Factors Controlling Pharmacokinetics of Intravenously Injected Nanoparticulate Systems

  • S. Moein Moghimi
  • Islam Hamad
Part of the Biotechnology: Pharmaceutical Aspects book series (PHARMASP, volume X)


Complement Activation PEGylated Liposome Sinus Endothelial Cell Prolonged Circulation Time Complement Consumption 


  1. Al-Hanbali, O., Rutt, K. J., Sarker, D. K., Hunter, A. C., & Moghimi, S. M. (2006). Concentration dependent structural ordering of poloxamine 908 on polystyrene nanoparticles and their modulatory role on complement consumption. J. Nanosci. Nanotechnol., 6, 3126–3133.CrossRefPubMedGoogle Scholar
  2. Andresen, T. L., Jensen, S. S., & Jørgensen, K. (2004). Advanced strategies in liposomal cancer therapy: problems and prospects of active tumor specific drug release. Prog. Lipid Res., 44, 68–97.CrossRefGoogle Scholar
  3. Allen, T. M. (2002). Ligand-targeted therapeutics in anticancer therapy. Nat. Rev. Cancer, 2, 750–763.CrossRefPubMedGoogle Scholar
  4. Bendas, G., Rothe, U., Scherphof, G. L., & Kamps, J. A. A. M. (2003). The influence of repeated injections on pharmacokinetics and biodistribution of different types of sterically stabilized immunoliposomes. Biochim. Biophys. Acta, 1609, 63–70.CrossRefPubMedGoogle Scholar
  5. Bhatia, S. K., King, M. R., & Hammer, D. A. (2003). The state diagram for cell adhesion mediated by two receptors. Biophys. J., 84, 2671–2690.CrossRefPubMedGoogle Scholar
  6. Charrois, G. J. R., & Allen, T. M. (2003). Multiple injections of PEGylated liposomal doxorubicin: pharmacokinetics and therapeutic activity. J. Pharmacol. Exp. Ther., 306, 1058–1067.CrossRefPubMedGoogle Scholar
  7. Cherukuri, P., Gannon, C. J., Leeuw, T. K., Schmidt, H. K., Smalley, R. E., Curley, S. A., & Weisman, R. B. (2006). Mammalian pharmacokinetics of carbon nanotubes using intrinsic near-infrared fluorescence. Proc. Natl. Acad. Sci. USA, 103, 18882–18886.CrossRefPubMedGoogle Scholar
  8. Chonn, A., Semple, S. C., & Cullis, P. R. (1992). Association of blood proteins with large unilamellar liposomes in vivo. Relation to circulation lifetimes. J. Biol. Chem., 267, 18759–18765.PubMedGoogle Scholar
  9. Chonn, A., Semple, S. C., & Cullis, P. R. (1995). β2-Glycoprotein I is a major protein associated with very rapidly cleared liposomes in vivo, suggesting a significant role in the immune clearance of ‘non-self’ particles. J. Biol. Chem., 270, 25845–25849.CrossRefPubMedGoogle Scholar
  10. Cornacoff, J. B., Hebert, L. A., Smead, W. L., & Van Aman, M. E. (1983). Primate erythrocyte-immune complex-clearing mechanism. J. Clin. Invest., 71, 236–247.CrossRefPubMedGoogle Scholar
  11. Dams, E. T. M., Laverman, P., Oyen, W. J. G., Storm, G., Scherphof, G. L., Van der Meer, J. W. M., Corstens, F. H., & Boerman, O. C. (2000). Accelerated blood clearance and altered biodistribution of repeated injections of sterically stabilized liposomes. J. Pharmacol. Exp. Ther., 292, 1071–1079.PubMedGoogle Scholar
  12. Decuzzi, P., & Ferrari, M. (2006). The adhesive strength of non-spherical particles mediated by specific interactions. Biomaterials, 27, 5307–5314.CrossRefPubMedGoogle Scholar
  13. Devine, D. V., Wong, K., Serrano, K., Chonn, A., & Cullis, P. R. (1994). Liposome-complement interactions in rat serum: implications for liposome survival studies. Biochim. Biophys. Acta, 1191, 43–51.CrossRefPubMedGoogle Scholar
  14. Gbadamosi, J. K., Hunter, A. C., & Moghimi, S. M. (2002). PEGylation of microspheres generates a heterogeneous population of particles with differential surface characteristics and biological performance. FEBS Lett., 532, 338–344.CrossRefPubMedGoogle Scholar
  15. Harisinghani, M. G., Barentsz, J., Hahn, P. F., Deserno, W. M., Tabatabaei, S., Hulsbergen van de Kaa, C., de la Rosette, J., & Weissleder, R. (2003). Noninvasive detection of clinically occult lymph-node metastases in prostate cancer. New Engl. J. Med., 348, 2491–2499.Google Scholar
  16. Harush-Frenkel, O., Debotton, N., Benita, S., & Altschuler, Y. (2007). Targeting of nanoparticles to the clathrin-mediated endocytic pathway. Biochem. Biophys. Res. Commun., 353, 26–32.CrossRefPubMedGoogle Scholar
  17. Hobbs, S. K., Monsky, W. L., Yuan, F., Roberts, W. G., Griffith, L., Torchilin, V. P., & Jain, R. K. (1998). Regulation of transport pathways in tumor vessels: Role of tumor type and microenvironment. Proc. Natl. Acad. Sci. USA, 95, 4607–4612.CrossRefPubMedGoogle Scholar
  18. Ishida, T., Atobe, K., Wang, X., & Kiwada, H. (2006a). Accelerated blood clearance of PEGylated liposomes upon repeated injections: effect of doxorubicin-encapsulation and high-dose first injection. J. Control. Rel., 115, 251–258.CrossRefGoogle Scholar
  19. Ishida, T., Ichihara, M., Wang, X., & Kiwada, H. (2006b). Spleen plays an important role in the induction of accelerated blood clearance of PEGylated liposomes. J. Control. Rel., 115, 243–250.CrossRefGoogle Scholar
  20. Ishida, T., Maeda, R., Ichihara, M., Irimura, K., & Kiwada, H. (2003). Accelerated clearance of PEGylated liposomes in rats after repeated injections. J. Control. Rel., 88, 35–42.CrossRefGoogle Scholar
  21. Klumpp, C., Kostarelos, K., Prato, M., & Bianco, A. (2006). Functionalized carbon nanotubes as emerging nanovectors for the delivery of therapeutics. Biochim. Biophys. Acta, 1758, 404–412.CrossRefPubMedGoogle Scholar
  22. Kreuter, J., Ramge, P., Petrov, V., Hamm, S., Gelperina, S. E., Engelhardt, B., Alyautdin, R., von Briesen, H., & Begley, D. J. (2003). Direct evidence that polysorbate-80-coated poly(butylcyanoacrylate) nanoparticles deliver drugs to the CNS via specific mechanisms requiring prior binding of drugs to the nanoparticles. Pharm. Res., 20, 409–416.CrossRefPubMedGoogle Scholar
  23. Liu, Z., Cai, W., He, L., Nakayama, N., Chen, K., Sun, X., Chen, X., & Dai, H. (2006). In vivo distribution and highly efficient tumour targeting of carbon nanotubes in mice. Nat. Nanotechnol., 2, 47–52.CrossRefPubMedGoogle Scholar
  24. Loughrey, H. C., Bally, M. B., Reinish, L. W., & Cullis, P. R. (1990). The binding of phosphatidylglycerol liposomes to rat platelets is mediated by complement. Thromb. Haemost., 64, 172–176.PubMedGoogle Scholar
  25. Lovrić, J., Cho, S. J., Winnik, F. M., & Maysinger, D. (2005). Unmodified cadmium telluride quantum dots induce reactive oxygen species formation leading to multiple organelle damage and cell death. Chem. Biol., 12, 1227–1234.CrossRefPubMedGoogle Scholar
  26. Lyass, O., Uziely, B., Ben-Yosef, R., Tzemach, D., Heshing, N. I., Lotem, M., Brufman, G., & Gabizon, A. (2000). Correlation of toxicity with pharmacokinetics of PEGylated liposomal doxorubicin (Doxil) in metastatic breast carcinoma. Cancer, 89, 1037–1047.CrossRefPubMedGoogle Scholar
  27. Marjan, J., Xie, Z., & Devine, D. V. (1994). Liposome-induced activation of the classical complement pathway does not require immunoglobulin. Biochim. Biophys. Acta, 1192, 35–44.CrossRefPubMedGoogle Scholar
  28. Moghimi, S. M. (1995). Exploiting bone marrow microvascular structure for drug delivery and future therapies. Adv. Drug Deliv. Rev., 17, 61–73.CrossRefGoogle Scholar
  29. Moghimi, S. M. (2003). Exploitation of macrophage clearance functions. In S. Gordon (Ed.), Hand-Book of Experimental Pharmacology: The macrophage as therapeutic target, Volume 158 (pp. 41–54). Berlin: Springer-Verlag.Google Scholar
  30. Moghimi, S. M. (2006). Recent development in polymeric nanoparticle engineering and their applications in experimental and clinical oncology. Anti-cancer Agent. Med. Chem., 6, 553–561.CrossRefGoogle Scholar
  31. Moghimi, S. M. (2007a). Passive targeting of solid tumors: pathophysiological principles and physicochemical aspects of delivery systems. In M. M. Amiji (Ed.), Nanotechnology for cancer therapy (p. 11–18). Boca Raton: CRC Press.Google Scholar
  32. Moghimi, S. M. (2007b). Nanotoxicology of synthetic gene-transfer vectors: poly(ethylenimine)- and polyfectin-mediated membrane damage and apoptosis in human cell lines. In C. S. S. R. Kumar (Ed.), Nanotechnologies for Life Sciences: Nanomaterials for medical diagnosis and therapy, Volume 10 (pp. 629–643). Berlin: Wiley-VCH Verlag.Google Scholar
  33. Moghimi, S. M., & Bonnemain, B. (1999). Subcutaneous and intravenous delivery of diagnostic agents to the lymphatic system: applications in lymphoscintigraphy and indirect lymphography. Adv. Drug Deliv. Rev., 37, 295–312.CrossRefPubMedGoogle Scholar
  34. Moghimi, S. M., & Gray, T. (1997). A single dose of intravenously injected poloxamine-coated long-circulating particles triggers macrophage clearance of subsequent doses in rats. Clin. Sci. (Lond.) 93, 371–379.Google Scholar
  35. Moghimi, S. M., Hamad, I., Andresen, T. L., Jørgensen, K., & Szebeni, J. (2006a). Methylation of the phosphate oxygen moiety of phospholipids-methoxy(polyethylene glycol) conjugate prevents PEGylated liposome-mediated complement activation and anaphylatoxin production. FASEB J., 20, 2591–2593 (doi: 10.1096/fj.06-6186fje, electronic pages: E2057–E2067).CrossRefGoogle Scholar
  36. Moghimi, S. M., Hamad, I., Bünger, R., Andresen, T. L., Jørgensen, K., Hunter, A. C., Baranji, L., Rosivall, L., & Szebeni, J. (2006b). Activation of the human complement system by cholesterol-rich and PEGylated liposomes–Modulation of cholesterol-rich liposome-mediated complement activation by elevated serum LDL and HDL levels. J. Liposome Res., 16, 167–174.CrossRefGoogle Scholar
  37. Moghimi, S. M., Hedeman, H., Muir, I. S., Illum, L., & Davis, S. S. (1993a). An investigation of the filtration capacity and the fate of large filtered sterically-stabilized microspheres in rats. Biochim. Biophys. Acta, 1157, 233–240.Google Scholar
  38. Moghimi, S. M., & Hunter, A. C. (2001). Recognition by macrophages and liver cells of opsonized phospholipids vesicles and phospholipids headgroups. Pharm. Res., 18, 1–8.CrossRefGoogle Scholar
  39. Moghimi, S. M., Hunter, A. C., & Murray, J. C. (2001). Long-circulating and target-specific nanoparticles: theory to practice. Pharmacol. Rev., 53, 283–318.PubMedGoogle Scholar
  40. Moghimi, S. M., Hunter, A. C., & Murray, J. C. (2005a). Nanomedicine: current status and future prospects. FASEB J., 19, 311–330.CrossRefGoogle Scholar
  41. Moghimi, S. M., Hunter, A. C., Murray, J. C., & Szewczyk, A. (2004). Cellular distribution of non-ionic micelles. Science, 303, 626–627.CrossRefPubMedGoogle Scholar
  42. Moghimi, S. M., & Kissel, T. (2006). Particulate nanomedicines. Adv. Drug Deliv. Rev., 58, 1451–1455.CrossRefPubMedGoogle Scholar
  43. Moghimi, S. M., Muir, I. S., Illum, L., Davis, S. S., & Kolb-Bachofen, V. (1993b). Coating particles with a block copolymer (poloxamine-908) suppresses opsonization but permits the activity of dysopsonins in the serum. Biochim. Biophys. Acta, 1179, 157–165.CrossRefGoogle Scholar
  44. Moghimi, S. M., Porter, C. J. H., Muir, I. S., Illum, L., & Davis, S. S. (1991). Non-phagocytic uptake of intravenously injected microspheres in rat spleen: influence of particle size and hydrophilic coating. Biochem. Biophys. Res. Commun., 177, 861–866.CrossRefPubMedGoogle Scholar
  45. Moghimi, S. M., Symonds, P., Murray, J. C., Hunter, A. C., Debska, G., & Szewczyk, A. (2005b). A two-stage poly(ethylenimine)-mediated cytotoxicity: implications for gene-transfer/therapy. Mol. Ther., 11, 990–995.CrossRefGoogle Scholar
  46. Moghimi, S. M., & Szebeni, J. (2003). Stealth liposomes and long circulating nanoparticles: critical issues in pharmacokinetics, opsonization and protein-binding properties. Prog. Lipid Res., 42, 463–478.CrossRefPubMedGoogle Scholar
  47. Moghimi, S. M., Vegas, E., Garcia, M. L., Al-Hanbali, O. A. R., & Rutt, K. J. (2006c). Polymeric nanoparticles as drug carriers and controlled release implant devices. In V. P. Torchilin (Ed.), Nanoparticles as drug carriers (p. 29–42). London: Imperial College Press.CrossRefGoogle Scholar
  48. Moore, Jr. F. D., Austen, K. F., & Fearon, D. T. (1982). Antibody restores human alternative complement pathway activation by mouse erythrocytes rendered functionally deficient by pre-treatment with pronase. J. Immunol., 128, 1302–1306.PubMedGoogle Scholar
  49. Munn, L. L. (2003). Aberrant vascular architecture in tumors and its importance in drug-based therapies. Drug Discov. Today, 8, 396–403.CrossRefPubMedGoogle Scholar
  50. Murray, J. C., & Moghimi, S. M. (2003). Endothelial cells as therapeutic targets in cancer: new biology and novel delivery systems. Crit. Rev. Ther. Drug Carr. Syst., 20, 139–152.CrossRefGoogle Scholar
  51. Patil, V. R. S., Campbell, C. J., Yun, Y. H., Slack, S. M., & Goettz, D. J. (2001). Particle diameter influences adhesion under flow. Biophys. J., 80, 1733–1743.CrossRefGoogle Scholar
  52. Porter, C. J. H., Moghimi, S. M., Illum, L., & Davis, S. S. (1992). The polyoxyethylene/polyoxypropylene block co-polymer poloxamer-407 selectively redirects intravenously injected microspheres to sinusoidal endothelial cells of rabbit bone marrow. FEBS Lett., 305, 62–66.CrossRefPubMedGoogle Scholar
  53. Poznansky, M., & Juliano, R. L. (1984). Biological approaches to controlled delivery of drugs: a critical review. Pharmacol. Rev., 36, 277–336.PubMedGoogle Scholar
  54. Qiang, Y., Antony, J., Sharma, A., Nutting, J., Sikes, D., & Meyer, D. (2006). Iron/iron oxide core-shell nanoclusters for biomedical applications. J. Nanoparticle Res., 8, 489–496.CrossRefGoogle Scholar
  55. Roberts, J. C., Bhalgat, M. K., & Zera, R. T. (1996). Preliminary biological evaluation of polyamidoamine (PAMAM) Starburst dendrimers. J. Biomed. Mat. Res., 30, 53–65.CrossRefGoogle Scholar
  56. Romberg, B., Oussoren, C., Snel, C. J., Carstens, M. G., Hennink, W. E., & Storm, G. (2007). Pharmacokinetics of poly(hydroxyethyl-L-asparagine)-coated liposomes is superior over that of PEG-coated liposomes at low lipid dose and upon repeated administration. Biochim. Biophys. Acta , doi: 10.1016/j.bbamem.2006.12.005, 1768, 2655–2666.Google Scholar
  57. Romero, E. L., Morilla, M. J., Regts, J., Koning, G. A., & Scherphof, G. L. (1999). On the mechanism of hepatic transendothelial passage of large liposomes. FEBS Lett., 448, 193–196.CrossRefPubMedGoogle Scholar
  58. Salvador-Morales, C., Flahaut, E., Sim, E., Sloan, J., Green, M. L. H., & Sim, R. B. (2006). Complement activation and protein adsorption by carbon nanotubes. Mol. Immunol., 43, 193–201.CrossRefPubMedGoogle Scholar
  59. Scherphof, G. L., & Kamps, J. A. A. M. (2001). The role of hepatocytes in the clearance of liposomes from the blood circulation. Prog. Lipid Res., 40, 149–166.CrossRefPubMedGoogle Scholar
  60. Singh, R., Pantarotto, D., lacerda, L., Pastorin, G., Klumpp, C., Prato, M., Bianco, A., & Kostarelos, K. (2006). Tissue distribution and blood clearance rates of intravenously administered carbon nanotube radiotracers. Proc. Natl. Acad. Sci. USA, 103, 3357–3362.CrossRefPubMedGoogle Scholar
  61. Sou, K., Goins, B., Takeoka, S., Tsuchida, E., & Phillips, W. T. (2006). Selective uptake of surface-modified vesicles by bone marrow macrophages in vivo. Biomaterials, 28, 2655–2666.Google Scholar
  62. Sudimack, J., & Lee, R. J. (2000). Targeted drug delivery via the folate receptor. Adv. Drug Deliv. Rev., 41, 147–162.CrossRefPubMedGoogle Scholar
  63. Volanakis, J. E., & Wirtz, K. W. A. (1979). Interaction of C-reactive protein with artificial phosphatidylcholine bilayers. Nature, 281, 155–157.CrossRefPubMedGoogle Scholar
  64. Yan, X., Kuipers, F., Havekes, L. M., Havinga, R., Dontje, B., Poelstra, K., Scherphof, G. L., & Kamps, J. A. A. M. (2005). The role of lipoprotein E in the elimination of liposomes from blood by hepatocytes in the mouse. Biochem. Biophys. Res. Commun., 328, 57–62.CrossRefPubMedGoogle Scholar
  65. Yan, X., Morselt, H. W. M., Scherphof, G. L., Poelstra, K., & Kamps, J. A. A. M. (2004). The role of beta(2)-glycoprotein I in liposome-hepatocyte interaction. Biochim. Biophys. Acta, 1667, 208–214.CrossRefPubMedGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2009

Authors and Affiliations

  • S. Moein Moghimi
    • 1
  • Islam Hamad
    • 2
  1. 1.Department of Pharmaceutics and Analytical Chemistry, Faculty of Pharmaceutical SciencesUniversity of CopenhagenCopenhagenφDenmark
  2. 2.The Molecular Targeting and Polymer Toxicology GroupSchool of Pharmacy, University of BrightonBrightonUK

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