Targeting therapeutics to endothelium: are we there yet?

Abstract

Vascular endothelial cells represent an important therapeutic target in many pathologies, including inflammation, oxidative stress, and thrombosis; however, delivery of drugs to this site is often limited by the lack of specific affinity of therapeutics for these cells. Selective delivery of both small molecule drugs and therapeutic proteins to the endothelium has been achieved through the use of targeting ligands, such as monoclonal antibodies, directed against endothelial cell surface markers, particularly cell adhesion molecules (CAMs). Careful selection of target molecules and targeting agents allows for precise delivery to sites of inflammation, thereby maximizing therapeutic drug concentrations at the site of injury. A good understanding of the physiological and pathological determinants of drug and drug carrier pharmacokinetics and biodistribution may allow for a priori identification of optimal properties of drug carrier and targeting agent. Targeted delivery of therapeutics such as antioxidants and antithrombotic agents to the injured endothelium has shown efficacy in preclinical models, suggesting the potential for translation into clinical practice. As with all therapeutics, demonstration of both efficacy and safety are required for successful clinical implementation, which must be considered not only for the individual components (drug, targeting agent, etc.) but also for the sum of the parts (e.g., the drug delivery system), as unexpected toxicities may arise with complex delivery systems. While the use of endothelial targeting has not been translated into the clinic to date, the preclinical results summarized here suggest that there is hope for successful implementation of these agents in the years to come.

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

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

References

  1. 1.

    Stan RV, Tse D, Deharvengt SJ, Smits NC, Xu Y, Luciano MR, et al. The diaphragms of fenestrated endothelia: gatekeepers of vascular permeability and blood composition. Dev Cell. 2011;23(6):1203–18. https://doi.org/10.1016/j.devcel.2012.11.003.

  2. 2.

    Stan RV. Endothelial stomatal and fenestral diaphragms in normal vessels and angiogenesis. J Cell Mol Med. 2007;11(4):621–43. https://doi.org/10.1111/j.1582-4934.2007.00075.x.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  3. 3.

    Feng D, Nagy JA, Pyne K, Hammel I, Dvorak HF, Dvorak AM. Pathways of macromolecular extravasation across microvascular endothelium in response to VPF/VEGF and other vasoactive mediators. Microcirculation. 1999;6(1):23–44. https://doi.org/10.1080/713773925.

    PubMed  CAS  Article  Google Scholar 

  4. 4.

    Davies PF. Endothelial mechanisms of flow-mediated athero-protection and susceptibility. Circ Res. 2007;101(1):10–2. https://doi.org/10.1161/CIRCRESAHA.107.156539.

    PubMed  CAS  Article  Google Scholar 

  5. 5.

    Thomas SR, Witting PK, Drummond GR. Redox control of endothelial function and dysfunction: molecular mechanisms and therapeutic opportunities. Antioxid Redox Signal. 2008;10(10):1713–65. https://doi.org/10.1089/ars.2008.2027.

    PubMed  CAS  Article  Google Scholar 

  6. 6.

    Aird WC. Endothelium in health and disease. Pharmacol Rep. 2008;60(1):139–43.

    PubMed  Google Scholar 

  7. 7.

    Oakley FD, Abbott D, Li Q, Engelhardt JF. Signaling components of redox active endosomes: the redoxosomes. Antioxid Redox Signal. 2009;11(6):1313–33. https://doi.org/10.1089/ars.2008.2363.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  8. 8.

    Shuvaev VV, Han J, Tliba S, Arguiri E, Christofidou-Solomidou M, Ramirez SH, et al. Anti-inflammatory effect of targeted delivery of SOD to endothelium: mechanism, synergism with NO donors and protective effects in vitro and in vivo. PLoS One. 2013;8(10):e77002. https://doi.org/10.1371/journal.pone.0077002.

  9. 9.

    Pober JS, Sessa WC. Evolving functions of endothelial cells in inflammation. Nat Rev Immunol. 2007;7(10):803–15. https://doi.org/10.1038/nri2171.

    PubMed  CAS  Article  Google Scholar 

  10. 10.

    Poredos P, Jezovnik MK. Endothelial Dysfunction and Venous Thrombosis. Angiology. 2017:3319717732238. doi:https://doi.org/10.1177/0003319717732238.

  11. 11.

    Preissler G, Loehe F, Huff IV, Ebersberger U, Shuvaev VV, Bittmann I, et al. Targeted endothelial delivery of nanosized catalase immunoconjugates protects lung grafts donated after cardiac death. Transplantation. 2011;92(4):380–7. https://doi.org/10.1097/TP.0b013e318226bc6b.

  12. 12.

    Eppinger MJ, Deeb GM, Bolling SF, Ward PA. Mediators of ischemia-reperfusion injury of rat lung. Am J Pathol. 1997;150(5):1773–84.

    PubMed  PubMed Central  CAS  Google Scholar 

  13. 13.

    King RC, Binns OA, Rodriguez F, Kanithanon RC, Daniel TM, Spotnitz WD, et al. Reperfusion injury significantly impacts clinical outcome after pulmonary transplantation. Ann Thorac Surg. 2000;69(6):1681–5. https://doi.org/10.1016/S0003-4975(00)01425-9.

    PubMed  CAS  Article  Google Scholar 

  14. 14.

    Novick RJ, Gehman KE, Ali IS, Lee J. Lung preservation: the importance of endothelial and alveolar type II cell integrity. Ann Thorac Surg. 1996;62(1):302–14. https://doi.org/10.1016/0003-4975(96)00333-5.

    PubMed  CAS  Article  Google Scholar 

  15. 15.

    Zimmerman MC. Angiotensin II and angiotensin-1-7 redox signaling in the central nervous system. Curr Opin Pharmacol. 2011;11(2):138–43. https://doi.org/10.1016/j.coph.2011.01.001.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  16. 16.

    Simonsen U, Christensen FH, Buus NH. The effect of tempol on endothelium-dependent vasodilatation and blood pressure. Pharmacol Ther. 2009;122(2):109–24. https://doi.org/10.1016/j.pharmthera.2009.02.002.

    PubMed  CAS  Article  Google Scholar 

  17. 17.

    Kowalski PS, Leus NG, Scherphof GL, Ruiters MH, Kamps JA, Molema G. Targeted siRNA delivery to diseased microvascular endothelial cells: cellular and molecular concepts. IUBMB Life. 2011;63(8):648–58. https://doi.org/10.1002/iub.487.

    PubMed  CAS  Article  Google Scholar 

  18. 18.

    Hood E, Simone E, Wattamwar P, Dziubla T, Muzykantov V. Nanocarriers for vascular delivery of antioxidants. Nanomedicine. 2011;6(7):1257–72. https://doi.org/10.2217/nnm.11.92.

    PubMed  CAS  Article  Google Scholar 

  19. 19.

    Muro S, Muzykantov VR. Targeting of antioxidant and anti-thrombotic drugs to endothelial cell adhesion molecules. Curr Pharm Des. 2005;11(18):2383–401. https://doi.org/10.2174/1381612054367274.

    PubMed  CAS  Article  Google Scholar 

  20. 20.

    Muzykantov VR. Biomedical aspects of targeted delivery of drugs to pulmonary endothelium. Expert Opinion on Drug Delivery. 2005;2(5):909–26. https://doi.org/10.1517/17425247.2.5.909.

    PubMed  CAS  Article  Google Scholar 

  21. 21.

    Muzykantov VR. Immunotargeting of drugs to the pulmonary vascular endothelium as a therapeutic strategy. Pathophysiology. 1998;5(1):15–33. https://doi.org/10.1016/S0928-4680(98)00006-6.

    CAS  Article  Google Scholar 

  22. 22.

    Oh P, Li Y, Yu J, Durr E, Krasinska KM, La C, et al. Subtractive proteomic mapping of the endothelial surface in lung and solid tumours for tissue-specific therapy. Nature. 2004;429(6992):629–35. https://doi.org/10.1038/nature02580.

    PubMed  CAS  Article  Google Scholar 

  23. 23.

    Schnitzer JE. Vascular targeting as a strategy for cancer therapy. N Engl J Med. 1998;339(7):472–4. https://doi.org/10.1056/NEJM199808133390711.

    PubMed  CAS  Article  Google Scholar 

  24. 24.

    Spragg DD, Alford DR, Greferath R, Larsen CE, Lee KD, Gurtner GC, et al. Immunotargeting of liposomes to activated vascular endothelial cells: a strategy for site-selective delivery in the cardiovascular system. Proc Natl Acad Sci U S A. 1997;94(16):8795–800. https://doi.org/10.1073/pnas.94.16.8795.

  25. 25.

    Kennel SJ, Lee R, Bultman S, Kabalka G. Rat monoclonal antibody distribution in mice: an epitope inside the lung vascular space mediates very efficient localization. Int J Rad Appl Instrum B. 1990;17(2):193–200. https://doi.org/10.1016/0883-2897(90)90147-S.

    PubMed  CAS  Article  Google Scholar 

  26. 26.

    McIntosh DP, Tan XY, Oh P, Schnitzer JE. Targeting endothelium and its dynamic caveolae for tissue-specific transcytosis in vivo: a pathway to overcome cell barriers to drug and gene delivery. Proc Natl Acad Sci U S A. 2002;99(4):1996–2001. https://doi.org/10.1073/pnas.251662398.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  27. 27.

    Muzykantov VR, Danilov SM. Targeting of radiolabeled monoclonal antibody against ACE to the pulmonary endothelium. In: Torchilin V, editor. Targeted Delivery of Imaging Agents. Roca Baton: CRC Press; 1995. p. 465–85.

    Google Scholar 

  28. 28.

    Goetz DJ, el-Sabban ME, Hammer DA, Pauli BU. Lu-ECAM-1-mediated adhesion of melanoma cells to endothelium under conditions of flow. Int J Cancer 1996;65(2):192–199, DOI: https://doi.org/10.1002/(SICI)1097-0215(19960117)65:2<192::AID-IJC11>3.0.CO;2-G.

  29. 29.

    Huang X, Molema G, King S, Watkins L, Edgington TS, Thorpe PE. Tumor infarction in mice by antibody-directed targeting of tissue factor to tumor vasculature. Science. 1997;275(5299):547–50. https://doi.org/10.1126/science.275.5299.547.

    PubMed  CAS  Article  Google Scholar 

  30. 30.

    Stan RV, Ghitescu L, Jacobson BS, Palade GE. Isolation, cloning, and localization of rat PV-1, a novel endothelial caveolar protein. J Cell Biol. 1999;145(6):1189–98. https://doi.org/10.1083/jcb.145.6.1189.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  31. 31.

    Rajotte D, Arap W, Hagedorn M, Koivunen E, Pasqualini R, Ruoslahti E. Molecular heterogeneity of the vascular endothelium revealed by in vivo phage display. J Clin Invest. 1998;102(2):430–7. https://doi.org/10.1172/JCI3008.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  32. 32.

    Danilov SM, Muzykantov VR, Martynov AV, Atochina EN, Sakharov I, Trakht IN, et al. Lung is the target organ for a monoclonal antibody to angiotensin-converting enzyme. Lab Investig. 1991;64(1):118–24.

    PubMed  CAS  Google Scholar 

  33. 33.

    Pasqualini R, McDonald DM, Arap W. Vascular targeting and antigen presentation. Nat Immunol. 2001;2(7):567–8. https://doi.org/10.1038/89704.

    PubMed  CAS  Article  Google Scholar 

  34. 34.

    Muzykantov VR, Atochina EN, Ischiropoulos H, Danilov SM, Fisher AB. Immunotargeting of antioxidant enzyme to the pulmonary endothelium. Proc Natl Acad Sci U S A. 1996;93(11):5213–8. https://doi.org/10.1073/pnas.93.11.5213.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  35. 35.

    Reynolds PN, Nicklin SA, Kaliberova L, Boatman BG, Grizzle WE, Balyasnikova IV, et al. Combined transductional and transcriptional targeting improves the specificity of transgene expression in vivo. Nat Biotechnol. 2001;19(9):838–42. https://doi.org/10.1038/nbt0901-838.

  36. 36.

    Koren E, Torchilin VP. Drug carriers for vascular drug delivery. IUBMB Life. 2011;63(8):586–95. https://doi.org/10.1002/iub.496.

    PubMed  CAS  Article  Google Scholar 

  37. 37.

    Danilov SM, Gavrilyuk VD, Franke FE, Pauls K, Harshaw DW, McDonald TD, et al. Lung uptake of antibodies to endothelial antigens: key determinants of vascular immunotargeting. Am J Physiol Lung Cell Mol Physiol. 2001;280(6):L1335–47.

  38. 38.

    Oh P, Li Y, Yu J, Durr E, Krasinska KM, Carver LA, et al. Subtractive proteomic mapping of the endothelial surface in lung and solid tumours for tissue-specific therapy. Nature. 2004;429(6992):629–35. https://doi.org/10.1038/nature02580.

  39. 39.

    Wang J, Tian S, Petros RA, Napier ME, Desimone JM. The complex role of multivalency in nanoparticles targeting the transferrin receptor for cancer therapies. J Am Chem Soc. 2010;132(32):11306–13. https://doi.org/10.1021/ja1043177.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  40. 40.

    Jacobson BS, Schnitzer JE, McCaffery M, Palade GE. Isolation and partial characterization of the luminal plasmalemma of microvascular endothelium from rat lungs. Eur J Cell Biol. 1992;58(2):296–306.

    PubMed  CAS  Google Scholar 

  41. 41.

    Wilson A, Zhou W, Champion HC, Alber S, Tang ZL, Kennel S, et al. Targeted delivery of oligodeoxynucleotides to mouse lung endothelial cells in vitro and in vivo. Mol Ther. 2005;12(3):510–8. https://doi.org/10.1016/j.ymthe.2005.04.005.

  42. 42.

    Jordan C, Shuvaev VV, Bailey M, Muzykantov VR, Dziubla TD. The role of carrier geometry in overcoming biological barriers to drug delivery. Curr Pharm Des. 2016;22(9):1259–73. https://doi.org/10.2174/1381612822666151216151856.

    PubMed  CAS  Article  Google Scholar 

  43. 43.

    Shuvaev VV, Brenner JS, Muzykantov VR. Targeted endothelial nanomedicine for common acute pathological conditions. J Control Release. 2015;219:576–95. https://doi.org/10.1016/j.jconrel.2015.09.055.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  44. 44.

    Yun X, Maximov VD, Yu J, Zhu H, Vertegel AA, Kindy MS. Nanoparticles for targeted delivery of antioxidant enzymes to the brain after cerebral ischemia and reperfusion injury. J Cereb Blood Flow Metab. 2013;33(4):583–92. https://doi.org/10.1038/jcbfm.2012.209.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  45. 45.

    Hua S. Targeting sites of inflammation: intercellular adhesion molecule-1 as a target for novel inflammatory therapies. Front Pharmacol. 2013;4:127. https://doi.org/10.3389/fphar.2013.00127.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  46. 46.

    Simone E, Ding BS, Muzykantov V. Targeted delivery of therapeutics to endothelium. Cell Tissue Res. 2009;335(1):283–300. https://doi.org/10.1007/s00441-008-0676-7.

    PubMed  CAS  Article  Google Scholar 

  47. 47.

    Atochina EN, Balyasnikova IV, Danilov SM, Granger DN, Fisher AB, Muzykantov VR. Immunotargeting of catalase to ACE or ICAM-1 protects perfused rat lungs against oxidative stress. Am J Phys. 1998;275(4 Pt 1):L806–17.

    CAS  Google Scholar 

  48. 48.

    Golias C, Tsoutsi E, Matziridis A, Makridis P, Batistatou A, Charalabopoulos K. Review. Leukocyte and endothelial cell adhesion molecules in inflammation focusing on inflammatory heart disease. In Vivo. 2007;21(5):757–69.

    PubMed  CAS  Google Scholar 

  49. 49.

    Hopkins AM, Baird AW, Nusrat A. ICAM-1: targeted docking for exogenous as well as endogenous ligands. Adv Drug Deliv Rev. 2004;56(6):763–78. https://doi.org/10.1016/j.addr.2003.10.043.

    PubMed  CAS  Article  Google Scholar 

  50. 50.

    Hubbard AK, Rothlein R. Intercellular adhesion molecule-1 (ICAM-1) expression and cell signaling cascades. Free Radic Biol Med. 2000;28(9):1379–86. https://doi.org/10.1016/S0891-5849(00)00223-9.

    PubMed  CAS  Article  Google Scholar 

  51. 51.

    Harari OA, Wickham TJ, Stocker CJ, Kovesdi I, Segal DM, Huehns TY, et al. Targeting an adenoviral gene vector to cytokine-activated vascular endothelium via E-selectin. Gene Ther. 1999;6(5):801–7. https://doi.org/10.1038/sj.gt.3300898.

  52. 52.

    Keelan ET, Harrison AA, Chapman PT, Binns RM, Peters AM, Haskard DO. Imaging vascular endothelial activation: an approach using radiolabeled monoclonal antibodies against the endothelial cell adhesion molecule E-selectin. J Nucl Med. 1994;35(2):276–81.

    PubMed  CAS  Google Scholar 

  53. 53.

    Kiely JM, Cybulsky MI, Luscinskas FW, Gimbrone MA Jr. Immunoselective targeting of an anti-thrombin agent to the surface of cytokine-activated vascular endothelial cells. Arterioscler Thromb Vasc Biol. 1995;15(8):1211–8. https://doi.org/10.1161/01.ATV.15.8.1211.

    PubMed  CAS  Article  Google Scholar 

  54. 54.

    Lindner JR, Song J, Christiansen J, Klibanov AL, Xu F, Ley K. Ultrasound assessment of inflammation and renal tissue injury with microbubbles targeted to P-selectin. Circulation. 2001;104(17):2107–12. https://doi.org/10.1161/hc4201.097061.

    PubMed  CAS  Article  Google Scholar 

  55. 55.

    Ding BS, Gottstein C, Grunow A, Kuo A, Ganguly K, Albelda SM, et al. Endothelial targeting of a recombinant construct fusing a PECAM-1 single-chain variable antibody fragment (scFv) with prourokinase facilitates prophylactic thrombolysis in the pulmonary vasculature. Blood. 2005;106(13):4191–8. https://doi.org/10.1182/blood-2005-05-2002.

  56. 56.

    Hood ED, Greineder CF, Dodia C, Han J, Mesaros C, Shuvaev VV, et al. Antioxidant protection by PECAM-targeted delivery of a novel NADPH-oxidase inhibitor to the endothelium in vitro and in vivo. J Control Release. 2012;163(2):161–9. https://doi.org/10.1016/j.jconrel.2012.08.031.

  57. 57.

    Shuvaev VV, Tliba S, Nakada M, Albelda SM, Muzykantov VR. Platelet-endothelial cell adhesion molecule-1-directed endothelial targeting of superoxide dismutase alleviates oxidative stress caused by either extracellular or intracellular superoxide. J Pharmacol Exp Ther. 2007;323(2):450–7. https://doi.org/10.1124/jpet.107.127126.

    PubMed  CAS  Article  Google Scholar 

  58. 58.

    Shuvaev VV, Han J, KJ Y, Huang S, Hawkins BJ, Madesh M, et al. PECAM-targeted delivery of SOD inhibits endothelial inflammatory response. FASEB J: Off Publ Fed Am Soc Exp Biol. 2011;25(1):348–57. https://doi.org/10.1096/fj.10-169789.

    Article  Google Scholar 

  59. 59.

    Richter WF, Bhansali SG, Morris ME. Mechanistic determinants of biotherapeutics absorption following SC administration. AAPS J. 2012;14(3):559–70. https://doi.org/10.1208/s12248-012-9367-0.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  60. 60.

    Vugmeyster Y, Xu X, Theil FP, Khawli LA, Leach MW. Pharmacokinetics and toxicology of therapeutic proteins: advances and challenges. World J Biol Chem. 2012;3(4):73–92. https://doi.org/10.4331/wjbc.v3.i4.73.

    PubMed  PubMed Central  Article  Google Scholar 

  61. 61.

    Sarin H. Physiologic upper limits of pore size of different blood capillary types and another perspective on the dual pore theory of microvascular permeability. J Angiogenes Res. 2010;2(1):14. https://doi.org/10.1186/2040-2384-2-14.

    PubMed  PubMed Central  Article  Google Scholar 

  62. 62.

    Campos-Martorell M, Cano-Sarabia M, Simats A, Hernandez-Guillamon M, Rosell A, Maspoch D, et al. Charge effect of a liposomal delivery system encapsulating simvastatin to treat experimental ischemic stroke in rats. Int J Nanomedicine. 2016;11:3035–48. https://doi.org/10.2147/Ijn.S107292.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  63. 63.

    Sawant RR, Torchilin VP. Challenges in development of targeted liposomal therapeutics. AAPS J. 2012;14(2):303–15. https://doi.org/10.1208/s12248-012-9330-0.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  64. 64.

    de Smet M, Heijman E, Langereis S, Hijnen NM, Grüll H. Magnetic resonance imaging of high intensity focused ultrasound mediated drug delivery from temperature-sensitive liposomes: an in vivo proof-of-concept study. J Control Release. 2011;150(1):102–10. https://doi.org/10.1016/j.jconrel.2010.10.036.

    PubMed  Article  Google Scholar 

  65. 65.

    Huang XY, Li M, Bruni R, Messa P, Cellesi F. The effect of thermosensitive liposomal formulations on loading and release of high molecular weight biomolecules. Int J Pharm. 2017;524(1–2):279–89. https://doi.org/10.1016/j.ijpharm.2017.03.090.

    PubMed  CAS  Article  Google Scholar 

  66. 66.

    Di Corato R, Bealle G, Kolosnjaj-Tabi J, Espinosa A, Clement O, Silva AK, et al. Combining magnetic hyperthermia and photodynamic therapy for tumor ablation with photoresponsive magnetic liposomes. ACS Nano. 2015;9(3):2904–16. https://doi.org/10.1021/nn506949t.

    PubMed  CAS  Article  Google Scholar 

  67. 67.

    Maack T, Johnson V, Kau ST, Figueiredo J, Sigulem D. Renal filtration, transport, and metabolism of low-molecular-weight proteins: a review. Kidney Int. 1979;16(3):251–70. https://doi.org/10.1038/ki.1979.128.

    PubMed  CAS  Article  Google Scholar 

  68. 68.

    Brambell FW. The transmission of immunity from mother to young and the catabolism of immunoglobulins. Lancet. 1966;2(7473):1087–93.

    PubMed  CAS  Article  Google Scholar 

  69. 69.

    Israel EJ, Wilsker DF, Hayes KC, Schoenfeld D, Simister NE. Increased clearance of IgG in mice that lack beta 2-microglobulin: possible protective role of FcRn. Immunology. 1996;89(4):573–8. https://doi.org/10.1046/j.1365-2567.1996.d01-775.x.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  70. 70.

    Junghans RP, Anderson CL. The protection receptor for IgG catabolism is the beta2-microglobulin-containing neonatal intestinal transport receptor. Proc Natl Acad Sci U S A. 1996;93(11):5512–6. https://doi.org/10.1073/pnas.93.11.5512.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  71. 71.

    Juliano RL. Factors affecting the clearance kinetics and tissue distribution of liposomes, microspheres and emulsions. Adv Drug Deliv Rev. 1988;2(1):31–54. https://doi.org/10.1016/0169-409X(88)90004-X.

    CAS  Article  Google Scholar 

  72. 72.

    Allen TM, Chonn A. Large unilamellar liposomes with low uptake into the reticuloendothelial system. FEBS Lett. 1987;223(1):42–6. https://doi.org/10.1016/0014-5793(87)80506-9.

    PubMed  CAS  Article  Google Scholar 

  73. 73.

    Allen TM, Hansen C. Pharmacokinetics of stealth versus conventional liposomes: effect of dose. Biochim Biophys Acta. 1991;1068(2):133–41. https://doi.org/10.1016/0005-2736(91)90201-I.

    PubMed  CAS  Article  Google Scholar 

  74. 74.

    Li SD, Huang L. Pharmacokinetics and biodistribution of nanoparticles. Mol Pharm. 2008;5(4):496–504. https://doi.org/10.1021/mp800049w.

    PubMed  CAS  Article  Google Scholar 

  75. 75.

    Levy G. Pharmacologic target-mediated drug disposition. Clin Pharmacol Ther. 1994;56(3):248–52. https://doi.org/10.1038/clpt.1994.134.

    PubMed  CAS  Article  Google Scholar 

  76. 76.

    Mager DE, Jusko WJ. General pharmacokinetic model for drugs exhibiting target-mediated drug disposition. J Pharmacokinet Pharmacodyn. 2001;28(6):507–32. https://doi.org/10.1023/A:1014414520282.

    PubMed  CAS  Article  Google Scholar 

  77. 77.

    Muro S, Wiewrodt R, Thomas A, Koniaris L, Albelda SM, Muzykantov VR, et al. A novel endocytic pathway induced by clustering endothelial ICAM-1 or PECAM-1. J Cell Sci. 2003;116(Pt 8):1599–609. https://doi.org/10.1242/jcs.00367.

    PubMed  CAS  Article  Google Scholar 

  78. 78.

    Muzykantov VR, Christofidou-Solomidou M, Balyasnikova I, Harshaw DW, Schultz L, Fisher AB, et al. Streptavidin facilitates internalization and pulmonary targeting of an anti-endothelial cell antibody (platelet-endothelial cell adhesion molecule 1): a strategy for vascular immunotargeting of drugs. Proc Natl Acad Sci U S A. 1999;96(5):2379–84. https://doi.org/10.1073/pnas.96.5.2379.

  79. 79.

    Scherpereel A, Rome JJ, Wiewrodt R, Watkins SC, Harshaw DW, Alder S, et al. Platelet-endothelial cell adhesion molecule-1-directed immunotargeting to cardiopulmonary vasculature. J Pharmacol Exp Ther. 2002;300(3):777–86. https://doi.org/10.1124/jpet.300.3.777.

  80. 80.

    Danielyan K, Ding BS, Gottstein C, Cines DB, Muzykantov VR. Delivery of anti-platelet-endothelial cell adhesion molecule single-chain variable fragment-urokinase fusion protein to the cerebral vasculature lyses arterial clots and attenuates postischemic brain edema. J Pharmacol Exp Ther. 2007;321(3):947–52. https://doi.org/10.1124/jpet.107.120535.

    PubMed  CAS  Article  Google Scholar 

  81. 81.

    Matter CM, Schuler PK, Alessi P, Meier P, Ricci R, Zhang D, et al. Molecular imaging of atherosclerotic plaques using a human antibody against the extra-domain B of fibronectin. Circ Res. 2004;95(12):1225–33. https://doi.org/10.1161/01.RES.0000150373.15149.ff.

  82. 82.

    Virmani R, Kolodgie FD, Burke AP, Finn AV, Gold HK, Tulenko TN, et al. Atherosclerotic plaque progression and vulnerability to rupture angiogenesis as a source of intraplaque hemorrhage. Arterioscler Thromb Vasc Biol. 2005;25(10):2054–61. https://doi.org/10.1161/01.ATV.0000178991.71605.18.

    PubMed  CAS  Article  Google Scholar 

  83. 83.

    Winter PM, Neubauer AM, Caruthers SD, Harris TD, Robertson JD, Williams TA, et al. Endothelial ανβ3 integrin-targeted fumagillin nanoparticles inhibit angiogenesis in atherosclerosis. Arterioscler Thromb Vasc Biol. 2006;26(9):2103–9. https://doi.org/10.1161/01.ATV.0000235724.11299.76.

    PubMed  CAS  Article  Google Scholar 

  84. 84.

    Moreno PR, Purushothaman K-R, Sirol M, Levy AP, Fuster V. Neovascularization in human atherosclerosis. Circulation. 2006;113(18):2245–52. https://doi.org/10.1161/CIRCULATIONAHA.105.578955.

    PubMed  Article  Google Scholar 

  85. 85.

    Sadeghi MM, Glover DK, Lanza GM, Fayad ZA, Johnson LL. Imaging atherosclerosis and vulnerable plaque. J Nucl Med. 2010;51(Supplement 1):51S–65S. https://doi.org/10.2967/jnumed.109.068163.

    PubMed  PubMed Central  Article  Google Scholar 

  86. 86.

    Gerrit L, Sijbrands EJ, Valkema R, Folkert J, Feinstein SB, Van der Steen AF, et al. Molecular imaging of inflammation and intraplaque vasa vasorum: a step forward to identification of vulnerable plaques? J Nucl Cardiol. 2010;17(5):897–912.

    Article  Google Scholar 

  87. 87.

    Schinkel AF, Krueger CG, Tellez A, Granada JF, Reed JD, Hall A, et al. Contrast-enhanced ultrasound for imaging vasa vasorum: comparison with histopathology in a swine model of atherosclerosis. Eur J Echocardiogr. 2010;11(8):659–64. https://doi.org/10.1093/ejechocard/jeq048.

    PubMed  Article  Google Scholar 

  88. 88.

    Atochina EN, Hiemisch HH, Muzykantov VR, Danilov SM. Systemic administration of platelet-activating factor in rat reduces specific pulmonary uptake of circulating monoclonal antibody to angiotensin-converting enzyme. Lung. 1992;170(6):349–58.

    PubMed  CAS  Article  Google Scholar 

  89. 89.

    Atochina EN, Muzykantov VR, Al-Mehdi AB, Danilov SM, Fisher AB. Normoxic lung ischemia/reperfusion accelerates shedding of angiotensin converting enzyme from the pulmonary endothelium. Am J Respir Crit Care Med. 1997;156(4 Pt 1):1114–9. https://doi.org/10.1164/ajrccm.156.4.96-12116.

    PubMed  CAS  Article  Google Scholar 

  90. 90.

    Ding BS, Hong N, Christofidou-Solomidou M, Gottstein C, Albelda SM, Cines DB, et al. Anchoring fusion thrombomodulin to the endothelial lumen protects against injury-induced lung thrombosis and inflammation. Am J Respir Crit Care Med. 2009;180(3):247–56. https://doi.org/10.1164/rccm.200809-1433OC.

  91. 91.

    Muzykantov VR, Puchnina EA, Atochina EN, Hiemish H, Slinkin MA, Meertsuk FE, et al. Endotoxin reduces specific pulmonary uptake of radiolabeled monoclonal antibody to angiotensin-converting enzyme. J Nucl Med. 1991;32(3):453–60.

  92. 92.

    Brenner JS, Bhamidipati K, Glassman P, Ramakrishnan N, Jiang D, Paris AJ, et al. Mechanisms that determine nanocarrier targeting to healthy versus inflamed lung regions. Nanomedicine. 2017;13(4):1495–506. https://doi.org/10.1016/j.nano.2016.12.019.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  93. 93.

    Gibiansky L, Gibiansky E, Kakkar T, Ma P. Approximations of the target-mediated drug disposition model and identifiability of model parameters. J Pharmacokinet Pharmacodyn. 2008;35(5):573–91. https://doi.org/10.1007/s10928-008-9102-8.

    PubMed  CAS  Article  Google Scholar 

  94. 94.

    Grimm HP. Gaining insights into the consequences of target-mediated drug disposition of monoclonal antibodies using quasi-steady-state approximations. J Pharmacokinet Pharmacodyn. 2009;36(5):407–20. https://doi.org/10.1007/s10928-009-9129-5.

    PubMed  CAS  Article  Google Scholar 

  95. 95.

    Mager DE, Krzyzanski W. Quasi-equilibrium pharmacokinetic model for drugs exhibiting target-mediated drug disposition. Pharm Res. 2005;22(10):1589–96. https://doi.org/10.1007/s11095-005-6650-0.

    PubMed  CAS  Article  Google Scholar 

  96. 96.

    Aston PJ, Derks G, Raji A, Agoram BM, van der Graaf PH. Mathematical analysis of the pharmacokinetic-pharmacodynamic (PKPD) behaviour of monoclonal antibodies: predicting in vivo potency. J Theor Biol. 2011;281(1):113–21. https://doi.org/10.1016/j.jtbi.2011.04.030.

    PubMed  CAS  Article  Google Scholar 

  97. 97.

    Thygesen P, Macheras P, Van Peer A. Physiologically-based PK/PD modelling of therapeutic macromolecules. Pharm Res. 2009;26(12):2543–50. https://doi.org/10.1007/s11095-009-9990-3.

    PubMed  CAS  Article  Google Scholar 

  98. 98.

    Abuqayyas L, Balthasar JP. Application of PBPK modeling to predict monoclonal antibody disposition in plasma and tissues in mouse models of human colorectal cancer. J Pharmacokinet Pharmacodyn. 2012;39(6):683–710. https://doi.org/10.1007/s10928-012-9279-8.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  99. 99.

    Davda JP, Jain M, Batra SK, Gwilt PR, Robinson DH. A physiologically based pharmacokinetic (PBPK) model to characterize and predict the disposition of monoclonal antibody CC49 and its single chain Fv constructs. Int Immunopharmacol. 2008;8(3):401–13. https://doi.org/10.1016/j.intimp.2007.10.023.

    PubMed  CAS  Article  Google Scholar 

  100. 100.

    Ferl GZ, Wu AM, DiStefano JJ 3rd. A predictive model of therapeutic monoclonal antibody dynamics and regulation by the neonatal Fc receptor (FcRn). Ann Biomed Eng. 2005;33(11):1640–52. https://doi.org/10.1007/s10439-005-7410-3.

    PubMed  Article  Google Scholar 

  101. 101.

    Garg A, Balthasar JP. Physiologically-based pharmacokinetic (PBPK) model to predict IgG tissue kinetics in wild-type and FcRn-knockout mice. J Pharmacokinet Pharmacodyn. 2007;34(5):687–709. https://doi.org/10.1007/s10928-007-9065-1.

    PubMed  CAS  Article  Google Scholar 

  102. 102.

    Carlander U, Li D, Jolliet O, Emond C, Johanson G. Toward a general physiologically-based pharmacokinetic model for intravenously injected nanoparticles. Int J Nanomedicine. 2016;11:625–40. https://doi.org/10.2147/IJN.S94370.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  103. 103.

    Li M, Zou P, Tyner K, Lee S. Physiologically based pharmacokinetic (PBPK) modeling of pharmaceutical nanoparticles. AAPS J. 2017;19(1):26–42. https://doi.org/10.1208/s12248-016-0010-3.

    PubMed  CAS  Article  Google Scholar 

  104. 104.

    Ichimura H, Parthasarathi K, Quadri S, Issekutz AC, Bhattacharya J. Mechano-oxidative coupling by mitochondria induces proinflammatory responses in lung venular capillaries. J Clin Invest. 2003;111(5):691–9. https://doi.org/10.1172/JCI17271.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  105. 105.

    Indo HP, Hawkins CL, Nakanishi I, Matsumoto KI, Matsui H, Suenaga S, et al. Role of mitochondrial reactive oxygen species in the activation of cellular signals, molecules, and function. Handb Exp Pharmacol. 2017; https://doi.org/10.1007/164_2016_117.

  106. 106.

    McCord JM, Roy RS, Schaffer SW. Free radicals and myocardial ischemia. The role of xanthine oxidase. Adv Myocardiol. 1985;5:183–9.

    PubMed  CAS  Article  Google Scholar 

  107. 107.

    Jiang F, Zhang Y, Dusting GJ. NADPH oxidase-mediated redox signaling: roles in cellular stress response, stress tolerance, and tissue repair. Pharmacol Rev. 2011;63(1):218–42. https://doi.org/10.1124/pr.110.002980.

    PubMed  CAS  Article  Google Scholar 

  108. 108.

    Kobayashi M, Yamamoto M. Nrf2-Keap1 regulation of cellular defense mechanisms against electrophiles and reactive oxygen species. Adv Enzym Regul. 2006;46(1):113–40. https://doi.org/10.1016/j.advenzreg.2006.01.007.

    CAS  Article  Google Scholar 

  109. 109.

    Gloire G, Piette J. Redox regulation of nuclear post-translational modifications during NF-kappaB activation. Antioxid Redox Signal. 2009;11(9):2209–22. https://doi.org/10.1089/ARS.2009.2463.

    PubMed  CAS  Article  Google Scholar 

  110. 110.

    Kumar S, Singh RK, Bhardwaj TR. Therapeutic role of nitric oxide as emerging molecule. Biomed Pharmacother. 2017;85:182–201. https://doi.org/10.1016/j.biopha.2016.11.125.

    PubMed  CAS  Article  Google Scholar 

  111. 111.

    Beckman JS, Koppenol WH. Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly. Am J Phys. 1996;271(5 Pt 1):C1424–37.

    CAS  Article  Google Scholar 

  112. 112.

    Fridovich I. Fundamental aspects of reactive oxygen species, or what’s the matter with oxygen? Ann N Y Acad Sci. 1999;893(1 OXIDATIVE/ENE):13–8. https://doi.org/10.1111/j.1749-6632.1999.tb07814.x.

    PubMed  CAS  Article  Google Scholar 

  113. 113.

    Ushio-Fukai M. Compartmentalization of redox signaling through NADPH oxidase-derived ROS. Antioxid Redox Signal. 2009;11(6):1289–99. https://doi.org/10.1089/ars.2008.2333.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  114. 114.

    Sies H, Berndt C, Jones DP. Oxidative stress. Annu Rev Biochem. 2017;86(1):715–48. https://doi.org/10.1146/annurev-biochem-061516-045037.

    PubMed  CAS  Article  Google Scholar 

  115. 115.

    Jhaveri A, Torchilin V. Intracellular delivery of nanocarriers and targeting to subcellular organelles. Expert Opin Drug Deliv. 2016;13(1):49–70. https://doi.org/10.1517/17425247.2015.1086745.

    PubMed  CAS  Article  Google Scholar 

  116. 116.

    Traber DL. Systemic cardiovascular changes with acute lung injury. Crit Care Med. 1995;23(1):7. https://doi.org/10.1097/00003246-199501000-00004.

    PubMed  CAS  Article  Google Scholar 

  117. 117.

    Prauchner CA. Oxidative stress in sepsis: pathophysiological implications justifying antioxidant co-therapy. Burns. 2017;43(3):471–85. https://doi.org/10.1016/j.burns.2016.09.023.

    PubMed  Article  Google Scholar 

  118. 118.

    Chang LY, Subramaniam M, Yoder BA, Day BJ, Ellison MC, Sunday ME, et al. A catalytic antioxidant attenuates alveolar structural remodeling in bronchopulmonary dysplasia. Am J Respir Crit Care Med. 2003;167(1):57–64. https://doi.org/10.1164/rccm.200203-232OC.

    PubMed  Article  Google Scholar 

  119. 119.

    Vujaskovic Z, Batinic-Haberle I, Rabbani ZN, Feng QF, Kang SK, Spasojevic I, et al. A small molecular weight catalytic metalloporphyrin antioxidant with superoxide dismutase (SOD) mimetic properties protects lungs from radiation-induced injury. Free Radic Biol Med. 2002;33(6):857–63. https://doi.org/10.1016/S0891-5849(02)00980-2.

    PubMed  CAS  Article  Google Scholar 

  120. 120.

    Gao B, Flores SC, Leff JA, Bose SK, McCord JM. Synthesis and anti-inflammatory activity of a chimeric recombinant superoxide dismutase: SOD2/3. Am J Physiol Lung Cell Mol Physiol. 2003;284(6):L917–25. https://doi.org/10.1152/ajplung.00374.2002.

    PubMed  CAS  Article  Google Scholar 

  121. 121.

    Watanabe N, Iwamoto T, Bowen KD, Dickinson DA, Torres M, Forman HJ. Bio-effectiveness of Tat-catalase conjugate: a potential tool for the identification of H2O2-dependent cellular signal transduction pathways. Biochem Biophys Res Commun. 2003;303(1):287–93. https://doi.org/10.1016/S0006-291X(03)00335-8.

    PubMed  CAS  Article  Google Scholar 

  122. 122.

    Morry J, Ngamcherdtrakul W, Yantasee W. Oxidative stress in cancer and fibrosis: opportunity for therapeutic intervention with antioxidant compounds, enzymes, and nanoparticles. Redox Biol. 2017;11:240–53. https://doi.org/10.1016/j.redox.2016.12.011.

    PubMed  CAS  Article  Google Scholar 

  123. 123.

    Weydert CJ, Waugh TA, Ritchie JM, Iyer KS, Smith JL, Li L, et al. Overexpression of manganese or copper-zinc superoxide dismutase inhibits breast cancer growth. Free Radic Biol Med. 2006;41(2):226–37. https://doi.org/10.1016/j.freeradbiomed.2006.03.015.

  124. 124.

    Carvalho AN, Firuzi O, Gama MJ, van Horssen J, Saso L. Oxidative stress and antioxidants in neurological diseases: is there still hope? Curr Drug Targets. 2016.

  125. 125.

    Duerbeck NB, Dowling DD, Duerbeck JM. Vitamin C: promises not kept. Obstet Gynecol Surv. 2016;71(3):187–93. https://doi.org/10.1097/OGX.0000000000000289.

    PubMed  Article  Google Scholar 

  126. 126.

    Suarna C, BJ W, Choy K, Mori T, Croft K, Cynshi O, et al. Protective effect of vitamin E supplements on experimental atherosclerosis is modest and depends on preexisting vitamin E deficiency. Free Radic Biol Med. 2006;41(5):722–30. https://doi.org/10.1016/j.freeradbiomed.2006.05.013.

    PubMed  CAS  Article  Google Scholar 

  127. 127.

    Siekmeier R, Steffen C, Marz W. Role of oxidants and antioxidants in atherosclerosis: results of in vitro and in vivo investigations. J Cardiovasc Pharmacol Ther. 2007;12(4):265–82. https://doi.org/10.1177/1074248407299519.

    PubMed  CAS  Article  Google Scholar 

  128. 128.

    Thomson MJ, Puntmann V, Kaski JC. Atherosclerosis and oxidant stress: the end of the road for antioxidant vitamin treatment? Cardiovasc Drugs Ther/ sponsored by the International Society of Cardiovascular Pharmacotherapy. 2007;21(3):195–210. https://doi.org/10.1007/s10557-007-6027-1.

    CAS  Article  Google Scholar 

  129. 129.

    Jin LH, Bahn JH, Eum WS, Kwon HY, Jang SH, Han KH, et al. Transduction of human catalase mediated by an HIV-1 TAT protein basic domain and arginine-rich peptides into mammalian cells. Free Radic Biol Med. 2001;31(11):1509–19. https://doi.org/10.1016/S0891-5849(01)00734-1.

  130. 130.

    Ding BS, Dziubla T, Shuvaev VV, Muro S, Muzykantov VR. Advanced drug delivery systems that target the vascular endothelium. Mol Interv. 2006;6(2):98–112. https://doi.org/10.1124/mi.6.2.7.

    PubMed  CAS  Article  Google Scholar 

  131. 131.

    Freeman BA, Young SL, Crapo JD. Liposome-mediated augmentation of superoxide dismutase in endothelial cells prevents oxygen injury. J Biol Chem. 1983;258(20):12534–42.

    PubMed  CAS  Google Scholar 

  132. 132.

    White CW, Jackson JH, Abuchowski A, Kazo GM, Mimmack RF, Berger EM, et al. Polyethylene glycol-attached antioxidant enzymes decrease pulmonary oxygen toxicity in rats. J Appl Physiol (1985). 1989;66(2):584–90.

  133. 133.

    Corvo ML, Boerman OC, Oyen WJ, Van Bloois L, Cruz ME, Crommelin DJ, et al. Intravenous administration of superoxide dismutase entrapped in long circulating liposomes. II. In vivo fate in a rat model of adjuvant arthritis. Biochim Biophys Acta. 1999;1419(2):325–34. https://doi.org/10.1016/S0005-2736(99)00081-4.

    PubMed  CAS  Article  Google Scholar 

  134. 134.

    Simone EA, Dziubla TD, Muzykantov VR. Polymeric carriers: role of geometry in drug delivery. Expert Opin Drug Deliv. 2008;5(12):1283–300. https://doi.org/10.1517/17425240802567846.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  135. 135.

    Kabanov AV, Batrakova EV, Alakhov VY. Pluronic block copolymers as novel polymer therapeutics for drug and gene delivery. J Control Release. 2002;82(2–3):189–212. https://doi.org/10.1016/S0168-3659(02)00009-3.

    PubMed  CAS  Article  Google Scholar 

  136. 136.

    Freeman BA, Turrens JF, Mirza Z, Crapo JD, Young SL. Modulation of oxidant lung injury by using liposome-entrapped superoxide dismutase and catalase. Fed Proc. 1985;44(10):2591–5.

    PubMed  CAS  Google Scholar 

  137. 137.

    Koyama S, Kobayashi T, Kubo K, Sekiguchi M, Ueda G. Recombinant-human superoxide dismutase attenuates endotoxin-induced lung injury in awake sheep. Am Rev Respir Dis. 1992;145(6):1404–9. https://doi.org/10.1164/ajrccm/145.6.1404.

    PubMed  CAS  Article  Google Scholar 

  138. 138.

    Shuvaev VV, Han J, Yu KJ, Huang S, Hawkins BJ, Madesh M, et al. PECAM-targeted delivery of SOD inhibits endothelial inflammatory response. FASEB J. 2011;25(1):348–57. https://doi.org/10.1096/fj.10-169789.

    PubMed  PubMed Central  Article  Google Scholar 

  139. 139.

    Stenesh J. Biochemistry. New York: Plenum; 1998. https://doi.org/10.1007/978-1-4757-9427-4.

    Google Scholar 

  140. 140.

    Shuvaev VV, Dziubla T, Wiewrodt R, Muzykantov VR. Streptavidin-biotin crosslinking of therapeutic enzymes with carrier antibodies: nanoconjugates for protection against endothelial oxidative stress. Methods Mol Biol. 2004;283:3–19. https://doi.org/10.1385/1-59259-813-7:003.

    PubMed  Article  CAS  Google Scholar 

  141. 141.

    Shuvaev VV, Tliba S, Nakada M, Albelda SM, Muzykantov VR. Platelet-endothelial cell adhesion molecule-1-directed endothelial targeting of superoxide dismutase alleviates oxidative stress caused by either extracellular or intracellular superoxide. J Pharmacol Exp Ther. 2007;323(2):450–7. https://doi.org/10.1124/jpet.107.127126.

    PubMed  CAS  Article  Google Scholar 

  142. 142.

    Shuvaev VV, Tliba S, Pick J, Arguiri E, Christofidou-Solomidou M, Albelda SM, et al. Modulation of endothelial targeting by size of antibody-antioxidant enzyme conjugates. J Control Release. 2011;149(3):236–41. https://doi.org/10.1016/j.jconrel.2010.10.026.

  143. 143.

    Shuvaev VV, Muro S, Arguiri E, Khoshnejad M, Tliba S, Christofidou-Solomidou M, et al. Size and targeting to PECAM vs ICAM control endothelial delivery, internalization and protective effect of multimolecular SOD conjugates. J Control Release. 2016;234:115–23. https://doi.org/10.1016/j.jconrel.2016.05.040.

  144. 144.

    Kozower BD, Christofidou-Solomidou M, Sweitzer TD, Muro S, Buerk DG, Solomides CC, et al. Immunotargeting of catalase to the pulmonary endothelium alleviates oxidative stress and reduces acute lung transplantation injury. Nat Biotechnol. 2003;21(4):392–8. https://doi.org/10.1038/nbt806.

    PubMed  CAS  Article  Google Scholar 

  145. 145.

    Shuvaev VV, Christofidou-Solomidou M, Bhora F, Laude K, Cai H, Dikalov S, et al. Targeted detoxification of selected reactive oxygen species in the vascular endothelium. J Pharmacol Exp Ther. 2009;331(2):404–11. https://doi.org/10.1124/jpet.109.156877.

  146. 146.

    Nowak K, Weih S, Metzger R, Albrecht RF 2nd, Post S, Hohenberger P, et al. Immunotargeting of catalase to lung endothelium via anti-angiotensin-converting enzyme antibodies attenuates ischemia-reperfusion injury of the lung in vivo. Am J Physiol Lung Cell Mol Physiol. 2007;293(1):L162–9. https://doi.org/10.1152/ajplung.00001.2007.

    PubMed  CAS  Article  Google Scholar 

  147. 147.

    Corr M, Lerman I, Keubel JM, Ronacher L, Misra R, Lund F, et al. Decreased Krev interaction-trapped 1 expression leads to increased vascular permeability and modifies inflammatory responses in vivo. Arterioscler Thromb Vasc Biol. 2012;32(11):2702–10. https://doi.org/10.1161/ATVBAHA.112.300115.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  148. 148.

    Glading A, Han J, Stockton RA, Ginsberg MH. KRIT-1/CCM1 is a Rap1 effector that regulates endothelial cell cell junctions. J Cell Biol. 2007;179(2):247–54. https://doi.org/10.1083/jcb.200705175.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  149. 149.

    Tanswell AK, Freeman BA. Liposome-entrapped antioxidant enzymes prevent lethal O2 toxicity in the newborn rat. J Appl Physiol. 1987;63(1):347–52.

    PubMed  CAS  Article  Google Scholar 

  150. 150.

    Stone WL, Smith M. Therapeutic uses of antioxidant liposomes. Mol Biotechnol. 2004;27(3):217–30. https://doi.org/10.1385/MB:27:3:217.

    PubMed  CAS  Article  Google Scholar 

  151. 151.

    Gonnet M, Lethuaut L, Boury F. New trends in encapsulation of liposoluble vitamins. J Control Release. 2010;146(3):276–90. https://doi.org/10.1016/j.jconrel.2010.01.037.

    PubMed  CAS  Article  Google Scholar 

  152. 152.

    Corvo LM, Jorge JCS, van’t Hof R, Cruz MEM, Crommelin DJA, Storm G. Superoxide dismutase entrapped in long-circulating liposomes: formulation design and therapeutic activity in rat adjuvant arthritis. Biochim Biophys Acta Biomembr. 2002;1564(1):227–36. https://doi.org/10.1016/S0005-2736(02)00457-1.

    Article  Google Scholar 

  153. 153.

    Gaspar MM, Martins MB, Corvo ML, Cruz ME. Design and characterization of enzymosomes with surface-exposed superoxide dismutase. Biochim Biophys Acta. 2003;1609(2):211–7. https://doi.org/10.1016/S0005-2736(02)00702-2.

    PubMed  CAS  Article  Google Scholar 

  154. 154.

    Gaspar MM, Boerman OC, Laverman P, Corvo ML, Storm G, Cruz ME. Enzymosomes with surface-exposed superoxide dismutase: in vivo behaviour and therapeutic activity in a model of adjuvant arthritis. J Control Release. 2007;117(2):186–95. https://doi.org/10.1016/j.jconrel.2006.10.018.

    PubMed  CAS  Article  Google Scholar 

  155. 155.

    Xu X, Costa A, Burgess DJ. Protein encapsulation in unilamellar liposomes: high encapsulation efficiency and a novel technique to assess lipid-protein interaction. Pharm Res. 2012;29(7):1919–31. https://doi.org/10.1007/s11095-012-0720-x.

    PubMed  CAS  Article  Google Scholar 

  156. 156.

    Hood ED, Greineder CF, Dodia C, Han J, Mesaros C, Shuvaev VV, et al. Antioxidant protection by PECAM-targeted delivery of a novel NADPH-oxidase inhibitor to the endothelium in vitro and in vivo. J Control Release. 2012;163(2):161–9. https://doi.org/10.1016/j.jconrel.2012.08.031.

  157. 157.

    Howard MD, Greineder CF, Hood ED, Muzykantov VR. Endothelial targeting of liposomes encapsulating SOD/catalase mimetic EUK-134 alleviates acute pulmonary inflammation. J Control Release. 2014;177:34–41. https://doi.org/10.1016/j.jconrel.2013.12.035.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  158. 158.

    Kee PH, Kim H, Huang S, Laing ST, Moody MR, Vela D, et al. Nitric oxide pretreatment enhances atheroma component highlighting in vivo with intercellular adhesion molecule-1-targeted echogenic liposomes. Ultrasound Med Biol. 2014;40(6):1167–76. https://doi.org/10.1016/j.ultrasmedbio.2013.12.013.

  159. 159.

    Kim H, Kee PH, Rim Y, Moody MR, Klegerman ME, Vela D, et al. Nitric oxide-enhanced molecular imaging of atheroma using vascular cellular adhesion molecule 1-targeted echogenic immunoliposomes. Ultrasound Med Biol. 2015;41(6):1701–10. https://doi.org/10.1016/j.ultrasmedbio.2015.02.002.

  160. 160.

    Hua S, Cabot PJ. Targeted nanoparticles that mimic immune cells in pain control inducing analgesic and anti-inflammatory actions: a potential novel treatment of acute and chronic pain condition. Pain Physician. 2013;16(3):E199–216.

    PubMed  Google Scholar 

  161. 161.

    Dziubla TD, Karim A, Muzykantov VR. Polymer nanocarriers protecting active enzyme cargo against proteolysis. J Control Release. 2005;102(2):427–39. https://doi.org/10.1016/j.jconrel.2004.10.017.

    PubMed  CAS  Article  Google Scholar 

  162. 162.

    Simone EA, Dziubla TD, Discher DE, Muzykantov VR. Filamentous polymer nanocarriers of tunable stiffness that encapsulate the therapeutic enzyme catalase. Biomacromolecules. 2009;10(6):1324–30. https://doi.org/10.1021/bm900189x.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  163. 163.

    Kartha S, Yan L, Weisshaar CL, Ita ME, Shuvaev VV, Muzykantov VR, et al. Superoxide dismutase-loaded porous polymersomes as highly efficient antioxidants for treating neuropathic pain. Adv Healthc Mater. 2017;6(17) https://doi.org/10.1002/adhm.201700500.

  164. 164.

    Dziubla TD, Shuvaev VV, Hong NK, Hawkins BJ, Madesh M, Takano H, et al. Endothelial targeting of semi-permeable polymer nanocarriers for enzyme therapies. Biomaterials. 2008;29(2):215–27. https://doi.org/10.1016/j.biomaterials.2007.09.023.

  165. 165.

    Chorny M, Hood E, Levy RJ, Muzykantov VR. Endothelial delivery of antioxidant enzymes loaded into non-polymeric magnetic nanoparticles. J Control Release. 2010;146(1):144–51. https://doi.org/10.1016/j.jconrel.2010.05.003.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  166. 166.

    Cornelius C, Crupi R, Calabrese V, Graziano A, Milone P, Pennisi G, et al. Traumatic brain injury: oxidative stress and neuroprotection. Antioxid Redox Signal. 2013;19(8):836–53. https://doi.org/10.1089/ars.2012.4981.

  167. 167.

    Bains M, Hall ED. Antioxidant therapies in traumatic brain and spinal cord injury. Biochim Biophys Acta. 2012;1822(5):675–84. https://doi.org/10.1016/j.bbadis.2011.10.017.

    PubMed  CAS  Article  Google Scholar 

  168. 168.

    Lutton EM, Razmpour R, Andrews AM, Cannella LA, Son YJ, Shuvaev VV, et al. Acute administration of catalase targeted to ICAM-1 attenuates neuropathology in experimental traumatic brain injury. Sci Rep. 2017;7(1):3846. https://doi.org/10.1038/s41598-017-03309-4.

  169. 169.

    Abraham E, Reinhart K, Opal S, Demeyer I, Doig C, Rodriguez AL, et al. Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial. JAMA. 2003;290(2):238–47. https://doi.org/10.1001/jama.290.2.238.

    PubMed  CAS  Article  Google Scholar 

  170. 170.

    Barst RJ, Rubin LJ, Long WA, McGoon MD, Rich S, Badesch DB, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med. 1996;334(5):296–301. https://doi.org/10.1056/nejm199602013340504.

  171. 171.

    Loscalzo J, Braunwald E. Tissue plasminogen activator. N Engl J Med. 1988;319(14):925–31. https://doi.org/10.1056/nejm198810063191407.

    PubMed  CAS  Article  Google Scholar 

  172. 172.

    Marsh N, Marsh A. A short history of nitroglycerine and nitric oxide in pharmacology and physiology. Clin Exp Pharmacol Physiol. 2000;27(4):313–9. https://doi.org/10.1046/j.1440-1681.2000.03240.x.

    PubMed  CAS  Article  Google Scholar 

  173. 173.

    Ranieri VM, Thompson BT, Barie PS, Dhainaut JF, Douglas IS, Finfer S, et al. Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med. 2012;366(22):2055–64. https://doi.org/10.1056/NEJMoa1202290.

  174. 174.

    Warren BL, Eid A, Singer P, Pillay SS, Carl P, Novak I, et al. Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. JAMA. 2001;286(15):1869–78. https://doi.org/10.1001/jama.286.15.1869.

  175. 175.

    Carnemolla R, Shuvaev VV, Muzykantov VR. Targeting antioxidant and antithrombotic biotherapeutics to endothelium. Semin Thromb Hemost. 2010;36(3):332–42. https://doi.org/10.1055/s-0030-1253455.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  176. 176.

    Muzykantov VR. Targeted drug delivery to endothelial adhesion molecules. ISRN Vascular Medicine. 2013;2013:1–27. https://doi.org/10.1155/2013/916254.

    Article  Google Scholar 

  177. 177.

    National Institute of Neurological D, Stroke rt PASSG. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333(24):1581–7. https://doi.org/10.1056/NEJM199512143332401.

    Article  Google Scholar 

  178. 178.

    Weintraub MI. Thrombolysis (tissue plasminogen activator) in stroke: a medicolegal quagmire. Stroke. 2006;37(7):1917–22. https://doi.org/10.1161/01.STR.0000226651.04862.da.

    PubMed  Article  Google Scholar 

  179. 179.

    Murciano JC, Medinilla S, Eslin D, Atochina E, Cines DB, Muzykantov VR. Prophylactic fibrinolysis through selective dissolution of nascent clots by tPA-carrying erythrocytes. Nat Biotechnol. 2003;21(8):891–6. https://doi.org/10.1038/nbt846.

    PubMed  CAS  Article  Google Scholar 

  180. 180.

    Esmon CT. Thrombomodulin as a model of molecular mechanisms that modulate protease specificity and function at the vessel surface. FASEB J. 1995;9(10):946–55.

    PubMed  CAS  Article  Google Scholar 

  181. 181.

    Stearns-Kurosawa DJ, Kurosawa S, Mollica JS, Ferrell GL, Esmon CT. The endothelial cell protein C receptor augments protein C activation by the thrombin-thrombomodulin complex. Proc Natl Acad Sci U S A. 1996;93(19):10212–6. https://doi.org/10.1073/pnas.93.19.10212.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  182. 182.

    Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001;344(10):699–709. https://doi.org/10.1056/nejm200103083441001.

  183. 183.

    Esmon CT. Inflammation and the activated protein C anticoagulant pathway. Semin Thromb Hemost. 2006;32(Suppl 1):49–60. https://doi.org/10.1055/s-2006-939554.

    PubMed  CAS  Article  Google Scholar 

  184. 184.

    Greineder CF, Brenza JB, Carnemolla R, Zaitsev S, Hood ED, Pan DC, et al. Dual targeting of therapeutics to endothelial cells: collaborative enhancement of delivery and effect. FASEB J. 2015;29(8):3483–92. https://doi.org/10.1096/fj.15-271213.

  185. 185.

    Greineder CF, Chacko AM, Zaytsev S, Zern BJ, Carnemolla R, Hood ED, et al. Vascular immunotargeting to endothelial determinant ICAM-1 enables optimal partnering of recombinant scFv-thrombomodulin fusion with endogenous cofactor. PLoS One. 2013;8(11):e80110. https://doi.org/10.1371/journal.pone.0080110.

  186. 186.

    Greineder CF, Hood ED, Yao A, Khoshnejad M, Brenner JS, Johnston IH, et al. Molecular engineering of high affinity single-chain antibody fragment for endothelial targeting of proteins and nanocarriers in rodents and humans. J Control Release. 2016;226:229–37. https://doi.org/10.1016/j.jconrel.2016.02.006.

  187. 187.

    Greineder CF, Johnston IH, Villa CH, Gollomp K, Esmon CT, Cines DB, et al. ICAM-1-targeted thrombomodulin prevents tissue-factor driven inflammatory thrombosis in a human endothelialized microfluidic model. Blood Adv. 2017;1(18):1452–65. https://doi.org/10.1182/%20bloodadvances.2017007229.

  188. 188.

    Chacko A-M, Nayak M, Greineder CF, Delisser HM, Muzykantov VR. Collaborative enhancement of antibody binding to distinct PECAM-1 epitopes modulates endothelial targeting. PLoS One. 2012;7(4):e34958. https://doi.org/10.1371/journal.pone.0034958.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  189. 189.

    Kiseleva R, Greineder CF, Villa CH, Hood ED, Shuvaev VV, Sun J, et al. Mechanism of collaborative enhancement of binding of paired antibodies to distinct epitopes of platelet endothelial cell adhesion molecule-1. PLoS One. 2017;12(1):e0169537. https://doi.org/10.1371/journal.pone.0169537.

  190. 190.

    Chacko AM, Han J, Greineder CF, Zern BJ, Mikitsh JL, Nayak M, et al. Collaborative enhancement of endothelial targeting of nanocarriers by modulating platelet-endothelial cell adhesion molecule-1/CD31 epitope engagement. ACS Nano. 2015;9(7):6785–93. https://doi.org/10.1021/nn505672x.

  191. 191.

    Lubeck M, Gerhard W. Conformational changes at topologically distinct antigenic sites on the influenza A/PR/8/34 virus HA molecule are induced by the binding of monoclonal antibodies. Virology. 1982;118(1):1–7. https://doi.org/10.1016/0042-6822(82)90313-0.

    PubMed  CAS  Article  Google Scholar 

  192. 192.

    Towbin H, Erard F, van Oostrum J, Schmitz A, Rordorf C. Neoepitope immunoassay: an assay for human interleukin 1$\beta$ based on an antibody induced conformational change. J Immunoass. 1996;17(4):353–69. https://doi.org/10.1080/01971529608005798.

    CAS  Article  Google Scholar 

  193. 193.

    Howard MD, Jay M, Dziubla TD, Lu X. PEGylation of Nanocarrier nanocarrier drug delivery systems: state of the art. J Biomed Nanotechnol. 2008;4(2):133–48. https://doi.org/10.1166/jbn.2008.021.

    CAS  Article  Google Scholar 

  194. 194.

    Shuvaev VV, Christofidou-Solomidou M, Scherpereel A, Simone E, Arguiri E, Tliba S, et al. Factors modulating the delivery and effect of enzymatic cargo conjugated with antibodies targeted to the pulmonary endothelium. J Control Release. 2007;118(2):235–44. https://doi.org/10.1016/j.jconrel.2006.12.025.

  195. 195.

    Kennel SJ, Falcioni R, Wesley JW. Microdistribution of specific rat monoclonal antibodies to mouse tissues and human tumor xenografts. Cancer Res. 1991;51(5):1529–36.

    PubMed  CAS  Google Scholar 

  196. 196.

    Christofidou-Solomidou M, Kennel S, Scherpereel A, Wiewrodt R, Solomides CC, Pietra GG, et al. Vascular immunotargeting of glucose oxidase to the endothelial antigens induces distinct forms of oxidant acute lung injury: targeting to thrombomodulin, but not to PECAM-1, causes pulmonary thrombosis and neutrophil transmigration. Am J Pathol. 2002;160(3):1155–69. https://doi.org/10.1016/S0002-9440(10)64935-8.

  197. 197.

    Muzykantov VR. Targeted therapeutics and nanodevices for vascular drug delivery: quo vadis? IUBMB Life. 2011;63(8):583–5. https://doi.org/10.1002/iub.480.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  198. 198.

    Chittasupho C, Xie SX, Baoum A, Yakovleva T, Siahaan TJ, Berkland CJ. ICAM-1 targeting of doxorubicin-loaded PLGA nanoparticles to lung epithelial cells. Eur J Pharm Sci: Off J Eur Fed Pharm Sci. 2009;37(2):141–50. https://doi.org/10.1016/j.ejps.2009.02.008.

    CAS  Article  Google Scholar 

  199. 199.

    Bartsch M, Weeke-Klimp AH, Morselt HW, Kimpfler A, Asgeirsdottir SA, Schubert R, et al. Optimized targeting of polyethylene glycol-stabilized anti-intercellular adhesion molecule 1 oligonucleotide/lipid particles to liver sinusoidal endothelial cells. Mol Pharmacol. 2005;67(3):883–90. https://doi.org/10.1124/mol.104.004523.

    PubMed  CAS  Article  Google Scholar 

  200. 200.

    Sweitzer TD, Thomas AP, Wiewrodt R, Nakada MT, Branco F, Muzykantov VR. PECAM-directed immunotargeting of catalase: specific, rapid and transient protection against hydrogen peroxide. Free Radic Biol Med. 2003;34(8):1035–46. https://doi.org/10.1016/S0891-5849(03)00029-7.

    PubMed  CAS  Article  Google Scholar 

  201. 201.

    Muro S, Koval M, Muzykantov V. Endothelial endocytic pathways: gates for vascular drug delivery. Curr Vasc Pharmacol. 2004;2(3):281–99. https://doi.org/10.2174/1570161043385736.

    PubMed  CAS  Article  Google Scholar 

  202. 202.

    Muro S, Gajewski C, Koval M, Muzykantov VR. ICAM-1 recycling in endothelial cells: a novel pathway for sustained intracellular delivery and prolonged effects of drugs. Blood. 2005;105(2):650–8. https://doi.org/10.1182/blood-2004-05-1714.

    PubMed  CAS  Article  Google Scholar 

  203. 203.

    Hood ED, Chorny M, Greineder CF, SA I, Levy RJ, Muzykantov VR. Endothelial targeting of nanocarriers loaded with antioxidant enzymes for protection against vascular oxidative stress and inflammation. Biomaterials. 2014;35(11):3708–15. https://doi.org/10.1016/j.biomaterials.2014.01.023.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  204. 204.

    Murciano JC, Muro S, Koniaris L, Christofidou-Solomidou M, Harshaw DW, Albelda SM, et al. ICAM-directed vascular immunotargeting of antithrombotic agents to the endothelial luminal surface. Blood. 2003;101(10):3977–84. https://doi.org/10.1182/blood-2002-09-2853.

  205. 205.

    Ding BS, Zhou YJ, Chen XY, Zhang J, Zhang PX, Sun ZY, et al. Lung endothelium targeting for pulmonary embolism thrombolysis. Circulation. 2003;108(23):2892–8. https://doi.org/10.1161/01.CIR.0000103685.61137.3D.

  206. 206.

    Runge MS, Quertermous T, Zavodny PJ, Love TW, Bode C, Freitag M, et al. A recombinant chimeric plasminogen activator with high affinity for fibrin has increased thrombolytic potency in vitro and in vivo. Proc Natl Acad Sci U S A. 1991;88(22):10337–41. https://doi.org/10.1073/pnas.88.22.10337.

  207. 207.

    Holvoet P, Laroche Y, Stassen JM, Lijnen HR, Van Hoef B, De Cock F, et al. Pharmacokinetic and thrombolytic properties of chimeric plasminogen activators consisting of a single-chain Fv fragment of a fibrin-specific antibody fused to single-chain urokinase. Blood. 1993;81(3):696–703.

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Vladimir R. Muzykantov.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Kiseleva, R.Y., Glassman, P.M., Greineder, C.F. et al. Targeting therapeutics to endothelium: are we there yet?. Drug Deliv. and Transl. Res. 8, 883–902 (2018). https://doi.org/10.1007/s13346-017-0464-6

Download citation

Keywords

  • Vascular immunotargeting
  • Endothelial targeting
  • Drug delivery
  • Antioxidants
  • Antithrombotic drugs