Skip to main content
SpringerLink
Log in

Hepatic Targeting: Physiological Basis and Design Strategy

  • Chapter
  • First Online:
Targeted Drug Delivery : Concepts and Design

Part of the book series: Advances in Delivery Science and Technology ((ADST))

Abstract

Most of the administered drugs achieve high hepatic concentration. However, different hepatic conditions obligate high accumulation of therapeutics and diagnostics within specific intrahepatic cells. This has fueled an exigent need for effective, safe, and affordable liver targeted drug delivery systems with high degree of specificity. Liver architecture divulges the presence of different hepatic cells—Kupffer cells (KC), hepatic stellate cells (HSC), sinusoidal endothelial cells (SEC), hepatocytes, biliary cells, and stem cells. Possibility of passive targeting and active targeting to specific cells in the liver with a focus on receptor mediated targeting is discussed. Various receptors on hepatic cells and targeting ligands for the same are detailed. Applications of liver targeting for various hepatic afflictions using different nanocarriers like lipoplexes, liposomes, nanocarriers, etc. are discussed. The use of hepatic targeted systems in diagnosis, an important application is touched upon. Improved therapeutic and diagnostic efforts have changed the status of hepatic cancer from dreadful to at least a treatable disease.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Li L, Wang H, Ong ZY, Xu K, Ee PLR, Zheng S, Hedrick JL, Yang YY (2010) Polymer- and lipid-based nanoparticle therapeutics for the treatment of liver diseases. Nano Today 5:296–312

    CAS  Google Scholar 

  2. Sawey ET, Chanrion M, Cai C, Wu G, Zhang J, Zender L, Zhao A, Busuttil RW, Yee H, Stein L, French DM, Finn RS, Lowe SW, Powers S (2011) Identification of a therapeutic strategy targeting amplified FGF19 in liver cancer by oncogenomic screening. Cancer Cell 19:347–358

    CAS  PubMed Central  PubMed  Google Scholar 

  3. Santi V, Buccione D, Di Micoli A, Fatti G, Frigerio M, Farinati F, Poggio PD, Rapaccini G, Di Nolfo MA, Benvegnù L, Zoli M, Borzio F, Giannini EG, Caturelli E, Chiaramonte M, Bernardi M, Trevisani F (2012) The changing scenario of hepatocellular carcinoma over the last two decades in Italy. J Hepatol 56:397–405

    PubMed  Google Scholar 

  4. Rustgi VK (1987) Epidemiology of hepatocellular carcinoma. Gastroenterol Clin North Am 16:545–551

    CAS  PubMed  Google Scholar 

  5. Avila MA, Berasain C, Sangro B, Prieto J (2006) New therapies for hepatocellular carcinoma. Oncogene 25(27):3866–3884

    CAS  PubMed  Google Scholar 

  6. Popovic Z, Liu W, Chauhan VP, Lee J, Wong C, Greytak AB, Insin N, Nocera DG, Fukumura D, Bawendi MG (2010) A nanoparticle size series for in vivo fluorescence imaging. Angew Chem Int Ed Engl 49:8649–8652

    CAS  PubMed Central  PubMed  Google Scholar 

  7. De Jong WH, Hagens WI, Krystek P, Burger MC, Sips AJ, Geertsma RE (2008) Particle size-dependent organ distribution of gold nanoparticles after intravenous administration. Biomaterials 29(12):1912–1919

    PubMed  Google Scholar 

  8. Suzuki A (2013) Artificial induction and disease-related conversion of the hepatic fate. Curr Opin Genet Dev 23:579–584

    CAS  PubMed  Google Scholar 

  9. Orrego H, Medline A, Blendis LM, Rankin JG, Kreaden DA (1979) Collagenisation of the disse space in alcoholic liver disease. Gut 20:673–679

    CAS  PubMed Central  PubMed  Google Scholar 

  10. Thomas P (2012) Kupffer cells. Encyclopedia of Cancer 1963–1965

    Google Scholar 

  11. Elvevold K, Simon-Santamaria J, Hasvold H, McCourt P, Smedsrod B, Sorensen KK (2008) Liver sinusoidal endothelial cells depend on mannose receptor-mediated recruitment of lysosomal enzymes for normal degradation capacity. Hepatology 48(6):2007–2015

    CAS  PubMed  Google Scholar 

  12. Elvevold K, Smedsrod B, Martinez I (2008) The liver sinusoidal endothelial cell: a cell type of controversial and confusing identity. Am J Physiol-Gastrointest Liver Physiol 294:G391–G400

    CAS  PubMed  Google Scholar 

  13. Saxena R, Theise ND, Crawford JM (1999) Microanatomy of the human liver-exploring the hidden interfaces. Hepatology 30:1339–1346

    CAS  PubMed  Google Scholar 

  14. Fausto N, Campbell JS (2003) The role of hepatocytes and oval cells in liver regeneration and repopulation. Mech Dev 120:117–130

    CAS  PubMed  Google Scholar 

  15. Bilzer M, Roggel F, Gerbes AL (2006) Role of Kupffer cells in host defense and liver disease. Liver Int 26:1175–1186

    CAS  PubMed  Google Scholar 

  16. Hilmer SN, Cogger VC, Le Couteur DG (2007) Basal activity of Kupffer cells increases with old age. J Gerontol A Biol Sci Med Sci 62(9):973–978

    PubMed  Google Scholar 

  17. Bouwens L, Baekeland M, Wisse E (1984) Importance of local proliferation in the expanding Kupffer cell population of rat liver after Zymosan stimulation and partial hepatectomy. Hepatology 4:213–219

    CAS  PubMed  Google Scholar 

  18. Kolios G, Valatas V, Kouroumalis E (2006) Role of Kupffer cells in the pathogenesis of liver disease. World J Gastroenterol 12(46):7413–7420

    CAS  PubMed Central  PubMed  Google Scholar 

  19. Huang W, Metlakunta A, Dedousis N, Zhang P, Sipula I, Dube JJ, Scott DK, O’Doherty RM (2010) Depletion of liver Kupffer cells prevents the development of diet-induced hepatic steatosis and insulin resistance. Diabetes 59:347–357

    CAS  PubMed Central  PubMed  Google Scholar 

  20. Traeger T, Mikulcak M, Eipel C, Abshagen K, Diedrich S, Heidecke CD, Maier S, Vollmar B (2010) Kupffer cell depletion reduces hepatic inflammation and apoptosis but decreases survival in abdominal sepsis. Eur J Gastroenterol Hepatol 22:1039–1049

    CAS  PubMed  Google Scholar 

  21. Sakai T, Liu L, Teng X, Ishimaru N, Mukai-Sakai R, Tran NH, Kim SM, Sano N, Hayashi Y, Kaji R, Fukui K (2010) Inflammatory disease and cancer with a decrease in Kupffer cell numbers in Nucling-knockout mice. Int J Cancer 126(5):1079–1094

    CAS  PubMed  Google Scholar 

  22. Loegering DJ (1986) Kupffer cell complement receptor clearance function and host defense. Circ Shock 20(4):321–333

    CAS  PubMed  Google Scholar 

  23. Kitani H, Takenouchi T, Sato M, Yoshioka M, Yamanaka N (2010) A novel isolation method for macrophage-likecells from mixed primary cultures of adult rat liver cells. J Immunol Methods 360:47–55

    CAS  PubMed  Google Scholar 

  24. Kmiec Z (2001) Cooperation of liver cells in health and disease. Adv Anat Embryol Cell Biol 161:III–XIII, 1–151

    CAS  PubMed  Google Scholar 

  25. Bayo NLG, Izquierdo MA, Sirovich I, Rooijen NV, Beelen RHJ, Meijer S (2003) Role of kupffer cells in arresting circulating tumor cells and controlling metastatic growth in the liver. Hepatology 23:1224–1231

    Google Scholar 

  26. Willekens FLA, Werre JM, Kruijt JK, Roerdinkholder-Stoelwinder B, Groenen-Döpp YA, van den Bos AG, Bosman GJ, van Berkel TJ (2005) Liver Kupffer cells rapidly remove red blood cell-derived vesicles from the circulation by scavenger receptors. Blood 105(5):2141–2145

    CAS  PubMed  Google Scholar 

  27. Ruf H, Gould BJ (1999) Size distributions of chylomicrons from human lymph from dynamic light scattering measurements. Eur Biophys J 28(1):1–11

    CAS  PubMed  Google Scholar 

  28. Jacobs F, Wisse E, De Geest B (2010) The role of liver sinusoidal cells in hepatocyte—directed gene transfer. Am J Pathol 176:14–21

    CAS  PubMed Central  PubMed  Google Scholar 

  29. Donald KJ, Tennent RJ (1975) The relative roles of platelets and macrophages in clearing particles from the blood; the value of carbon clearance as a measure of reticuloendothelial phagocytosis. J Pathol 117:235–245

    CAS  PubMed  Google Scholar 

  30. Foley EM, Esko JD (2010) Hepatic heparan sulfate proteoglycans and endocytic clearance of triglyceride-rich lipoproteins. Prog Mol Biol Transl Sci 93:213–233

    CAS  PubMed  Google Scholar 

  31. Malovic I, Sorensen KK, Elvevold KH, Nedredal GI, Paulsen S, Erofeev AV, Smedsrod BH, McCourt PA (2007) The mannose receptor on murine liver sinusoidal endothelial cells is the main denatured collagen clearance receptor. Hepatology 45(6):1454–1461

    CAS  PubMed  Google Scholar 

  32. Benten D, Follenzi A, Bhargava KK, Kumaran V, Palestro CJ, Gupta S (2005) Hepatic targeting of transplanted liver sinusoidal endothelial cells in intact mice. Hepatology 42(1):140–148

    CAS  PubMed  Google Scholar 

  33. DeLeve LD (2011) Vascular liver disease and the liver sinusoidal endothelial cell. In: DeLeve LD, Garcia-Tsao G (eds) Vascular liver disease: mechanisms and management. LLC, Springer Science Business Media, New York, pp 25–40

    Google Scholar 

  34. Vogel S, Piantedosi R, Frank J, Lalazar A, Rockey DC, Friedman SL, Blaner WS (2000) An immortalized rat liver stellate cell line (HSC-T6): a new cell model for the study of retinoid metabolism in vitro. J Lipid Res 41:882–893

    CAS  PubMed  Google Scholar 

  35. Pinzani M, Marra F (2001) Cytokine receptors and signaling in hepatic stellate cells. Semin Liver Dis 21(3):397–416

    CAS  PubMed  Google Scholar 

  36. Geerts A (2001) History, heterogeneity, developmental biology, and functions of quiescent hepatic stellate cells. Semin Liver Dis 21(3):311–335

    CAS  PubMed  Google Scholar 

  37. Winau F, Hegasy G, Weiskirchen R, Weber S, Cassan C, Sieling PA, Modlin RL, Liblau RS, Gressner AM, Kaufmann SH (2007) Ito cells are liver-resident antigen-presenting cells for activating T cell responses. Immunity 26(1):117–129

    CAS  PubMed  Google Scholar 

  38. Moreira RK (2007) Hepatic stellate cells and liver fibrosis. Arch Pathol Lab Med 131(11):1728–1734

    CAS  PubMed  Google Scholar 

  39. Friedman SL (2008) Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol Rev 88(1):125–172

    CAS  PubMed Central  PubMed  Google Scholar 

  40. Dancygier H (2010) Microscopic anatomy. In: Dancygier H (ed) Clinical hepatology: principles and practice of hepatobiliary diseases, vol 1. Springer, Berlin, pp 15–52

    Google Scholar 

  41. Luo DZ, Vermijlen D, Ahishali B, Triantis V, Plakoutsi G, Braet F, Vanderkerken K, M 5076 metastasis-bearing mice. Canc Chemother Pharmacol 26:122–126

    Google Scholar 

  42. Vermijlen D, Luo D, Froelich CJ, Medema JP, Kummer JA, Willems E, Braet F, Wisse E (2004) Pit cells exclusively kill P815 tumor cells by the perforin/granzyme pathway. Comp Hepatol 3(Suppl 1):S58

    PubMed Central  PubMed  Google Scholar 

  43. Wang SR, Renaud G, Infante J, Catala D, Infante R (1985) Isolation of rat hepatocytes with EDTA and their metabolic functions in primary culture. In Vitro Cell Dev Biol 21(9):526–530

    CAS  PubMed  Google Scholar 

  44. Sabine C, Perret C (2011) Liver Zonation. In: Monga SPS (ed) Molecular pathology of liver diseases, molecular pathology library 5. Springer Science + Business Media, LLC, New York, pp 7–16

    Google Scholar 

  45. Kan NG, Junghans D, Belmonte JCI (2009) Compensatory growth mechanisms regulated by BMP and FGF signaling mediate liver regeneration in zebrafish after partial hepatectomy. FASEB J 23(10):3518–3525

    Google Scholar 

  46. Donthamsetty S, Bhave VS, Kliment CS, Bowen WC, Mars WM, Bell AW, Stewart RE, Orr A, Wu C, Michalopoulos GK (2011) Excessive hepatomegaly of mice with hepatocyte-targeted elimination of integrin linked kinase following treatment with 1,4-bis (2-(3,5-dichaloropyridyloxy)) benzene. Hepatology 53(2):587–595

    CAS  PubMed Central  PubMed  Google Scholar 

  47. Chavez PR, Lian F, Chung J, Liu C, Paiva SA, Seitz HK, Wang XD (2011) Long-term ethanol consumption promotes hepatic tumorigenesis but impairs normal hepatocyte proliferation in rats. J Nutr 141(6):1049–1055

    CAS  PubMed Central  PubMed  Google Scholar 

  48. Liu WH, Zhao YS, Gao SY, Li SD, Cao J, Zhang KQ, Zou CG (2010) Hepatocyte proliferation during liver regeneration is impaired in mice with methionine diet-induced hyperhomocysteinemia. Am J Pathol 177(5):2357–2365

    CAS  PubMed Central  PubMed  Google Scholar 

  49. Lemaigre F, Zaret KS (2004) Liver development update: new embryo models, cell lineage control, and morphogenesis. Curr Opin Genet Dev 14(5):582–590

    CAS  PubMed  Google Scholar 

  50. Ramaa CS, Tilekar KN, Patil VM (2010) Liver cancer: different approaches for targeting. Int J PharmTech Res 2:834–842

    CAS  Google Scholar 

  51. Sell S (2003) The hepatocyte: heterogeneity and plasticity of liver cells. Int J Biochem Cell Biol 35:267–271

    CAS  PubMed  Google Scholar 

  52. Chiba T, Kita K, Zheng YW, Yokosuka O, Saisho H, Iwama A, Nakauchi H, Taniguchi H (2006) Side population purified from hepatocellular carcinoma cells harbors cancer stem cell-like properties. Hepatology 44:240–251

    CAS  PubMed  Google Scholar 

  53. Suetsugu A, Nagaki M, Aoki H, Motohashi T, Kunisada T (2006) Moriwaki H (2006) Characterization of CD133+ hepatocellular carcinoma cells ascancer stem/progenitor cells. Biochem Biophys Res Commun 351(4):820–824

    CAS  PubMed  Google Scholar 

  54. Yang ZF, Ngai P, Ho DW, Yu WC, Ng MN, Lau CK, Li ML, Tam KH, Lam CT, Poon RT, Fan ST (2008) Identification of local and circulating cancer stem cells in human liver cancer. Hepatology 47:919–928

    CAS  PubMed  Google Scholar 

  55. Dai H, Jiang X, Tan GC, Chen Y, Torbenson M, Leong KW, Mao HQ (2006) Chitosan-DNA nanoparticles delivered by intrabiliary infusion enhance liver-targeted gene delivery. Int J Nanomedicine 1(4):507–522

    CAS  PubMed Central  PubMed  Google Scholar 

  56. Gao L, Lisi Xie L, Long X, Wang Z, He CY, Chen ZY, Zhang L, Nan X, Lei H, Liu X, Liu G, Lu J, Qiu B (2013) Efficacy of MRI visible iron oxide nanoparticles in delivering minicircle DNA into liver via intrabiliary infusion. Biomaterials 34(14):3688–3696

    CAS  PubMed  Google Scholar 

  57. Jiang X, Ren Y, Williford JM, Li Z, Mao HQ (2013) Liver-targeted gene delivery through retrograde intrabiliary infusion. Methods Mol Biol 948:275–284

    CAS  PubMed  Google Scholar 

  58. Fumoto S, Kawakami S, Hashida M, Nishida K (2013) Targeted gene delivery: importance of administration routes. In Wei M, Good D (eds) Novel gene therapy approaches ISBN: 978-953-51-0966-2, InTech, DOI: 10.5772/54741

  59. Allen TM, Murray L, MacKeigan S, Shah M (1984) Chronic liposome administration in mice: effects on reticuloendothelial function and tissue distribution. J Pharmacol Exp Ther 229:267–275

    CAS  PubMed  Google Scholar 

  60. Hsu MJ, Juliano RL (1982) Interactions of liposomes with the reticuloendothelial system. Non-specific and receptor-mediated uptake of liposomes by mouse peritoneal macrophages. Biochim Biophys Acta 720:411–419

    CAS  PubMed  Google Scholar 

  61. Nie S (2010) Understanding and overcoming major barriers in cancer nanomedicine. Nanomedicine (Lond) 5(4):523–528

    Google Scholar 

  62. Bachmann MF, Jennings GT (2010) Vaccine delivery: a matter of size, geometry, kinetics and molecular patterns. Nat Rev Immunol 10:787–796

    CAS  PubMed  Google Scholar 

  63. Brannon-Peppas L, Blanchette JO (2004) Review Nanoparticle and targeted systems for cancer therapy. Adv Drug Deliv Rev 56(11):1649–1659

    CAS  PubMed  Google Scholar 

  64. Rensen PCN, Sliedregt LAJM, Ferns M, Kieviet E, van Rossenberg SMW, van Leeuwen SH, van Berkel TJC, Biessen EAL (2001) Determination of the upper size limit for uptake and processing of ligands by the asialoglycoprotein receptor on hepatocytes in vitro and in vivo. J Biol Chem 276(40):37577–37584

    CAS  PubMed  Google Scholar 

  65. Petros RA, DeSimone JM (2010) Strategies in the design of nanoparticles for therapeutic applications. Nat Rev Drug Discov 9:615–627

    CAS  PubMed  Google Scholar 

  66. Venturoli D, Rippe B (2005) Ficoll and dextran vs. globular proteins as probes for testing glomerular permselectivity: effects of molecular size, shape, charge, and deformability. Am J Physiol Renal Physiol 288:F605–F613

    CAS  PubMed  Google Scholar 

  67. Bertrand N, Leroux JC (2012) The journey of a drug-carrier in the body: an anatomo-physiological perspective. J Control Release 161:152–163

    CAS  PubMed  Google Scholar 

  68. Cannon GJ, Swanson JA (1992) The macrophage capacity for phagocytosis. J Cell Sci 101:907–913

    PubMed  Google Scholar 

  69. Liu D, Mori A, Huang L (1991) Large liposomes containing ganglioside GM1 accumulate effectively in spleen. Biochim Biophys Acta 1066:159–165

    CAS  PubMed  Google Scholar 

  70. Porter CJH, Moghimi SM, Illum L, Davis SS (1992) The polyoxyethylene polyoxypropylene block copolymer Poloxamer-407 selectively redirects intravenously injected microspheres to sinusoidal endothelial-cells of rabbit bone-marrow. FEBS Lett 305:62–66

    CAS  PubMed  Google Scholar 

  71. Vasir JK, Reddy MK, Labhasetwar VD (2005) Nanosystems in drug targeting: opportunities and challenges. Curr Nanosci 1:47–64

    CAS  Google Scholar 

  72. Angart P, Vocelle D, Chan C, Walton SP (2013) Design of siRNA therapeutics from the molecular scale. Pharmaceuticals (Basel) 6:440–468

    CAS  Google Scholar 

  73. He C, Hu Y, Yin L, Tang C, Yin C (2010) Effects of particle size and surface charge on cellular uptake and biodistribution of polymeric nanoparticles. Biomaterials 31:3657–3666

    CAS  PubMed  Google Scholar 

  74. Li SD, Huang L (2010) Stealth nanoparticles: high density but sheddable PEG is a key for tumor targeting. J Control Release 145(3):178–181

    CAS  PubMed Central  PubMed  Google Scholar 

  75. Alexis F, Pridgen E, Molnar LK, Farokhzad OC (2008) Factors affecting the clearance and biodistribution of polymeric nanoparticles. Mol Pharm 5(4):505–515

    CAS  PubMed Central  PubMed  Google Scholar 

  76. Socha M, Lamprecht AE, Ghazouani F, Emond E, Maincent P, Barré J, Hoffman M, Ubrich N (2008) Increase in the vascular residence time of propranolol-loaded nanoparticles coated with heparin. J Nanosci Nanotechnol 8(5):2369–2376

    CAS  PubMed  Google Scholar 

  77. Wu J, Liu L, Yen RD, Catana A, Nantz MH, Zern MA (2004) Liposome-mediatedextracellular superoxide dismutase gene delivery protects against acuteliver injury in mice. Hepatology 40:195–204

    CAS  PubMed  Google Scholar 

  78. Park JH, Cho HJ, Yoon HY, Yoon IS, Ko SH, Shim JS, Cho JH, Park JH, Kim K, Kwon IC, Kim DD (2014) Hyaluronic acid derivative-coated nanohybrid liposomes for cancer imaging and drug delivery. J Control Release 174:98–108

    CAS  PubMed  Google Scholar 

  79. Carmona S, Jorgensen MR, Kolli S, Crowther C, Salazar FH, MarionPL FM, Natori Y, Thanou M, Arbuthnot P, Miller AD et al (2009) Controlling HBV replication in vivo by intravenous administration of triggered PEGylated siRNA-nanoparticles. Mol Pharm 6:706–717

    CAS  PubMed  Google Scholar 

  80. Champion JA, Katare YK, Mitragotri S (2007) Particle shape: a new design parameter for micro- and nanoscale drug delivery carriers. J Control Release 121(1–2):3–9

    CAS  PubMed Central  PubMed  Google Scholar 

  81. Champion JA, Mitragotri S (2006) Role of target geometry in phagocytosis. Proc Natl Acad Sci U S A 103:4930–4934

    CAS  PubMed Central  PubMed  Google Scholar 

  82. Devarajan PV, Jindal AB, Patil RR, Mulla F, Gaikwad RV, Samad A (2010) Particle shape: a new design parameter for passive targeting in splenotropic drug delivery. J Pharm Sci 99(6):2576–2581

    CAS  PubMed  Google Scholar 

  83. Decuzzi P, Pasqualini R, Arap W, Ferrari M (2009) Intravascular delivery of particulate systems: does geometry really matter? Pharm Res 26(1):235–243

    CAS  PubMed  Google Scholar 

  84. Qiu Y, Liu Y, Wang L, Xu L, Bai R, Ji Y, Wu X, Zhao Y, Li Y, Chen C (2010) Surface chemistry and aspect ratio mediated cellular uptake of Au nanorods. Biomaterials 31(30):7606–7619

    CAS  PubMed  Google Scholar 

  85. Banquy X, Suarez F, Argaw A, Rabanel JM, Grutter P, Bouchard JF, Hildgen P, Giasson S (2009) Effect of mechanical properties of hydrogel nanoparticles on macrophage cell uptake. Soft Matter 5:3984–3991

    CAS  Google Scholar 

  86. Romero EL, Morilla MJ, Regts J, Koning GA, Scherphof GL (1999) On the mechanism of hepatic transendothelial passage of large liposomes. FEBS Lett 448:193

    CAS  PubMed  Google Scholar 

  87. Beningo KA, YL (2002) Fc-receptor-mediated phagocytosis is regulated by mechanical properties of the target. J Cell Sci 115:849–856

    Google Scholar 

  88. Protzer U, Maini MK, Knolle PA (2012) Living in the liver: hepatic infections. Nat Rev Immunol 12:201–213

    CAS  PubMed  Google Scholar 

  89. Kapse SV, Gaikwad RV, Samad A, Devarajan PV (2012) Self nanoprecipitating preconcentrate of tamoxifen citrate for enhanced bioavailability. Int J Pharm 429(1–2):104–112

    CAS  PubMed  Google Scholar 

  90. Galvin P, Thompson D, Ryan KB, McCarthy A, Moore AC, Burke CS, Dyson M, MacCraith BD, Gunko YK, Byrne MT, Volkov Y, Keely C, Keehan E, Howe M, Duffy C, MacLoughlin R (2012) Nanoparticle-based drug delivery: case studies for cancer and cardiovascular applications. Cell Mol Life Sci 69:389–404

    CAS  PubMed  Google Scholar 

  91. Hillaireau H, Couvreur P (2009) Nanocarriers’ entry into the cell: relevance to drug delivery. Cell Mol Life Sci 66:2873–2896

    CAS  PubMed  Google Scholar 

  92. Shah NB, Vercellotti GM, Bischof JC (2012) Blood—nanoparticle interactions and in vivo biodistribution: impact of surface PEG and ligand properties. Mol Pharm 9:2146–2155

    CAS  PubMed Central  PubMed  Google Scholar 

  93. Kong F, Ge L, Liu X, Huang N, Zhou F (2012) Mannan-modified PLGA nanoparticles for targeted gene delivery. Int J Photoenerg Article ID 926754, 7p. doi:10.1155/2012/926754

  94. Ganta S, Devalapally H, Shahiwala A, Amiji M (2008) A review of stimuli-responsive nanocarriers for drug and gene delivery. J Control Release 126(3):187–204

    CAS  PubMed  Google Scholar 

  95. Muro S (2012) Challenges in design and characterization of ligand-targeted drug delivery systems. J Control Release 164:125–137

    CAS  PubMed Central  PubMed  Google Scholar 

  96. Torchilin VP (2000) Drug targeting. Eur J Pharm Sci 11(Suppl. 2):S81–91

    Google Scholar 

  97. Lammers T, Kiessling F, Hennink WE, Storm G (2012) Drug targeting to tumors: principles, pitfalls and (pre-) clinical progress. J Control Release 161(2):175–187

    CAS  PubMed  Google Scholar 

  98. Heath TD, Fraley RT, Bentz J, Voss EWJ, Herron JN, Papahadjopoulos D (1984) Antibody-directed liposomes. Determination of affinity constants for soluble and liposome bound antifluorescein. Biochim Biophys Acta 770:148–158

    CAS  PubMed  Google Scholar 

  99. Conner SD, Schmid SL (2003) Regulated portals of entry into the cell. Nature 422:37–44

    CAS  PubMed  Google Scholar 

  100. Sahay G, Alakhova DY, Kabanov AV (2010) Endocytosis of nanomedicines. J Control Release 145:182–195

    CAS  PubMed Central  PubMed  Google Scholar 

  101. Xu C, Yang Y, Yang J, Chen X, Wang G (2012) Analysis of the role of the integrin signaling pathway in hepatocytes during rat liver regeneration. Cell Mol Biol Lett 17(2):274–288

    CAS  PubMed  Google Scholar 

  102. Roger E, Lagarce F, Garcion E, Benoit JP (2010) Biopharmaceutical parameters to consider in order to alter the fate of nanocarriers after oral delivery. Nanomedicine (Lond) 5:287–306

    CAS  Google Scholar 

  103. Albanese A, Tang PS, Chan WC (2012) The effect of nanoparticle size, shape, and surface chemistry on biological systems. Annu Rev Biomed Eng 14:1–16

    CAS  PubMed  Google Scholar 

  104. Beljaars L, Poelstra K, Molema G, Meijer DKF (1998) Targeting of sugar- and charge modified albumins to fibrotic rat livers: the accessibility of hepatic cells after chronic bile duct ligation. J Hepatol 29:579–588

    CAS  PubMed  Google Scholar 

  105. Higuchi Y, Nishikawa M, Kawakami S, Yamashita F, Hashida M (2004) Uptake characteristics of mannosylated and fucosylated bovine serum albumin in primary cultured rat sinusoidal endothelial cells and Kupffer cells. Int J Pharm 287:147–154

    CAS  PubMed  Google Scholar 

  106. Melgert BN, Olinga P, Jack VK, Molema G, Meijer DKF, Poelstra K (2000) Dexamethasone coupled to albumin is selectively taken up by rat nonparenchymal liver cells and attenuates LPS-induced activation of hepatic cells. J Hepatol 32:603–611

    CAS  PubMed  Google Scholar 

  107. Ishimoto N, Nemoto T, Nagayoshi F, Yamashita MH (2006) Improved antioxidant activity of superoxide dismutase by direct chemical modification. J Control Release 111:204–211

    CAS  PubMed  Google Scholar 

  108. Schumann J, Wolf D, Pahl A, Brune K, Papadopoulos T, van Rooijen N, Tiegs G (2000) Importance of Kupffer cells for T-cell-dependent liver injury in mice. Am J Pathol 157:1671–1683

    CAS  PubMed Central  PubMed  Google Scholar 

  109. Seki S, Habu Y, Kawamura T, Takeda K, Dobashi H, Ohkawa T, Hiraide H (2000) The liver as a crucial organ in the first line of host defense: the roles of Kupffer cells, natural killer (NK) cells and NK1.1 Ag + T cells in T helper 1 immune responses. Immunol Rev 174:35–46

    CAS  PubMed  Google Scholar 

  110. Kelly C, Jefferies C, Cryan SA (2011) Targeted liposomal drug delivery to monocytes and macrophages. J Drug Deliv. http://dx.doi.org/10.1155/2011/727241

  111. Dong L, Gao S, Diao H, Chen J, Zhang J (2007) Galactosylated low molecular weight chitosan as acarrier delivering oligonucleotides to Kupffer cells instead of hepatocytes in vivo. J Biomed Mater Res A 84(3):777–784

    Google Scholar 

  112. Miyoshi E, Moriwaki K, Terao N, Tan CC, Terao M, Nakagawa T, Matsumoto H, Shinzaki S, Kamada Y (2012) Fucosylation is a promising target for cancer diagnosis and therapy. Biomolecules 2:34

    CAS  PubMed Central  PubMed  Google Scholar 

  113. Hagiwara SI, Takeya M, Suzuki H, Kodama T, van der Laan LJW, Kraal G, Kitamura N, Takahashi K (1999) Role of macrophage scavenger receptors in hepatic granuloma formation in mice. Am J Pathol 154(3):705–720

    CAS  PubMed Central  PubMed  Google Scholar 

  114. Van Rooyen DM, Larter CZ, Haigh WG et al (2011) Hepatic free cholesterolaccumulates in obese, diabetic mice and causes nonalcoholicsteatohepatitis. Gastroenterology 141:1393–1403

    PubMed Central  PubMed  Google Scholar 

  115. Ramprasad MP, Fischer W, Witztum JL, Sambrano GR, Quehenberger O, Steinberg D (1995) The 94- to 97-kDa mouse macrophage membrane protein that recognizes oxidized low density lipoprotein and phosphatidylserine-rich liposomes is identical to macrosialin, the mouse homologue of human CD68. Proc Natl Acad Sci U S A 92(21):9580–9584

    CAS  PubMed Central  PubMed  Google Scholar 

  116. Rensen PCN, Gras JCE, Lindfors EK, van DijkKW JJW, van BerkelTJC BEAL (2006) Selective targeting of liposomes to macrophages using a ligand with high affinity for the macrophage scavenger receptor class A. Curr Drug Discov Technol 3:135–144

    CAS  PubMed  Google Scholar 

  117. Kamps JAAM, Scherphof GL (1997) Massive targeting of liposomes, surface-modified with anionized albumins, to hepatic endothelial cells. Proc Natl Acad Sci U S A 94:11681–11685

    CAS  PubMed Central  PubMed  Google Scholar 

  118. Terpstra V, van Berkel TJ (2000) Scavenger receptors on liver Kupffer cells mediate the in vivo uptake of oxidatively damaged red blood cells in mice. Blood 95(6):2157–2163

    CAS  PubMed  Google Scholar 

  119. Lovdal T, Andersen E, Brech A, Berg T (2000) Fc receptor mediated endocytosis of small soluble immunoglobulin G immune complexes in Kupffer and endothelial cells from rat liver. J Cell Sci 113:3255–3266

    CAS  PubMed  Google Scholar 

  120. Peterson TC (1992) Mode of communication between Kupffer cells and Hepatocytes under normal and pathological conditions. In: Billiar TR, Curran RD (eds) Hepatocyte and Kupffer cell interactions. CRC, Boca Raton

    Google Scholar 

  121. Duryee MJ, Freeman TL, Willis MS, Hunter CD, Hamilton BC, Suzuki H, Tuma DJ, Klassen LW, Thiele GM (2005) Scavenger receptors on sinusoidal liver endothelial cells are involved in the uptake of aldehyde-modified proteins. Mol Pharmacol 68:1423–1430

    CAS  PubMed  Google Scholar 

  122. Schledzewski K, Geraud C, Arnold B, Wang S, Gröne HJ, Kempf T, Wollert KC, Straub BK, Schirmacher P, Demory A, Schönhaber H, Gratchev A, Dietz L, Thierse HJ, Kzhyshkowska J, Goerdt S (2011) Deficiency of liver sinusoidal scavenger receptors stabilin-1 and -2 in mice causes glomerulofibrotic nephropathy via impaired hepatic clearance of noxious blood factors. J Clin Invest 121(2):703–714

    CAS  PubMed Central  PubMed  Google Scholar 

  123. Friedman SL, Bansal MB (2006) Reversal of hepatic fibrosis—fact or fantasy? Hepatology 43:S82–S88

    CAS  PubMed  Google Scholar 

  124. Fischer HD, Gonzalez-Noriega A, Sly WS, Morré DJ (1980) Phosphomannosyl-enzyme receptors in rat liver. Subcellular distribution and role in intracellular transport of lysosomal enzymes. J Biol Chem 255(20):9608–9615

    CAS  PubMed  Google Scholar 

  125. Ghosh P, Dahms NM, Kornfeld S (2003) Mannose 6-phosphate receptors: new twists in the tale. Nat Rev Mol Cell Biol 4(3):202–212

    CAS  PubMed  Google Scholar 

  126. Beljaars L, Olinga P, Molema G, de Bleser P, Geerts A, Groothuis GM, Meijer DK, Poelstra K (2001) Characteristics of the hepatic stellate cell-selective carrier mannose6-phosphate modified albumin (M6P28-HSA). Liver 21:320–328

    CAS  PubMed  Google Scholar 

  127. Adrian JE, Kamps JA, Poelstra K, Scherphof GL, Meijer DK, Kaneda Y (2007) Delivery of viral vectors to hepatic stellate cells in fibrotic livers using HVJ envelopes fused with targeted liposomes. J Drug Target 15:75–82

    CAS  PubMed  Google Scholar 

  128. Lepreux S, Bioulac-Sage P, Gabbiani G, Sapin V, Housset C, Rosenbaum J, Balabaud C, Desmoulière A (2004) Cellular retinol-binding protein-1 expression in normal and fibrotic/cirrhotic human liver: different patterns of expression in hepatic stellate cells and (myo) fibroblast subpopulations. J Hepatol 40(5):774–780

    CAS  PubMed  Google Scholar 

  129. Sato Y, Murase K, Kato J, Kobune M, Sato T, Kawano Y, Takimoto R, Takada K, Miyanishi K, Matsunaga T, Takayama T, Niitsu Y (2008) Resolution ofliver cirrhosis using vitamin A-coupled liposomes to deliver siRNA against acollagen-specific chaperone. Nat Biotechnol 26:431–442

    CAS  PubMed  Google Scholar 

  130. Beljaars L, Molema G, Schuppan D, Geerts A, De Bleser PJ, Weert B, Meijer DK, Poelstra K (2000) Successful targeting to rat hepatic stellate cells using albumin modified with cyclic peptides that recognize the collagen type VI receptor. J Biol Chem 275:12743–12751

    CAS  PubMed  Google Scholar 

  131. Du SL, Pan H, Lu WY, Wang J, Wu J, Wang JY (2007) Cyclic Arg-Gly-Asp peptide labeled liposomes for targeting drug therapy of hepatic fibrosis in rats. J Pharmacol Exp Ther 322:560–568

    CAS  PubMed  Google Scholar 

  132. Wieckowska A, McCullough AJ, Feldstein AE (2007) Noninvasive diagnosis and monitoring of nonalcoholic steatohepatitis: present and future. Hepatology 46:582–589

    CAS  PubMed  Google Scholar 

  133. Wisse E et al (2008) The size of endothelial fenestrae in human liver sinusoids: implications for hepatocyte-directed gene transfer. Gene Ther 15:1193–1199

    CAS  PubMed  Google Scholar 

  134. Sorensen AL, Rumjantseva V, Nayeb-Hashemi S, Clausen H, Hartwig JH, Wandall HH, Hoffmeister KM (2009) Role of sialic acid for platelet life span: exposure of β-galactose results in the rapid clearance of platelets from the circulation by Asialoglycoprotein receptor—expressing liver macrophages and hepatocytes. Blood 114:1645–1654

    PubMed Central  PubMed  Google Scholar 

  135. Baenziger JU, Maynard Y (1980) Human hepatic lectin. Physiochemical properties and specificity. J Biol Chem 255:4607–4613

    CAS  PubMed  Google Scholar 

  136. Iobst ST, Drickamer K (1996) Selective sugar binding to the carbohydrate recognition domains of the rat hepatic and macrophage asialoglycoprotein receptors. J Biol Chem 271(12):6686–6693

    CAS  PubMed  Google Scholar 

  137. Fuhrer C, Geffen I, Huggel K, Spiess M (1994) The two subunits of the asialoglycoprotein receptor contain different sorting information. J Biol Chem 269(5):3277–3282

    CAS  PubMed  Google Scholar 

  138. Ashwell G, Harford J (1982) Carbohydrate-specific receptors of the liver. Annu Rev Biochem 51:531–554

    CAS  PubMed  Google Scholar 

  139. Murao A, Nishikawa M, Managit C, Wong J, Kawakami S, Yamastuta F, Hashida M (2002) Targeting efficiency of galactosylated liposomes to hepatocytes in vivo: effect of lipid composition. Pharm Res 19:1808–1813

    CAS  PubMed  Google Scholar 

  140. Managit C, Kawakami S, Nishikawa M, Yamashita F, Hashida M (2003) Targeted and sustained drug delivery using PEGylated galactosylated liposomes. Int J Pharm 266(1–2):77–84

    CAS  PubMed  Google Scholar 

  141. Managit C, Kawakami S, Yamashita F, Hashida M (2005) Effect of galacatose density on asialoglycoprotein receptor mediated uptake of galactosylated liposomes. J Pharm Sci 94(10):2266–2275

    CAS  PubMed  Google Scholar 

  142. Bijsterbosch MK, Bernini F, Bakkeren HF, Gotto AM, Smith LC, Van Berkel TJ (1991) Enhanced hepatic uptake and processing of cholesterol esters from low density lipoprotein by specific lactosaminated fab fragments. Arterioscler Thromb Vasc Biol 11:1806–1813

    CAS  Google Scholar 

  143. Sliedregt LAJM, Rensen PCN, Rump ET, van Santbrink PJ, Bijsterbosch MK, Valentijn ARPM, van der Marel GA, van Boom JH, van Berkel TJC, Biessen EAL (1999) Design and synthesis of novel amphiphilic dendritic galactosides for selective targeting of liposomes to the hepatic asialoglycoprotein receptor. J Med Chem 42:609–618

    CAS  PubMed  Google Scholar 

  144. Zhou X, Zhang M, Yung B, Li H, Zhou C, Lee LJ, Lee RJ (2012) Lactosylated liposomes for targeted delivery of doxorubicin to hepatocellular carcinoma. Int J Nanomedicine 7:5465–5547

    CAS  PubMed Central  PubMed  Google Scholar 

  145. Seymour LW, Ferry DR, Anderson D, Hesslewood S, Julyan PJ, Poyner R, Doran J, Young AM, Burtles S, Kerr DJ (2002) Cancer research campaign phase I/II clinical trials committee. Hepatic drug targeting: phase I evaluation of polymer-bound doxorubicin. J Clin Oncol 20(6):1668–1676

    CAS  PubMed  Google Scholar 

  146. D’Souza AA, Jain P, Galdhar CN, Samad A, Degani MS, Devarajan PV (2013) Comparative in silico-in vivo evaluation of ASGP-R ligands for hepatic targeting of curcumin gantrez nanoparticles. AAPS J 15(3):696–706

    PubMed Central  PubMed  Google Scholar 

  147. Popielarski SR, Hu-Lieskovan S, French SW, Triche TJ, Davis ME (2005) A nanoparticle-based model delivery system to guidethe rational design of gene delivery to the liver. 2. In vitro and invivo uptake results. Bioconjug Chem 16(5):1071–1080

    CAS  PubMed  Google Scholar 

  148. Wu F, Wuensch SA, Azadniv M, Ebrahimkhani MR, Crispe IN (2009) Galactosylated LDL nanoparticles: a novel targetingdelivery system to deliver antigen to macrophages and enhance antigen specific T cell responses. Mol Pharm 6(5):1506–1517

    CAS  PubMed Central  PubMed  Google Scholar 

  149. Biessen EAL, Bakkeren HF, Beuting DM, Kuiper J, Van Berkel TJC (1994) Ligand size is a major determinant of high-affinity binding of fucose- and galactose-exposing (lipo)proteins by the hepatic fucose receptor. Biochem J 299:291–296

    CAS  PubMed Central  PubMed  Google Scholar 

  150. Schlepper-Schafer J, Hulsmann D, Djovkar A, Meyer HE, Herbertz L, Kolb H, Kolb-Bachofen V (1986) Endocytosis via galactose receptors in vivo. Ligand size directs uptake by hepatocytes and/or liver macrophages. Exp Cell Res 165:494–506

    CAS  PubMed  Google Scholar 

  151. Nishikawa M, Takemura S, Takakura Y, Hashida M (1998) Targeted delivery of plasmid DNA to hepatocytes in vivo: optimization of the pharmacokinetics of plasmid dna/galactosylated poly(l-Lysine) complexes by controlling their physicochemical properties. J Pharmacol Exp Ther 287:408–415

    CAS  PubMed  Google Scholar 

  152. Negishi M, Irie A, Nagata N, Ichikawa A (1991) Specific binding of glycyrrhetinic acid to the rat liver membrane. Biochim Biophys Acta 1066:77–82

    CAS  PubMed  Google Scholar 

  153. Lin AH, Liu Y, Huang Y, Sun J, Wu Z, Zhang X, Ping Q (2008) Glycyrrhizin surface modified chitosan nanoparticles for hepatocyte-targeted delivery. Int J Pharm 359:247–253

    CAS  PubMed  Google Scholar 

  154. Akao T (2000) Differences in the metabolism of glycyrrhizin, glycyrrhetic acid and glycyrrhetic acid monoglucuronide by human intestinal flora. Biol Pharm Bull 23(12):1418–1423

    CAS  PubMed  Google Scholar 

  155. Huang W, Wang W, Wang P, Zhang CN, Tian Q, Zhang Y, Wang XH, Cha RT, Wang CH, Yuan Z (2011) Glycyrrhetinic acid-functionalized degradable micelles as liver-targeted drug carrier. J Mater Sci Mater Med 22(4):853–863

    CAS  PubMed  Google Scholar 

  156. Shi L, Tang C, Yin C (2012) Glycyrrhizin-modified O-carboxymethyl chitosan nanoparticles as drug vehicles targeting hepatocellular carcinoma. Biomaterials 33(30):7594–7604

    CAS  PubMed  Google Scholar 

  157. Tian Q, Wang X, Wang W, Zhang C, Liu Y, Yuan Z (2010) Insight into glycyrrhetinic acid: the role of the hydroxyl group on liver targeting. Int J Pharm 400:153–157

    CAS  PubMed  Google Scholar 

  158. Tian Q, Wang X, Wang W, Zhang C, Yuan Z, Chen X (2011) Understanding the role of the C3-hydroxyl group in glycyrrhetinic acid on liver targeting. J Control Release 152:e192–e269

    Google Scholar 

  159. Tian Q, Wang XH, Wang W, Zhang CN, Wang P, Yuan Z (2012) Self-assembly and liver targeting of sulfated chitosan nanoparticles functionalized with glycyrrhetinic acid. Nanomedicine 8:870–879

    CAS  PubMed  Google Scholar 

  160. Tian Q, Zhang CN, Wang XH, Wang W, Huang W, Wang CH, Yuan Z, Liu M, Wan HY, Tang H, Cha RT (2010) Glycyrrhetinic acid-modified chitosan/poly(ethylene glycol) nanoparticles for liver-targeted delivery. Biomaterials 31:4748–4756

    CAS  PubMed  Google Scholar 

  161. Wu F, Xu T, Liu C, Chen C, Song X, Zheng Y, He G (2013) Glycyrrhetinic acid-poly(ethylene glycol)-glycyrrhetinic acid tri-block conjugates based self-assembled micelles for hepatic targeted delivery of poorly water soluble drug. Scientific World Journal 2013:913654

    PubMed Central  PubMed  Google Scholar 

  162. Mao SJ, Hou SX, He R, Zhang LK, Wei DP, Bi YQ, Jin H (2005) Uptake of albumin nanoparticle surface modified with glycyrrhizin by primary cultured rat hepatocytes. World J Gastroenterol 11(20):3075–3079

    CAS  PubMed  Google Scholar 

  163. Zhang L, Yao J, Zhou J, Wang T, Zhang Q (2013) Glycyrrhetinic acid-graft-hyaluronic acid conjugate as a carrier for synergistic targeted delivery of antitumor drugs. Int J Pharm 441(1–2):654–664

    CAS  PubMed  Google Scholar 

  164. Li FQ, Su H, Chen X, Qin XJ, Liu JY, Zhu QG, Hu JH (2009) Mannose 6-phosphate-modified bovine serum albumin nanoparticles for controlled and targeted delivery of sodium ferulate for treatment of hepatic fibrosis. J Pharm Pharmacol 61:1155–1161

    CAS  PubMed  Google Scholar 

  165. Follenzi A, Sabatino G, Lombardo A, Boccaccio C, Naldini L (2002) Efficient gene delivery and targeted expression to hepatocytes in vivo by improved lentiviral vectors. Hum Gene Ther 13:243–260

    CAS  PubMed  Google Scholar 

  166. Haisma HJ, Bellu AR (2011) Pharmacological interventions for improving adenovirus usage in gene therapy. Mol Pharm 8:50–55

    CAS  PubMed  Google Scholar 

  167. Kaneda Y (2001) Improvements in gene therapy technologies. Mol Urol 5:85–89

    CAS  PubMed  Google Scholar 

  168. Kawashita Y, Fujioka H, Ohtsuru A, Kaneda Y, Kamohara Y, Kawazoe Y, Yamashita S, Kanematsu T (2005) The efficacy and safety of gene transfer into the porcine liver in vivo by HVJ (Sendai virus) liposome. Transplantation 80:1623–1629

    CAS  PubMed  Google Scholar 

  169. Yamada T, Iwasaki Y, Tada H, Iwabuki H, Chuah MKL, VandenDriessche T, Fukuda H, Kondo A, Ueda M, Seno M, Tanizawa K, Kuroda S (2003) Nanoparticles for the delivery of genes and drugs to human hepatocytes. Nat Biotechnol 21:885–890

    CAS  PubMed  Google Scholar 

  170. Smith T, Idamakanti N, Kylefjord H, Rollence M, King L, Kaloss M, Kaleko M, Stevenson SC (2002) In vivo hepatic adenoviral gene delivery occurs independently of the coxsackie virus-adenovirus receptor. Mol Ther 5(6):770–779

    CAS  PubMed  Google Scholar 

  171. Xu Z, Tian J, Smith JS, Byrnes AP (2008) Clearance of adenovirus by kupffer cells is mediated by scavenger receptors, natural antibodies, and complement. J Virol 82(23):11705–11713

    CAS  PubMed Central  PubMed  Google Scholar 

  172. Gullberg D, Turner DC, Borg TK, Terracio L, Rubin K (1990) Different beta 1-integrin collagen receptors on rat hepatocytes and cardiac fibroblasts. Exp Cell Res 190(2):254–264

    CAS  PubMed  Google Scholar 

  173. Chen K, Chen X (2011) Integrin targeted delivery of chemotherapeutics. Theranostics 1:189–200

    CAS  PubMed Central  PubMed  Google Scholar 

  174. Marelli UK, Rechenmacher F, Sobahi TR, Mas-Moruno C, Kessler H (2013) Tumor targeting via integrin ligands. Front Oncol 3:222

    PubMed Central  PubMed  Google Scholar 

  175. Murphy EA, Majeti BK, Barnes LA, Makale M, Weis SM, Lutu-Fuga K, Wrasidlo W, Cheresh DA (2008) Nanoparticle-mediated drug delivery to tumor vasculature suppresses metastasis. Proc Natl Acad Sci U S A 105(27):9343–9348

    CAS  PubMed Central  PubMed  Google Scholar 

  176. Brown MS, Goldstein JL (1976) Receptor-mediated control of cholesterol metabolism. Science 191:150–154

    CAS  PubMed  Google Scholar 

  177. Pieper-Furst U, Lammert F (2013) Low-density lipoprotein receptors in liver: old acquaintances and a newcomer. Biochim Biophys Acta 1831(7):1191–1198

    CAS  PubMed  Google Scholar 

  178. Ye Q, Chen Y, Lei H, Liu Q, Moorhead JF, Varghese Z, Ruan XZ (2009) Inflammatory stress increases unmodified LDL uptake via LDL receptor: an alternative pathway for macrophage foam-cell formation. Inflamm Res 58:809–818

    CAS  PubMed  Google Scholar 

  179. Kamps JA, Kruijt JK, Kuiper J, Van Berkel TJ (1991) Uptake and degradation of human low-density lipoprotein by human liver parenchymal and Kupffer cells in culture. Biochem J 276(1):135–140

    CAS  PubMed Central  PubMed  Google Scholar 

  180. Rui M, Guo W, Ding Q, Wei X, Xu J, Xu Y (2012) Recombinant high-density lipoprotein nanoparticles containing gadolinium-labeled cholesterol for morphologic and functional magnetic resonance imaging of the liver. Int J Nanomedicine 7:3751–3768

    CAS  PubMed Central  PubMed  Google Scholar 

  181. Jin H, Lovell JF, Chen J, Lin Q, Ding L, Ng KK, Pandey RK, Manoharan M, Zhang Z, Zheng G (2012) Mechanistic insights into LDL nanoparticle-mediated siRNA delivery. Bioconjug Chem 23(1):33–41

    CAS  PubMed  Google Scholar 

  182. Wan C, Allen TM, Cullis PR (2013) Lipid nanoparticle delivery systems for siRNA-based therapeutics. Drug Deliv Transl Res 4:74–83

    Google Scholar 

  183. Kim SI, Shin D, Choi TH, Lee JC, Cheon GJ, Kim KY, Park M, Kim M (2007) Systemic and specific delivery of small interfering RNSs to the liver mediated by apolipoprotein A-I. Mol Ther 15:1145–1152

    CAS  PubMed  Google Scholar 

  184. Kim SI, Shin D, Lee H, Ahn BY, Yoon Y, Kim M (2009) Targeted delivery of siRNA against hepatitis C virus by apolipoprotein A-I-bound cationic liposomes. J Hepatol 50:479–488

    CAS  PubMed  Google Scholar 

  185. Volpes R, Van den Oord JJ, Desmet VJ (1990) Adhesive molecules in liver disease: immune histochemical distribution of thrombospondin receptors in chronic HBV infection. J Hepatol 10:297–304

    CAS  PubMed  Google Scholar 

  186. Feng M, Cai Q, Huang H, Zhou P (2008) Liver targeting and anti-HBV activity of reconstituted HDL-acyclovir palmitate complex. Eur J Pharm Biopharm 68:688–693

    CAS  PubMed  Google Scholar 

  187. Reddy LH, Couvreur P (2011) Nanotechnology for therapy and imaging of liver diseases. J Hepatol 55(6):1461–1466

    CAS  PubMed  Google Scholar 

  188. Suzuki M, Fujimoto Y, Suzuki Y, Hosoki Y, Saito H, Nakayama K, Ohtake T, Kohgo Y (2004) Induction of transferrin receptor by ethanol in rat primary hepatocyte culture. Alcohol Clin Exp Res 28:98S–105S

    CAS  PubMed  Google Scholar 

  189. Suzuki Y, Saito H, Suzuki M, Hosoki Y, Sakurai S, Fujimoto Y, Kohgo Y (2002) Up-regulation of transferrin receptor expression in hepatocytes by habitual alcohol drinking is implicated in hepatic iron overload in alcoholic liver disease. Alcohol Clin Exp Res 26:26S–31S

    CAS  PubMed  Google Scholar 

  190. Qian ZM, Li H, Sun H, Ho K (2002) Targeted drug delivery via the transferrin receptor-mediated endocytosis pathway. Pharmacol Rev 54(4):561–587

    CAS  PubMed  Google Scholar 

  191. He Q, Yuan WM, Liu J, Zhang ZR (2008) Study on in vivo distribution of liver-targeting nanoparticles encapsulating thymidine kinase gene (TK gene) in mice. J Mater Sci Mater Med 19:559–565

    CAS  PubMed  Google Scholar 

  192. Kramer W, Wess G, Schubert G, Bickel M, Girbig F, Gutjahr U, Kowalewski S, Baringhaus KH, Enhsen A, Glombik H, Mullner S, Neckermann G, Schulz S, Petzinger E (1992) Liver-specific drug targeting by coupling to bile acids. J Biol Chem 267(26):18598–18604

    CAS  PubMed  Google Scholar 

  193. Vaquero J, Briz O, Herraez E, Muntané J, Marin JJ (2013) Activation of the nuclear receptor FXR enhances hepatocyte chemoprotection and liver tumor chemoresistance against genotoxic compounds. Biochim Biophys Acta 1833(10):2212–2219

    CAS  PubMed  Google Scholar 

  194. Annoni A, Goudy K, Akbarpour M, Naldini L, Roncarolo MG (2013) Immune responses in liver-directed lentiviral gene therapy. Transl Res 161:230–240

    CAS  PubMed  Google Scholar 

  195. Mallat A, Teixeira-Clerc F, Lotersztajn S (2013) Cannabinoid signaling and liver therapeutics. J Hepatol 59(4):891–896

    CAS  PubMed  Google Scholar 

  196. He ZG, Cai HJ, Chen XY, Wang N (1990) Modulation of rat Kupffer cells on high density lipoprotein receptors on hepatocytes. Sci China B 33(5):584–591

    CAS  PubMed  Google Scholar 

  197. Jindadamrongwech S, Thepparit C, Smith DR (2004) Identification of GRP 78 (BiP) as a liver cell expressed receptor element for dengue virus serotype 2. Arch Virol 149(5):915–927

    CAS  PubMed  Google Scholar 

  198. Thepparit C, Smith DR (2004) Serotype-specific entry of dengue virus into liver cells: Identification of the 37-kilodalton/67-kilodalton high-affinity laminin receptor as a dengue virus serotype 1 receptor. J Virol 78(22):12647–12656

    CAS  PubMed Central  PubMed  Google Scholar 

  199. Cabrera-Hernandez A, Smith DR (2005) Mammalian dengue virus receptors. Dengue Bull 29(662):119–135

    Google Scholar 

  200. Hidari KI, Suzuki T (2011) Dengue virus receptor. Trop Med Health 39(4):37–43

    PubMed Central  PubMed  Google Scholar 

  201. Ding X, Saxena NK, Lin S, Gupta NA, Anania FA (2006) Exendin-4, a glucagon-like protein-1 (GLP-1) receptor agonist, reverses hepatic steatosis in ob/ob mice. Hepatology 43(1):173–181

    CAS  PubMed Central  PubMed  Google Scholar 

  202. Gupta NA, Mells J, Dunham RM, Grakoui A, Handy J, Saxena NK, Anania FA (2010) Glucagon-like peptide-1 receptor is present on human hepatocytes and has a direct role in decreasing hepatic steatosis in vitro by modulating elements of the insulin signaling pathway. Hepatology 51(5):1584–1592

    CAS  PubMed Central  PubMed  Google Scholar 

  203. Kim JS, Lemasters JJ (2006) Opioid receptor-independent protection of ischemic rat hepatocytes by morphine. Biochem Biophys Res Commun 351(4):958–964

    CAS  PubMed Central  PubMed  Google Scholar 

  204. Pacher P, Batkai S, Kunos G (2006) The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev 58(3):389–462

    CAS  PubMed Central  PubMed  Google Scholar 

  205. Pertwee RG (2006) The pharmacology of cannabinoid receptors and their ligands: an overview. Int J Obes (Lond) 30:S13–S18

    CAS  Google Scholar 

  206. Donnenberg VS, Donnenberg AD (2005) Multiple drug resistance in cancer revisited: the cancer stem cell hypothesis. J Clin Pharmacol 45:872–877

    CAS  PubMed  Google Scholar 

  207. Breuhahn K, Longerich T, Schirmacher P (2006) Dysregulation of growth factor signaling in human hepatocellular carcinoma. Oncogene 25:3787–3800

    CAS  PubMed  Google Scholar 

  208. Merle P, de la Monte S, Kim M, Herrmann M, Tanaka S, Von Dem Bussche A, Kew MC, Trepo C, Wands JR (2004) Functional consequences of frizzled-7 receptor overexpression in human hepatocellular carcinoma. Gastroenterology 127:1110–1122

    CAS  PubMed  Google Scholar 

  209. Marquardt JU, Galle PR, Teufel A (2012) Molecular diagnosis and therapy of hepatocellular carcinoma (HCC): an emerging field for advanced technologies. J Hepatol 56:267–275

    PubMed  Google Scholar 

  210. Oishi N, Wang XW (2011) Novel therapeutic strategies for targeting liver cancer stem cells. Int J Biol Sci 7(5):517–535

    CAS  PubMed Central  PubMed  Google Scholar 

  211. Seo SB, Yang J, Hyung W, Cho EJ, Lee TI, Song YJ, Yoon HG, Suh JS, Huh YM, Haam S (2007) Novel multifunctional PHDCA/PEI nano-drug carriers for simultaneous magnetically targeted cancer therapy and diagnosis via magnetic resonance imaging. Nanotechnology 18:1–8

    Google Scholar 

  212. Marin A, Sun H, Husseini GA, Pitt WG, Christensen DA, Rapoport NY (2000) Drug delivery in pluronic micelles: effect of high-frequency ultrasound on drug release from micelles and intracellular uptake. J Control Release 84:39–47

    Google Scholar 

  213. Bawa P, Pillay V, Choonara YE, du Toit LC (2009) Stimuli-responsive polymers and their applications in drug delivery. Biomed Mater 4(2):022001

    PubMed  Google Scholar 

  214. Qing G, Li M, Deng L, Lv Z, Ding P, Sun T (2013) Smart drug release systems based on stimuli-responsive polymers. Mini Rev Med Chem 13(9):1369–1380

    CAS  PubMed  Google Scholar 

  215. Lee ES, Kun N, Bae YH (2005) Super pH-Sensitive multifunctional polymeric micelle. Nano Lett 5:325–329

    CAS  PubMed  Google Scholar 

  216. Chen Q, Tong S, Dewhirst MW, Yuan F (2004) Targeting tumor microvessels using doxorubicin encapsulated in a novel thermosensitive liposome. Mol Cancer Ther 3:1311–1317

    CAS  PubMed  Google Scholar 

  217. Kono K (2001) Thermosensitive polymer-modified liposomes. Adv Drug Deliv Rev 53:307–319

    CAS  PubMed  Google Scholar 

  218. Johnson RP, Jeong YI, John JV, Chung CW, Kang DH, Selvaraj M, Suh H, Kim I (2013) Dual stimuli-responsive poly(N-isopropylacrylamide)-b-poly(l-histidine) chimeric materials for the controlled delivery of doxorubicin into liver carcinoma. Biomacromolecules 14(5):1434–1443

    CAS  PubMed  Google Scholar 

  219. Ponce AM, Vujaskovic Z, Yuan F, Needham D, Dewhirst MW (2006) Int J Hyperthermia 22:205

    CAS  PubMed  Google Scholar 

  220. Khandare JJ, Minko T (2006) Antibodies and peptides in cancer therapy. Crit Rev Ther Drug Carrier Syst 25:401–435

    Google Scholar 

  221. Mastrobattista E, Koning GA, Storm G (1999) Immunoliposomes for the targeted delivery of antitumor drugs. Adv Drug Deliv Rev 40:103–127

    CAS  PubMed  Google Scholar 

  222. Patil RR, Guhagarkar SA, Devarajan PV (2008) Engineered nanocarriers of doxorubicin: a current update. Crit Rev Ther Drug Carrier Syst 25(1):1–61

    CAS  PubMed  Google Scholar 

  223. Trahtenherts A, Benhar I (2009) An internalizing antibody specific for the human asialoglycoprotein receptor. Hybridoma (Larchmt) 28(4):225–233

    CAS  Google Scholar 

  224. Coulstock E, Sosabowski J, Ovečka M, Prince R, Goodall L, Mudd C, Sepp A, Davies M, Foster J, Burnet J, Dunlevy G, Walker A (2013) Liver-targeting of interferon-alpha with tissue-specific domain antibodies. PLoS One 8(2):e57263

    CAS  PubMed Central  PubMed  Google Scholar 

  225. Feng M, Ho M (2014) Glypican-3 antibodies: a new therapeutic target for liver cancer. FEBS Lett 588(2):377–382

    CAS  PubMed  Google Scholar 

  226. Jin C, Bai L, Li H, He Y, An J, Dou K (2013) Paclitaxel-loaded nanoparticles decorated with anti-CD133 antibody for targeting liver cancer stem cells. J Control Release 172(1):e20–e21

    CAS  Google Scholar 

  227. Douglass A, Wallace K, Koruth M, Barelle C, Porter AJ, Wright MC (2010) Using a recombinant single chain antibody for targeting liver myofibroblasts with anti-fibrogenic therapeutics. Arab J Gastroenterol 10:S3–S6

    Google Scholar 

  228. Elrick LJ, Leel V, Blaylock MG, Duncan L, Drever MR, Strachan G, Charlton KA, Koruth M, Porter AJ, Wright MC (2005) Generation of a monoclonal human single chain antibody fragment to hepatic stellate cells—a potential mechanism for targeting liver anti-fibrotic therapeutics. J Hepatol 42:888–896

    CAS  PubMed  Google Scholar 

  229. Praetorius NP, Mandal TK (2007) Engineered nanoparticles in cancer therapy. Recent Pat Drug Deliv Formul 1(1):37–51

    CAS  PubMed  Google Scholar 

  230. Mishra N, Yadav NP, Rai VK, Sinha P, Yadav KS, Jain S, Arora S (2013) Efficient hepatic delivery of drugs: novel strategies and their significance. Biomed Res Int 2013:382184

    PubMed Central  PubMed  Google Scholar 

  231. Zhang L, Gu FX, Chan JM, Wang AZ, Langer RS, Farokhzad OC (2008) Nanoparticles in medicine: therapeutic applications and developments. Clin Pharmacol Ther 83(5):761

    CAS  PubMed  Google Scholar 

  232. Hirabayashi H, Nishikawa M, Takakura Y, Hashida M (1996) Development and pharmacokinetics of galactosylated poly-l-glutamic acid as a biodegradable carrier for liver-specific drug delivery. Pharm Res 13(6):880–884

    CAS  PubMed  Google Scholar 

  233. Palumbo E (2009) PEG-interferon in acute and chronic hepatitis C: a review. Am J Ther 16(6):573–578

    PubMed  Google Scholar 

  234. Arangoa MA, Duzgunes N, de Ilarduya CT (2003) Increased receptor-mediated gene delivery to the liver by protamine-enhanced-asialofetuin-lipoplexes. Gene Ther 10:5–14

    CAS  PubMed  Google Scholar 

  235. Dirk L, Edith J, Andreas Z (2004) Drug delivery of oligonucleotides by peptides. Eur J Pharm Biopharm 58(2):237–251

    Google Scholar 

  236. Gu W, Wu C, Chen J, Xiao Y (2013) Nanotechnology in the targeted drug delivery for bone diseases and bone regeneration. Int J Nanomedicine 8(1):2305–2317

    PubMed Central  PubMed  Google Scholar 

  237. Allen TM, Cullis PR (2013) Liposomal drug delivery systems: from concept to clinical applications. Adv Drug Deliv Rev 65:36–48

    CAS  PubMed  Google Scholar 

  238. Bae YH, Park K (2011) Targeted drug delivery to tumors: myths, reality and possibility. J Control Release 153(3):198–205

    CAS  PubMed Central  PubMed  Google Scholar 

  239. Wei H, Huang J, Yang J, Zhang X, Lin L, Xue E, Chen Z (2013) Ultrasound exposure improves the targeted therapy effects of galactosylated docetaxel nanoparticles on hepatocellular carcinoma xenografts. PLoS One 8(3):e58133

    CAS  PubMed Central  PubMed  Google Scholar 

  240. Czaja AJ (2013) Hepatocellular carcinoma and other malignancies in autoimmune hepatitis. Dig Dis Sci 58(6):1459–1476

    CAS  PubMed  Google Scholar 

  241. Wang H, Chen L (2013) Tumor microenviroment and hepatocellularcarcinoma metastasis. J Gastroenterol Hepatol 28(S1):43–48

    PubMed  Google Scholar 

  242. Edens HA, Levi BP, Jaye DL, Walsh S, Reaves TA, Turner JR, Nusrat A, Parkos CA (2002) Neutrophil transepithelial migration: evidence for sequential, contact-dependent signaling events and enhanced paracellular permeability independent of transjunctional migration. J Immunol 169:476–486

    CAS  PubMed  Google Scholar 

  243. Iyer AK, Khaled G, Fang J, Maeda H (2006) Exploiting the enhanced permeability and retention effect for tumor targeting. Drug Discov Today 11(17–18):812–818

    CAS  PubMed  Google Scholar 

  244. Maeda H, Wu J, Sawa T, Matsumura Y, Hori K (2000) Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. J Control Release 65:271

    CAS  PubMed  Google Scholar 

  245. Yuan F, Dellian M, Fukumura D, Leunig M, Berk DA, Torchilin VP, Jain RK (1995) Vascular permeability in a human tumor xenograft: molecular size dependence and cutoff size. Cancer Res 55:3752

    CAS  PubMed  Google Scholar 

  246. Moghimi SM, Hunter AC, Murray JC (2001) Long-circulating and target-specific nanoparticles: theory to practice. Pharmacol Rev 53(2):283–318

    CAS  PubMed  Google Scholar 

  247. Cho K, Wang X, Nie S, Chen Z, Shin DM (2008) Therapeutic nanoparticles for drug delivery in cancer. Clin Cancer Res 14:1310

    CAS  PubMed  Google Scholar 

  248. Villa R, Cerroni B, Viganòa L, Margheritelli S, Abolafio G, Oddo L, Paradossi G, Zaffaroni N (2013) Targeted doxorubicin delivery by chitosan-galactosylated modified polymer microbubbles to hepatocarcinoma cells. Colloids Surf B Biointerfaces 110:434–442

    CAS  PubMed  Google Scholar 

  249. Varshosaz J, Hassanzadeh F, Sadeghi H, Khan ZG, Rostami M (2013) Retinoic Acid Decorated albumin-chitosan nanoparticles for targeted delivery of doxorubicin hydrochloride in hepatocellular carcinoma. J Nanomaterials Article ID 254127, 12 p. http://dx.doi.org/10.1155/2013/254127

  250. Zhang C, Wang W, Liu T, Wu Y, Guo H, Wang P, Wang Y, Yuan Z, Tian Q (2012) Doxorubicin loaded glycyrrhetinic acid-modified alginate nanoparticles for liver tumor chemotherapy. Biomaterials 33:2187–2196

    CAS  PubMed  Google Scholar 

  251. Jain A, Jain K, Mehra NK, Jain NK (2013) Lipoproteins tethered dendrimeric nanoconstructs for effective targeting to cancer cells. J Nanopart Res 15:2003

    Google Scholar 

  252. Zhu XL, Du YZ, Yu RS, Liu P, Shi D, Chen Y, Wang Y, Huang FF (2013) Galactosylated chitosan oligosaccharide nanoparticles for hepatocellular carcinoma cell-targeted delivery of adenosine triphosphate. Int J Mol Sci 14(8):15755–15766

    PubMed Central  PubMed  Google Scholar 

  253. Greish K (2012) Enhanced permeability and retention effect for selective targeting of anticancer nanomedicine: are we there yet? Drug Discov Today Technol 9(2):e161–e166

    CAS  Google Scholar 

  254. Konno T, Maeda H, Iwai K, Maki S, Tashiro S, Uchida M, Miyauchi Y (1984) Selective targeting of anti-cancer drug and simultaneous image enhancement in solid tumors by arterially administered lipid contrast medium. Cancer 54:2367–2374

    CAS  PubMed  Google Scholar 

  255. Maeda H (2001) SMANCS and polymer-conjugated macromolecular drugs: advantages in cancer chemotherapy. Adv Drug Deliv Rev 46(1–3):169–185

    CAS  PubMed  Google Scholar 

  256. Yamaoka T, Tabata Y, Ikada Y (1994) Distribution and tissue uptake of poly(ethylene glycol) with different molecular weights after intravenous administration to mice. J Pharm Sci 83(4):601–606

    CAS  PubMed  Google Scholar 

  257. Ruoslahti E, Bhatia SN, Sailor MJ (2010) Targeting of drugs and nanoparticles to tumors. J Cell Biol 188(6):759–768

    CAS  PubMed Central  PubMed  Google Scholar 

  258. Angulo-Barturen I, Santiago Ferrer S (2013) Humanised models of infection in the evaluation of anti-malarial drugs. Drug Discov Today Technol 10(3):e351–e357

    PubMed  Google Scholar 

  259. Pradel G, Garapaty S, Frevert U (2004) Kupffer and stellate cell proteoglycans mediate malaria sporozoitetargeting to the liver. Comp Hepatol 3(Suppl 1):S47

    PubMed Central  PubMed  Google Scholar 

  260. Arica B, Ozer AY, Ercan MT, Hincal AA (1995) Characterization, in vitro and in vivo studies on primaquine diphosphate liposomes. J Microencapsul 12:469–485

    CAS  PubMed  Google Scholar 

  261. Pirson P, Steiger RF, Trouet A, Gillet J, Herman F (1980) Primaquine liposomes in the chemotherapy of experimental murine malaria. Ann Trop Med Parasitol 74:383–391

    CAS  PubMed  Google Scholar 

  262. Labhasetwar VD, Dorle AK (1990) Nanoparticles—a colloidal drug delivery system for primaquine and metronidazole. J Control Release 12:113–119

    CAS  Google Scholar 

  263. Dierling AM, Cui Z (2005) Targeting primaquine into liver using chylomicron emulsions for potential vivax malaria therapy. Int J Pharm 33:148–152

    Google Scholar 

  264. Bhadra D, Yadav AK, Bhadra S, Jain NK (2005) Glycodendrimeric nanoparticulate carriers of primaquine phosphate for liver targeting. Int J Pharm 295:221–233

    CAS  PubMed  Google Scholar 

  265. Dolina JS, Sung SSJ, Novobrantseva TI, Nguyen TM, Hahn YS (2013) Lipidoid nanoparticles containing PD-L1 siRNA delivered in vivo enter Kupffer cells and enhance NK and CD8+ T Cell-mediated hepatic antiviral immunity. Mol Ther Nucleic Acids 2:e72

    PubMed Central  PubMed  Google Scholar 

  266. Midoux P, Pichon C, Yaouanc JJ, Jaffres PA (2009) Chemical vectors for gene delivery: a current review on polymers, peptides and lipids containing histidine or imidazole as nucleic acids carriers. Br J Pharmacol 157(2):166–178

    CAS  PubMed Central  PubMed  Google Scholar 

  267. Rozema DB, Lewis DL, Wakefield DH, Wong SC, Klein JJ, Roesch PL, Bertin SL, Reppen TW, Chu Q, Blokhin AV, Hagstrom JE, Wolff JA (2007) Dynamic polyconjugates for targeted in vivo delivery of siRNA to hepatocytes. Proc Natl Acad Sci U S A 104:12982–12987

    CAS  PubMed Central  PubMed  Google Scholar 

  268. Craparo EF, Triolo D, Pitarresi G, Giammona G, Cavallaro G (2013) Galactosylated micelles for a ribavirin prodrug targeting to hepatocytes. Biomacromolecules 14(6):1838–1849

    CAS  PubMed  Google Scholar 

  269. Lim DW, Yeom YI, Park TG (2000) Poly(DMAEMA-NVP)-b-PEG-galactose as gene delivery vector for hepatocytes. Bioconjug Chem 11:688–695

    CAS  PubMed  Google Scholar 

  270. Szabo G, Bala S (2013) MicroRNAs in liver disease. Nat Rev Gastroenterol Hepatol 10:542–552

    CAS  PubMed Central  PubMed  Google Scholar 

  271. Giri N, Tomar P, Karwasara VS, Pandey RS, Dixit VK (2011) Targeted novel surface-modified nanoparticles for interferon delivery for the treatment of hepatitis B. Acta Biochim Biophys Sin 43:877–883

    CAS  PubMed  Google Scholar 

  272. Rosen HR (2011) Chronic hepatitis C infection. N Engl J Med 364:2429–2438

    CAS  PubMed  Google Scholar 

  273. Poelstra K, Prakash J, Beljaars L (2012) Drug targeting to the diseased liver. J Control Release 161:188–197

    CAS  PubMed  Google Scholar 

  274. Jung J, Matsuzaki T, Tatematsu K, Okajima T, Tanizawa K, Kuroda S (2008) Bionanocapsule conjugated with liposomes for in vivo pinpoint delivery of various materials. J Control Release 126:255–264

    CAS  PubMed  Google Scholar 

  275. Liu L, Hitchens TK, Ye Q, Wu Y, Barbe B, Prior DE, Li WF, Yeh FC, Foley LM, Bain DJ, Ho C (2013) Decreased reticuloendothelial system clearance and increased blood half-life and immune cell labeling for nano and micron sized superparamagnetic iron-oxide particles upon pre-treatment with Intralipid. Biochim Biophys Acta 1830(6):3447–3453

    CAS  PubMed Central  PubMed  Google Scholar 

  276. Liu YJ, Chen ZJ, Zhang N (2011) Novel nanovectors as liver targeting MRI contrast agents. J Chin Pharmaceut Sci 20:105–117

    CAS  Google Scholar 

  277. Yasuharu O, Ishida H, Hayashi A, Kamagata S, Hirobe S, Ishii K (2002) The mean transit time and functional imagein asialoglycoprotein receptor scintigraphy: a novel modality for evaluating theregional dynamic function of hepatocytes. J Nucl Med 43:1611–1615

    Google Scholar 

  278. Ni HM, Williams JA, Yang H, Shi YH, Fan J, Ding WX (2012) Targeting autophagy for the treatment of liver diseases. Pharmacol Res 66:463–474

    CAS  PubMed Central  PubMed  Google Scholar 

  279. Stern ST, Adiseshaiah PP, Crist RM (2012) Autophagy and lysosomal dysfunction as emerging mechanisms of nanomaterial toxicity. Part Fibre Toxicol 9:20

    CAS  PubMed Central  PubMed  Google Scholar 

  280. Sano A, Taylor ME, Leaning MS, Summerfield JA (1990) Uptake and processing of glycoproteins by isolated rat hepatic endothelial and Kupffer cells. J Hepatol 10(2):211–216

    CAS  PubMed  Google Scholar 

  281. Opanasopit P, Nishikawa M, Yamashita F, Takakura Y, Hashida M (2001) Pharmacokinetic analysis of lectin-dependent biodistribution of fucosylated bovine serum albumin: a possible carrier for Kupffer cells. J Drug Target 9(5):341–351

    CAS  PubMed  Google Scholar 

  282. Ahmed SS, Muro H, Nishimura M, Kosugi I, Tsutsi Y, Shirasawa H (1995) Fc receptors in liver sinusoidal endothelial cells in NZB/WF1 lupus mice: a histological analysis using soluble immunoglobulin G-immune complexes and a monoclonal antibody (2.4G2). Hepatology 22(1):316–324

    CAS  PubMed  Google Scholar 

  283. Huang Z, Hoffmann FW, Fay JD, Hashimoto AC, Chapagain ML, Kaufusi PH, Hoffmann PR (2012) Stimulation of unprimed macrophages with immune complexes triggers a low output of nitric oxide by calcium-dependent neuronal nitric-oxide synthase. J Biol Chem 287(7):4492–4502

    CAS  PubMed Central  PubMed  Google Scholar 

  284. Terpstra V, van Amersfoort ES, van Velzen AG, Kuiper J, van Berkel TJC (2000) Hepatic and extrahepatic scavenger receptors function in relation to disease. Arterioscler Thromb Vasc Biol 20:1860–1872

    CAS  PubMed  Google Scholar 

  285. Van Oosten M, van de Bilt E, van Berkel TJ, Kuiper J (1998) New scavenger receptor-like receptors for the binding of lipopolysaccharide to liver endothelial and Kupffer cells. Infect Immun 66(11):5107–5112

    PubMed Central  PubMed  Google Scholar 

  286. Van Berkel TJ, De Rijke YB, Kruijt JK (1991) Different fate in vivo of oxidatively modified low density lipoprotein and acetylated low density lipoprotein in rats. Recognition by various scavenger receptors on Kupffer and endothelial liver cells. J Biol Chem 266(4):2282–2289

    PubMed  Google Scholar 

  287. Cardarelli PM, Blumenstock FA, McKeown-Longo PJ, Saba TM, Mazurkiewicz JE, Dias JA (1990) High-affinity binding of fibronectin to cultured Kupffer cells. J Leukoc Biol 48(5):426–437

    CAS  PubMed  Google Scholar 

  288. Hansen B, Arteta B, Smedsrød B (2002) The physiological scavenger receptor function of hepatic sinusoidal endothelial and Kupffer cells is independent of scavenger receptor class A type I and II. Mol Cell Biochem 240(1–2):1–8

    CAS  PubMed  Google Scholar 

  289. Li R, Oteiza A, Sorensen KK, McCourt P, Olsen R, Smedsrod B, Svistounov D (2011) Role of liver sinusoidal endothelial cells and stabilins in elimination of oxidized low-density lipoproteins. Am J Physiol Gastrointest Liver Physiol 300:G71–G81

    CAS  PubMed Central  PubMed  Google Scholar 

  290. Mousavi SA, Sporstol M, Fladeby C, Kjeken R, Barois N, Berg T (2007) Receptor-mediated endocytosis of immune complexes in rat liver sinusoidal endothelial cells is mediated by FcRIIb2. Hepatology 46(3):871–884

    CAS  PubMed  Google Scholar 

  291. Muro H, Shirasawa H, Kosugi I, Nakamura S (1993) Defect of Fc receptors and phenotypical changes in sinusoidal endothelial cells in human liver cirrhosis. Am J Pathol 143(1):105–120

    CAS  PubMed Central  PubMed  Google Scholar 

  292. McGary CT, Raja R, Weigel PH (1989) Endocytosis of hyaluronic acid by rat liver endothelial cells.evidence for receptor recycling. Biochem J 257(3):875

    CAS  PubMed Central  PubMed  Google Scholar 

  293. Stefanovic L, Stefanovic B (2012) Role of cytokine receptor-like factor 1 in hepatic stellate cells and fibrosis. World J Hepatol 4(12):356–364

    PubMed Central  PubMed  Google Scholar 

  294. March S, Graupera M, Sarrias MR, Lozano F, Pizcueta P, Bosch J, Engel P (2007) Identification and functional characterization of the hepatic stellate cell CD38 cell surface molecule. Am J Pathol 170(1):176–187

    CAS  PubMed Central  PubMed  Google Scholar 

  295. Bridle KR, Crawford DH, Rammer GA (2003) Identification and characterization of the hepatic stellate cell transferrin receptor. Am J Pathol 162(5):1661–1667

    CAS  PubMed Central  PubMed  Google Scholar 

  296. Olaso E, Ikeda K, Eng FJ, Xu L, Wang LH, Lin HC, Friedman SL (2001) DDR2 receptor promotes MMP-2-mediated proliferation and invasion by hepatic stellate cells. J Clin Invest 108(9):1369–1378

    CAS  PubMed Central  PubMed  Google Scholar 

  297. Leyland H, Gentry J, Arthur MJ, Benyon RC (1996) The plasminogen-activating system in hepatic stellate cells. Hepatology 24(5):1172–1178

    CAS  PubMed  Google Scholar 

  298. Zhang LP, Takahara T, Yata Y, Furui K, Jin B, Kawada N, Watanabe A (1999) Increased expression of plasminogen activator and plasminogen activator inhibitor during liver fibrogenesis of rats: role of stellate cells. J Hepatol 31(4):703–711

    CAS  PubMed  Google Scholar 

  299. Bataller R, Nicolas JM, Ginès P, Esteve A, Nieves Görbig M, Garcia-Ramallo E, Pinzani M, Ros J, Jiménez W, Thomas AP, Arroyo V, Rodes J (1997) Arginine vasopressin induces contraction and stimulates growth of cultured human hepatic stellate cells. Gastroenterology 113(2):615–624

    CAS  PubMed  Google Scholar 

  300. Hinglais N, Kazatchkine MD, Mandet C, Appay MD, Bariety J (1989) Human liver Kupffer cells express CR1, CR3, and CR4 complement receptor antigens. An immunohistochemical study. Lab Invest 61(5):509–514

    CAS  PubMed  Google Scholar 

  301. Yan J, Vetvicka V, Xia Y, Hanikyrova M, Mayadas TN, Ross GD (2000) Critical role of Kupffer cell CR3 (CD11b/rCD18) in the clearanceof IgM-opsonized erythrocytes or soluble b-glucan. Immunopharmacology 46:39–54

    CAS  PubMed  Google Scholar 

  302. Hirose S, Ise H, Uchiyama M, Cho CS, Akaike T (2001) Regulation of asialoglycoprotein receptor expression in the proliferative state of hepatocytes. Biochem Biophys Res Commun 287(3):675–681

    CAS  PubMed  Google Scholar 

  303. Gumpricht E, Dahl R, Devereaux MW, Sokol RJ (2005) Licorice compounds glycyrrhizin and 18β-glycyrrhetinic acid are potent modulators of bile acid-induced cytotoxicity in rat hepatocytes. J Biol Chem 280:10556–10563

    CAS  PubMed  Google Scholar 

  304. Shu Y, Xiao L, Zhao J, Zhu H, Zhou Z, Cheng N (1999) Change of high density lipoprotein receptor of hepatocyte during cholesterol gallstone formation in rabbit model. Hua Xi Yi Ke Da Xue Xue Bao 30(3):296–298

    CAS  PubMed  Google Scholar 

  305. Albecka A, Belouzard S, Op de Beeck A, Descamps V, Goueslain L, Bertrand-Michel J, Terce F, Duverlie G, Rouillé Y, Dubuisson J (2012) Role of low-density lipoprotein receptor in the hepatitis C virus life cycle. Hepatology 55(4):998–1007

    CAS  PubMed  Google Scholar 

  306. Molina S, Castet V, Fournier-Wirth C, Pichard-Garcia L, Avner R, Harats D, Roitelman J, Barbaras R, Graber P, Ghersa P, Smolarsky M, Funaro A, Malavasi F, Larrey D, Coste J, Fabre JM, Sa-Cunha A, Maurel P (2007) The low-density lipoprotein receptor plays a role in the infection of primary human hepatocytes by hepatitis C virus. J Hepatol 46(3):411–419

    CAS  PubMed  Google Scholar 

  307. Nenseter MS, Myklebost O, Blomhoff R, Drevon CA, Nilsson A, Norum KR, Berg T (1989) Low-density-lipoprotein receptors in different rabbit liver cells. Biochem J 261(2):587–593

    CAS  PubMed Central  PubMed  Google Scholar 

  308. Barth H, Cerino R, Arcuri M, Hoffmann M, Schürmann P, Adah MI, Gissler B, Zhao X, Ghisetti V, Lavezzo B, Blum HE, von Weizsäcker F, Vitelli A, Scarselli E, Baumert TF (2005) Scavenger receptor class B type I and hepatitis C virus infection of primary tupaia hepatocytes. J Virol 79(9):5774–5785

    CAS  PubMed Central  PubMed  Google Scholar 

  309. Hoekstra M, Van Berkel TJ, Van Eck M (2010) Scavenger receptor BI: a multi-purpose player in cholesterol and steroid metabolism. World J Gastroenterol 16(47):5916–5924

    CAS  PubMed Central  PubMed  Google Scholar 

  310. Akiko HK, Hiroshi S, Nobu A (1984) Increase of transferrin receptors in hepatocytes during rat liver regeneration. Int J Biochem 16(6):601–605

    Google Scholar 

  311. Kishimoto T, Tavassoli M (1986) Recovery of transferrin receptors on hepatocytes membrane after collagenase perfusion. Biochem Biophys Res Commun 134:711–715

    CAS  PubMed  Google Scholar 

  312. Rapisarda C, Puppi J, Hughes RD, Dhawan A, Farnaud S, Evans RW, Sharp PA (2010) Transferrin receptor 2 is crucial for iron sensing in human hepatocytes. Am J Physiol Gastrointest Liver Physiol 299:G778–G783

    CAS  PubMed Central  PubMed  Google Scholar 

  313. McClain DA, Olefsky JM (1988) Evidence for two independent pathways of insulin-receptor internalization in hepatocytes and hepatoma cells. Diabetes 37(6):806–815

    CAS  PubMed  Google Scholar 

  314. Michael MD, Kulkarni RN, Postic C, Previs SF, Shulman GI, Magnuson MA, Kahn CR (2000) Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction. Mol Cell 6(1):87–97

    CAS  PubMed  Google Scholar 

  315. Emmett DS, Feranchak A, Kilic G, Puljak L, Miller B, Dolovcak S, McWilliams R, Doctor RB, Fitz JG (2008) Characterization of ionotrophic purinergic receptors in hepatocytes. Hepatology 47(2):698–705

    CAS  PubMed  Google Scholar 

  316. Liu J, Zhou L, Xiong K, Godlewski G, Mukhopadhyay B, Tam J, Yin S, Gao P, Shan X, Pickel J, Bataller R, O’Hare J, Scherer T, Buettner C, Kunos G (2012) Hepatic cannabinoid receptor-1 mediates diet-induced insulin resistance via inhibition of insulin signaling and clearance in mice. Gastroenterology 142(5):1218–1228

    CAS  PubMed Central  PubMed  Google Scholar 

  317. Miyata R, Ueda M, Jinno H, Konno T, Ishihara K, Ando N, Kitagawa Y (2009) Selective targeting by preS1 domain of hepatitis B surface antigen conjugated with phosphorylcholine-based amphiphilic block copolymer micelles as a biocompatible, drug delivery carrier for treatment of human hepatocellular carcinoma with paclitaxel. Int J Cancer 124:2460

    CAS  PubMed  Google Scholar 

  318. Li C, Zhang D, Guo H, Hao L, Zheng D, Shen J, Tian X, Zhang Q (2013) Preparation and characterization of galactosylated bovine serum albumin nanoparticles for liver-targeted delivery of oridonin. Int J Pharm 448:79–86

    CAS  PubMed  Google Scholar 

  319. Bu L, Gan LC, Guo XQ, Chen FZ, Song Q, Gou XJ, Hou SX, Yao Q, Zhao Q (2013) Trans-resveratrol loaded chitosan nanoparticles modified with biotin and avidin to target hepatic carcinoma. Int J Pharm 452:355–362

    CAS  PubMed  Google Scholar 

  320. Li F, Sun JY, Wang JY, Du SL, Lu WY, Liu M, Xie C, Shi JY (2008) Effect of hepatocyte growth factor encapsulated in targeted liposomes on liver cirrhosis. J Control Release 131:77–82

    CAS  PubMed  Google Scholar 

  321. Li X, Wu Q, Chen Z, Gong X, Lin X (2008) Preparation, characterization and controlled release of liver-targeting nanoparticles from the amphiphilic random copolymer. Polymer 49:4769–4775

    CAS  Google Scholar 

  322. Hagens WI, Mattos A, Greupink R, de Jager-Krikken A, Reker-Smit C, van Loenen-Weemaes A, Gouw IA, Poelstra K, Beljaars L (2007) Targeting 15d-prostaglandin J2 to hepatic stellate cells: two options evaluated. Pharm Res 24:566

    CAS  PubMed Central  PubMed  Google Scholar 

  323. Mandal AK, Das S, BasuMK C, DasN RN (2007) Hepatoprotective activityof liposomal flavonoid against arsenite-induced liver fibrosis. J Pharmacol Exp Ther 320:994–1001

    CAS  PubMed  Google Scholar 

  324. Takei Y, Maruyama A, Ferdous A, Nishimura Y, Kawano S, Ikejima K, Okumura S, Asayama S, Nogawa M, Hashimoto M, Makino Y, Kinoshita M, Watanabe S, Akaike T, Lemasters JJ, Sato N (2004) Targeted gene delivery to sinusoidal endothelial cells: DNA nanoassociate bearing hyaluronan-glycocalyx. FASEB J 18(6):699–701

    CAS  PubMed  Google Scholar 

  325. Toriyabe N, Hayashi Y, Hyodo M, Harashima H (2011) Synthesis and evaluation of stearylated hyaluronic acid for the active delivery of liposomes to liver endothelial cells. Biol Pharm Bull 34:1084–1089

    CAS  PubMed  Google Scholar 

  326. Kim EM, Jeong HJ, Park IK, Cho CS, Kim CG, Bom HS (2005) Hepatocyte-targeted nuclear imaging using 99mTc-galactosylated chitosan: conjugation, targeting, and biodistribution. J Nucl Med 46:141–145

    PubMed  Google Scholar 

  327. Diebold SS, Plank C, Cotten M, Wagner E, Zenke M (2002) Mannose receptor-mediated gene delivery into antigen presenting dendritic cells. Somat Cell Mol Genet 27(1–6):65–74

    CAS  PubMed  Google Scholar 

  328. Wang HX, Xiong MH, Wang YC, Zhu J, Wang J (2013) N-acetylgalactosamine functionalized mixed micellar nanoparticles for targeted delivery of siRNA to liver. J Control Release 166:106–114

    CAS  PubMed  Google Scholar 

  329. Wang Y, Zhang X, Yu P, Li C (2013) Glycopolymer micelles with reducible ionic cores for hepatocytes-targeting delivery of DOX. Int J Pharm 441(1–2):170–180

    CAS  PubMed  Google Scholar 

  330. Díez S, Navarro G, de ILarduya CT (2009) In vivo targeted gene delivery by cationic nanoparticles for treatment of hepatocellular carcinoma. J Gene Med 11(1):38–45

    PubMed  Google Scholar 

  331. Singh KK, Vingkar SK (2008) Formulation, antimalarial activity and biodistribution of oral lipid nanoemulsion of primaquine. Int J Pharm 347(1–2):136–143

    CAS  PubMed  Google Scholar 

  332. Vyas SP, Sihorkar V (2000) Endogenous carriers and ligands in nonimmunogenic site-specific drug delivery. Adv Drug Deliv Rev 43(2–3):101–164

    CAS  PubMed  Google Scholar 

  333. Kim KS, Kim S, Beack S, Yang JA, Yun SH, Hahn SK (2012) In vivo real-time confocal microscopy for target-specific delivery of hyaluronic acid-quantum dot conjugates. Nanomedicine 8:1070–1073

    CAS  PubMed  Google Scholar 

  334. Kikkeri R, Lepenies B, Adibekian A, Laurino P, Seeberger PH (2009) In vitro imaging and in vivo liver targeting with carbohydrate capped quantum dots. J Am Chem Soc 131:2110–2112

    CAS  PubMed  Google Scholar 

  335. Park JO, Stephen Z, Sun C, Veiseh O, Kievit FM, Fang C, Leung M, Mok H, Zhang M (2011) Glypican-3 targeting of liver cancer cells using multifunctional nanoparticles. Mol Imaging 10(1):69–77

    CAS  PubMed Central  PubMed  Google Scholar 

  336. Kim EM, Jeong HJ, Kim SL, Sohn MH, Nah JW, Bom HS, Park IK, Cho CS (2006) Asialoglycoprotein-receptor-targeted hepatocyte imaging using 99mTc galactosylated chitosan. Nucl Med Biol 33:529–534

    CAS  PubMed  Google Scholar 

  337. Ocampo-García BE, Ramírez Fde M, Ferro-Flores G, De León-Rodríguez LM, Santos-Cuevas CL, Morales-Avila E, de Murphy CA, Pedraza-López M, Medina LA, Camacho-López MA (2011) 99mTc-labelled gold nanoparticles capped with HYNIC-peptide/mannose for sentinel lymph node detection. Nucl Med Biol 38(1):1–11

    PubMed  Google Scholar 

  338. Langereis S, de Lussanet QG, van Genderen MHP, Baces WH, Hackeng TM, van Engelshoven JM, Meijer EW (2004) Abstr Paper Am Chem Soc 228:U420–U420

    Google Scholar 

  339. Chen Z, Yu D, Wang S, Zhang N, Ma C, Lu Z (2009) Biocompatible nanocomplexes for molecular targeted MRI contrast agent. Nanoscale Res Lett 4:618–626

    CAS  PubMed Central  PubMed  Google Scholar 

  340. Yang SH, Heo D, Lee E, Kim E, Lim EK, Lee YH, Haam S, Suh JS, Huh YM, Yang J, Park SW (2013) Galactosylated manganese ferrite nanoparticles for targeted MR imaging of asialoglycoprotein receptor. Nanotechnology 24(47):475103

    PubMed  Google Scholar 

  341. Vu-Quang H, Yoo MK, Jeong HJ, Lee HJ, Muthiah M, Rhee JH, Lee JH, Cho CS, Jeong YY, Park IK (2011) Targeted delivery of mannan-coated superparamagnetic iron oxide nanoparticles to antigen-presenting cells for magnetic resonance-based diagnosis of metastatic lymph nodes in vivo. Acta Biomater 7(11):3935–3945

    CAS  PubMed  Google Scholar 

  342. Corbin IR, Li H, Chen J, Lund-Katz S, Zhou R, Glickson JD, Zheng G (2006) Low-density lipoprotein nanoparticles as magnetic resonance imaging contrast agents. Neoplasia 8(6):488–498

    CAS  PubMed Central  PubMed  Google Scholar 

  343. Barraud L, Merle P, Soma E, Lefrancois L, Guerret S, Chevallier M, Dubernet C, Couvreur P, Trépo C, Vitvitski L (2005) Increase of doxorubicin sensitivity by doxorubicin-loaded into nanoparticles for hepatocellular carcinoma cells in vitro and in vivo. J Hepatol 42:736–743

    CAS  PubMed  Google Scholar 

  344. Fu S, Naing A, Moulder SL, Culotta KS, Madoff DC, Ng CS, Madden TL, Falchook GS, Hong DS, Kurzrock R (2011) Phase I trial of hepatic arterial infusion of nanoparticle albumin–bound paclitaxel: toxicity, pharmacokinetics, and activity. Mol Cancer Ther 10:1300

    CAS  PubMed  Google Scholar 

  345. Wagner V, Dullaart A, Bock AK, Zweck A (2006) The emerging nanomedicine landscape. Nat Biotechnol 24:1211–1217

    CAS  PubMed  Google Scholar 

  346. Apostolov EO, Shah SV, Ray D, Basnakian AG (2009) Scavenger receptors of endothelial cells mediate the uptake and cellular proatherogenic effects of carbamylated LDL. Arterioscler Thromb Vasc Biol 29(10):1622–1630

    CAS  PubMed  Google Scholar 

  347. Chen ZJ, Yu DX, Liu CX, Yang XY, Zhang N, Ma CH, Song JB, Lu ZJ (2011) Gadolinium-conjugated PLA-PEG nanoparticles as liver targeted molecular MRI contrast agent. J Drug Target 19(8):657–665

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology (Elite status), Deemed University, Matunga, Mumbai, India

    Anisha A. D’Souza, Vishvesh M. Joshi & Padma V. Devarajan

Authors
  1. Anisha A. D’Souza
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vishvesh M. Joshi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Padma V. Devarajan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Padma V. Devarajan .

Editor information

Editors and Affiliations

  1. Institute of Chemical Technology, Department of Pharmaceutical Sciences and Technology, Mumbai, India

    Padma V. Devarajan

  2. National Institute of Pharmaceutical Education and Research (NIPER), Centre for Pharmaceutical Nanotechnology, Department of Pharmaceutics, Mohali, Punjab, India

    Sanyog Jain

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Controlled Release Society

About this chapter

Cite this chapter

D’Souza, A.A., Joshi, V.M., Devarajan, P.V. (2015). Hepatic Targeting: Physiological Basis and Design Strategy. In: Devarajan, P., Jain, S. (eds) Targeted Drug Delivery : Concepts and Design. Advances in Delivery Science and Technology. Springer, Cham. https://doi.org/10.1007/978-3-319-11355-5_6

Download citation

Publish with us

Policies and ethics

Search

Navigation