Differential expression of matrix metalloproteinases after stent implantation and balloon angioplasty in the hypercholesterolemic rabbit. Circulation. 2001;103(25):3117–22.PubMedCrossRefGoogle Scholar
  100. 100.
    Majmudar MD, Keliher EJ, Heidt T, Leuschner F, Truelove J, Sena BF, et al. Monocyte-directed RNAi targeting CCR2 improves infarct healing in atherosclerosis-prone mice. Circulation. 2013;127(20):2038–46.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    van Amerongen MJ, Harmsen MC, van Rooijen N, Petersen AH, van Luyn MJ. Macrophage depletion impairs wound healing and increases left ventricular remodeling after myocardial injury in mice. Am J Pathol. 2007;170(3):818–29.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Diez-Roux G, Lang RA. Macrophages induce apoptosis in normal cells in vivo. Development. 1997;124(18):3633–8.PubMedGoogle Scholar
  103. 103.
    Leibovich SJ, Wiseman DM. Macrophages, wound repair and angiogenesis. Prog Clin Biol Res. 1988;266:131–45.PubMedGoogle Scholar
  104. 104.
    Vandervelde S, van Amerongen MJ, Tio RA, Petersen AH, van Luyn MJ, Harmsen MC. Increased inflammatory response and neovascularization in reperfused vs. non-reperfused murine myocardial infarction. Cardiovasc Pathol. 2006;15(2):83–90.PubMedCrossRefGoogle Scholar
  105. 105.
    Minatoguchi S, Takemura G, Chen XH, Wang NY, Uno Y, Koda M, et al. Acceleration of the healing process and myocardial regeneration may be important as a mechanism of improvement of cardiac function and remodeling by postinfarction granulocyte colony-stimulating factor treatment. Circulation. 2004;109(21):2572–80.PubMedCrossRefGoogle Scholar
  106. 106.
    Danon D, Kowatch MA, Roth GS. Promotion of wound repair in old mice by local injection of macrophages. Proc Natl Acad Sci U S A. 1989;86(6):2018–20.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Doggrell SA. Statins in the 21st century: end of the simple story? Expert Opin Investig Drugs. 2001;10(9):1755–66.PubMedCrossRefGoogle Scholar
  108. 108.
    Liao JK. Beyond lipid lowering: the role of statins in vascular protection. Int J Cardiol. 2002;86(1):5–18.PubMedCrossRefGoogle Scholar
  109. 109.
    Horlitz M, Sigwart U, Niebauer J. Fighting restenosis after coronary angioplasty: contemporary and future treatment options. Int J Cardiol. 2002;83(3):199–205.PubMedCrossRefGoogle Scholar
  110. 110.
    Indolfi C, Cioppa A, Stabile E, Di Lorenzo E, Esposito G, Pisani A, et al. Effects of hydroxymethylglutaryl coenzyme A reductase inhibitor simvastatin on smooth muscle cell proliferation in vitro and neointimal formation in vivo after vascular injury. J Am Coll Cardiol. 2000;35(1):214–21.PubMedCrossRefGoogle Scholar
  111. 111.
    Walter DH, Rittig K, Bahlmann FH, Kirchmair R, Silver M, Murayama T, et al. Statin therapy accelerates reendothelialization: a novel effect involving mobilization and incorporation of bone marrow-derived endothelial progenitor cells. Circulation. 2002;105(25):3017–24.PubMedCrossRefGoogle Scholar
  112. 112.
    Mulder HJ, Bal ET, Jukema JW, Zwinderman AH, Schalij MJ, van Boven AJ, et al. Pravastatin reduces restenosis two years after percutaneous transluminal coronary angioplasty (REGRESS trial). Am J Cardiol. 2000;86(7):742–6.PubMedCrossRefGoogle Scholar
  113. 113.
    Bunch TJ, Muhlestein JB, Anderson JL, Horne BD, Bair TL, Jackson JD, et al. Effects of statins on six-month survival and clinical restenosis frequency after coronary stent deployment. Am J Cardiol. 2002;90(3):299–302.PubMedCrossRefGoogle Scholar
  114. 114.
    Horlitz M, Sigwart U, Niebauer J. Statins do not prevent restenosis after coronary angioplasty: where to go from here? Herz. 2001;26(2):119–28.PubMedCrossRefGoogle Scholar
  115. 115.
    Blum A, Shamburek R. The pleiotropic effects of statins on endothelial function, vascular inflammation, immunomodulation and thrombogenesis. Atherosclerosis. 2009;203(2):325–30.PubMedCrossRefGoogle Scholar
  116. 116.
    Kwak B, Mulhaupt F, Myit S, Mach F. Statins as a newly recognized type of immunomodulator. Nat Med. 2000;6(12):1399–402.PubMedCrossRefGoogle Scholar
  117. 117.
    Jain MK, Ridker PM. Anti-inflammatory effects of statins: clinical evidence and basic mechanisms. Nat Rev Drug Discov. 2005;4(12):977–87.PubMedCrossRefGoogle Scholar
  118. 118.
    Fildes JE, Shaw SM, Mitsidou A, Rogacev K, Leonard CT, Williams SG, et al. HMG-CoA reductase inhibitors deplete circulating classical and non-classical monocytes following human heart transplantation. Transpl Immunol. 2008;19(2):152–7.PubMedCrossRefGoogle Scholar
  119. 119.
    Elazar V, Adwan H, Bauerle T, Rohekar K, Golomb G, Berger MR. Sustained delivery and efficacy of polymeric nanoparticles containing osteopontin and bone sialoprotein antisenses in rats with breast cancer bone metastasis. Int J Cancer. 2010;126(7):1749–60.PubMedGoogle Scholar
  120. 120.
    Cohen-Sela E, Teitlboim S, Chorny M, Koroukhov N, Danenberg HD, Gao J, et al. Single and double emulsion manufacturing techniques of an amphiphilic drug in PLGA nanoparticles: formulations of mithramycin and bioactivity. J Pharm Sci. 2009;98(4):1452–62.PubMedCrossRefGoogle Scholar
  121. 121.
    Monkkonen J, Brown CS, Thompson TT, Heath TD. Liposome-mediated delivery of gallium to macrophage-like cells in-vitro—demonstration of a transferrin-independent route for intracellular delivery of metal-ions. Pharm Res. 1993;10(8):1130–5.PubMedCrossRefGoogle Scholar
  122. 122.
    Ruttinger D, Vollmar B, Wanner GA, Messmer K. In vivo assessment of hepatic alterations following gadolinium chloride-induced Kupffer cell blockade. J Hepatol. 1996;25(6):960–7.PubMedCrossRefGoogle Scholar
  123. 123.
    Mizgerd JP, Molina RM, Stearns RC, Brain JD, Warner AE. Gadolinium induces macrophage apoptosis. J Leukoc Biol. 1996;59(2):189–95.PubMedCrossRefGoogle Scholar
  124. 124.
    Duan SZ, Usher MG, Mortensen RM. Peroxisome proliferator-activated receptor-gamma-mediated effects in the vasculature. Circ Res. 2008;102(3):283–94.PubMedCrossRefGoogle Scholar
  125. 125.
    Erdmann E, Dormandy JA, Charbonnel B, Massi-Benedetti M, Moules IK, Skene AM. The effect of pioglitazone on recurrent myocardial infarction in 2,445 patients with type 2 diabetes and previous myocardial infarction: results from the PROactive (PROactive 05) study. J Am Coll Cardiol. 2007;49(17):1772–80.PubMedCrossRefGoogle Scholar
  126. 126.
    Banai S, Finkelstein A, Almagor Y, Assali A, Hasin Y, Rosenschein U, et al. Targeted anti-inflammatory systemic therapy for restenosis: the biorest liposomal alendronate with stenting study (BLAST)-a double blind, randomized clinical trial. Am Heart J. 2013;165(2):234–40. e1PubMedCrossRefGoogle Scholar
  127. 127. Biorest liposomal alendronate administration for diabetic patients undergoing drug-eluting stent percutaneous coronary intervention (BLADE). 2015.
  128. 128. Administration of NK-104-NP to treat chronic critical limb ischemia. 2012.
  129. 129.
    Dou H, Grotepas CB, McMillan JM, Destache CJ, Chaubal M, Werling J, et al. Macrophage delivery of nanoformulated antiretroviral drug to the brain in a murine model of neuroAIDS. J Immunol. 2009;183(1):661–9.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Choi MR, Bardhan R, Stanton-Maxey KJ, Badve S, Nakshatri H, Stantz KM, et al. Delivery of nanoparticles to brain metastases of breast cancer using a cellular Trojan horse. Cancer Nanotechnol. 2012;3(1–6):47–54.PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Burke B, Sumner S, Maitland N, Lewis CE. Macrophages in gene therapy: cellular delivery vehicles and in vivo targets. J Leukoc Biol. 2002;72(3):417–28.PubMedGoogle Scholar
  132. 132.
    Fishbein I, Levy RJ, Inventors; Ex vivo-modified monocytes as local delivery vehicles to treat diseased arteries patent US WO2013071015 A1. 2013.Google Scholar
  133. 133.
    Chokri M, Lallot C, Ebert M, Poindron P, Bartholeyns J. Biodistribution of indium-labeled macrophages in mice bearing solid tumors. Int J Immunother. 1990;6(2):79–84.Google Scholar
  134. 134.
    Audran R, Collet B, Moisan A, Toujas L. Fate of mouse macrophages radiolabelled with PKH-95 and injected intravenously. Nucl Med Biol. 1995;22(6):817–21.PubMedCrossRefGoogle Scholar
  135. 135.
    Michalet X, Pinaud FF, Bentolila LA, Tsay JM, Doose S, Li JJ, et al. Quantum dots for live cells, in vivo imaging, and diagnostics. Science. 2005;307(5709):538–44.PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Waiskopf N, Shweky I, Lieberman I, Banin U, Soreq H. Quantum dot labeling of butyrylcholinesterase maintains substrate and inhibitor interactions and cell adherence features. ACS Chem Neurosci. 2011;2(3):141–50.PubMedCrossRefGoogle Scholar

Copyright information

© Controlled Release Society 2017

Authors and Affiliations

  1. 1.Institute for Drug Research, School of Pharmacy, Faculty of MedicineThe Hebrew University of JerusalemJerusalemIsrael

Personalised recommendations