Drug Targeting Organ-Specific Strategies

843 Pulmonary Drug Delivery: Delivery To and Through the Lung

[6]Inhalation Aerosols: Physical and Biological Basis for Therapy (Ed. Hickey AJ). Marcel Dekker Inc., New York, 1996.

[7]In: Proceedings of the International Workshop on Aerosol Inhalation, Lung Transport, Deposition and the Relation to the Environment: Recent Research Frontiers, Warsaw, Poland, 14–16 September 1995 (Eds Marijnissen JCM, Grado’n L). Kluwer Academic Publishers, Dordrecht, 1996.

[8]Aerosol Technology: Properties, Behaviour, and Measurement of Airborne Particles (Ed. Hinds WC) John Wiley & Sons, New York, 1982.

[9]Ganderton D, Jones T, Drug Delivery to the Respiratory Tract. Ellis Horwood Ltd., Chichester,

1987.

[10]Patton JS, Adv. Drug Deliv. Rev. 1996, 19, 3–36.

[11]Wu-Pong S, Byron PR, Adv. Drug Deliv. Rev. 1996, 19, 47–71.

[12]Schulz H, Pharm. Sci. Technol. Today 1998, 1, 336–344.

[13]Li W-I, Perzl M, Ferron GA, Batycky R, Heyder J, Edwards DA, J. Aerosol Sci. 1998, 29, 995–1010.

[14]Ashurst I, Malton A, Prime D, Sumby B, Pharm. Sci. Technol. Today 2000, 3, 246–256.

[15]Yu J, Chien Y, Crit. Rev. Ther. Drug Carrier Syst. 1997, 14, 395–453.

[16]Niven RW, Crit. Rev. Ther. Drug Carrier Syst. 1995, 12, 151–231.

[17]Li W-I, Edwards DA, Adv. Drug Deliv. Rev. 1997, 26, 41–49.

[18]Morrow PE, Yu CP, In: Aerosols in Medicine: Principles, Diagnosis and Therapy (Eds Morén F, Newhouse M, Dolovich M), pp. 149–191. Elsevier Scientific Publishers, Biomedical Division, London, 1985.

[19]Martonen TB, Yang Y, Hwang D, Fleming JS, Comput. Biol. Med. 1995, 25, 431–446.

[20]Weibel ER, Morphometry of the Human Lung. Springer Verlag, Berlin, 1963.

[21]Netter FH, In: Respiratory System: A Compilation of Paintings Depicting Anatomy and Embryology, Physiology, Pathology, Pathophysiology, and Clinical Features and Treatment of Diseases

(Eds Divertie MB, Brass A), pp. 46–59. CIBA Pharmaceutical Company, Summit, NJ, 1980.

[22]de Boer AH, Winter HMI, Lerk CF, Int. J. Pharm. 1996, 130, 231–244.

[23]Newman SP, Deposition and Effects of Inhalation Aerosols, ISBN: 91-86058-03-07, AB DRACO, Lund, 1983.

[24]Staniforth JN, Int. Patent Publication: WO97/03649, 1997.

[25]Timsina MP, Martin GP, Marriott C, Ganderton D, Yianneskis M, Int. J. Pharm. 1994, 101, 1–13.

[26]Kirk WF, Pharm. Int. 1986, 7, 150–154.

[27]Byron PR, Drug Develop. Ind. Pharm. 1986, 12, 993–1015.

[28]Moren F, Drug Develop. Ind. Pharm. 1987, 13, 695–728.

[29]Jackson WF, Inhalers in Asthma: The New Perspective, ISBN: 1-899520-02-3, Astra Draco AB, Lund, 1995.

[30]Newman SP, Pavia D, In: Aerosols in Medicine: Principles, Diagnosis and Therapy (Eds Morén F, Newhouse MT, Dolovich MB), pp. 193–218. Elsevier Scientific Publishers, Biomedical Division, London, 1985.

[31]Morén F, Andersson J, Int. J. Pharm. 1980, 6, 295–300.

[32]Adjei AL, In: Inhalation Delivery of Therapeutic Peptides and Proteins (Eds Adjei AL, Gupta PK), pp. 771–814. Marcel Dekker Inc., New York, 1997.

[33]Niven RW, Lott FD, Yp AY, Cribbs JM, Pharm. Res. 1994, 11, 1101–1109.

[34]Forbes B, Pharm. Sci. Technol. Today 2000, 3, 18–27.

[35]Forbes B, Wilson CG, Gumbleton M, Int. J. Pharm. 1999, 180, 225–234.

[36]Elbert KJ, Schäfer UF, Schäfers H-J, Kim K-J, Lee VHL, Lehr C-M, Pharm. Res. 1999, 16, 601–608.

[37]Lehr C-M, J. Control. Rel. 2000, 65, 19–29.

[38]Shen Z, Zhang Q, Wei S, Nagai T, Int. J. Pharm. 1999, 192, 115–121.

[39]Suzuki M, Machida M, Adachi K, Otabe K, Sugimoto T, Hayashi M, Awazu S, J. Toxicol. Sci. 2000, 25, 49–55.

[40]Gonda I, Schuster JA, Rubsamen RM, Lloyd P, Cipolla D, Farr SJ, J. Control. Rel. 1998, 53, 269–274.

[41]Rubsamen R, In: Inhalation Delivery of Therapeutic Peptides and Proteins (Eds Adjei AL, Gupta PK), pp. 703–731. Marcel Dekker Inc., New York, 1997.

[42]Newman SP, Nebulizer Therapy: Scientific and Technical Aspects. AB DRACO, Lund, 1989.

[43]Le Brun PPH, de Boer AH, Heijerman HGM, Frijlink HW, Pharm. World Sci. 2000, 22, 75–81.

[44]McCallion ONM, Taylor KMG, Bridges PA, Thomas M, Taylor AJ, Int. J. Pharm. 1996, 130, 1–11.

References 85

[45]Niven RW, Brain JD, Int. J. Pharm. 1994, 104, 73–85.

[46]Le Brun PPH, de Boer AH, Gjaltema D, Hagedoorn P, Heijerman HGM, Frijlink HW, Int. J.

Pharm. 1999, 189, 205–214.

[47]O’Callaghan C, Barry PW, Thorax 1997, 52, S31–S44.

[48]Denyer J, Nikander K, In: Proceedings of Respiratory Drug Delivery VI (Hilton Head, SC), pp. 311–314. Interpharm Press, Buffalo Grove, IL, 1998.

[49]Bridges PA, Taylor KMG, Int. J. Pharm. 1998, 173, 117–125.

[50]Vervaet C, Byron PR, Int. J. Pharm. 1999, 186, 13–30.

[51]Brambilla G, Ganderton D, Garzia R, Lewis D, Meakin B, Ventura P, Int. J. Pharm. 1999, 186, 53–61.

[52]Keller M, Int. J. Pharm. 1999, 186, 81–90.

[53]Malcolmson RJ, Embleton JK, Pharm. Sci. Technol. Today 1998, 1, 394–398.

[54]Reiners M, Stang N, Wolf-Heuss E, In: Respiratory Drug Delivery VII (Eds Dalby RN, Byron PR, Farr SJ, Peart J), pp. 333–336. Serentec Press, Raleigh, 2000.

[55]de Boer AH, Hagedoorn P, Gjaltema D, Eur. Respir. J. 1997, 10, 236S–236S.

[56]Newman SP, Pellow PGD, Clarke SW, Atomiz. Spray Technol. 1987, 3, 1–11.

[57]McCallion ONM, Taylor KMG, Thomas M, Taylor AJ, Pharm. Res. 1995, 12, 1682–1688.

[58]Le Brun PPH, de Boer AH, Gjaltema D, Hagedoorn P, Heijerman HGM, Frijlink HW, Int. J. Pharm. 1999, 189, 215–225.

[59]Boucher RMG, Kreuter J, Ann. Allergy 1968, 26, 591–600.

[60]McCallion ONM, Taylor KMG, Thomas M, Taylor AJ, Int. J. Pharm. 1996, 129, 123–136.

[61]Staniforth JN, In: Respiratory Drug Delivery V: Program and Proceedings. Proceedings of the

Symposium on Respiratory Drug Delivery, Phoenix, Arizona, 28 April–2 May 1996 (Eds Dalby RN, Byron PR, Farr SJ), pp. 65–73. Interpharm Press, Buffalo Grove, 1996.

[62]Hickey AJ, Concessio NM, Adv. Drug Deliv. Rev. 1997, 26, 29–40.

[63]Buckton G, Adv. Drug Deliv. Rev. 1997, 26, 17–27.

[64]Buckton G, Choularton A, Breezer AE, Chatham SM, Int. J. Pharm. 1988, 47, 121–128.

[65]Johnson KA, Adv. Drug Deliv. Rev. 1997, 26, 3–15.

[66]Boerefijn R, Ning Z, Ghadiri M, Int. J. Pharm. 1998, 172, 199–209.

[67]Concessio NM, VanOort MM, Knowles MR, Hickey AJ, Pharm. Res. 1999, 16, 828–834.

[68]Larhrib H, Zeng XM, Martin GP, Marriott C, Pritchard J, Int. J. Pharm. 1999, 191, 1–14.

[69]Zeng XM, Martin GP, Marriott C, Pritchard J, Int. J. Pharm. 2000, 200, 93–106.

[70]Kawashima Y, Serigano T, Hino T, Yamamoto H, Takeuchi H, Int. J. Pharm. 1998, 172, 179–188.

[71]Shekunov BY, York P, J. Crystal Growth 2000, 211, 122–136.

[72]York P, Hanna M, In: Respiratory Drug Delivery V: Program and Proceedings. Proceedings of the Symposium on Respiratory Drug Delivery, Phoenix, Arizona, 28 April–2 May 1996 (Eds Dalby RN, Byron PR, Farr SJ), pp. 231–239. Interpharm Press, Buffallo Grove, 1996.

[73]Byron PR, Naini V, Philips EM, In: Respiratory Drug Delivery V: Program and Proceedings. Proceedings of the Symposium on Respiratory Drug Delivery, Phoenix, Arizona, 28 April–2 May 1996

(Eds Dalby RN, Byron PR, Farr SJ), pp. 103–111. Interpharm Press, Buffalo Grove, 1996.

[74]Adjei AL and Gupta PK, In: Inhalation Delivery of Therapeutic Peptides and Proteins (Eds Adjei AL, Gupta PK), pp. 625–665. Marcel Dekker Inc., New York, 1997.

[75]Lucas P, Anderson K, Staniforth JN, Pharm. Res. 1998, 15, 562–569.

[76]Maa Y-F, Nguyen P-A, Sweeney T, Shire SJ, Hsu CC, Pharm. Res. 1999, 16, 249–254.

[77]Wang W, Int. J. Pharm. 2000, 203, 1–60.

[78]Wang W, Int. J. Pharm. 1999, 185, 129–188.

[79]Wong D, Parasrampuria J, Pharm. Technol. 1997, 21, 34–50.

[80]Andya JD, Maa Y-F, Costantino HR, Nguyen P-A, Dasovich N, Sweeney TD, Hsu CC, Shire SJ,

Pharm. Res. 1999, 16, 350–358.

[81]Costantino HR, Carrasquillo KG, Cordero RA, Mumenthaler M, Hsu CC, Griebenow K, J. Pharm. Sci. 1998, 87, 1412–1420.

[82]Won CM, Molnar TE, McKean RE, Spenlehauer GA, Int. J. Pharm. 1998, 167, 25–36.

[83]Fox KC, Science 1995, 267, 1922–1923.

[84]Levine H, Slade L, Cryo-letters 1988, 9, 21–63.

[85]Angell CA, Science 1995, 267, 1924–1935.

[86]Chan H-K, Clark A, Gonda I, Mumenthaler M, Hsu C, Pharm. Res. 1997, 14, 431–437.

[87]Vanbever R, Mintzes JD, Wang J, Nice J, Chen D, Batycky R, Langer R, Edwards DA, Pharm. Res. 1999, 16, 1735–1742.

[88]Edwards DA, Ben-Jebria A, Langer R, J. Appl. Physiol. 1998, 85, 379–385.

863 Pulmonary Drug Delivery: Delivery To and Through the Lung

[89]Vanbever R, Ben-Jebria A, Mintzes JD, Langer R, Edwards DA, Drug Develop. Res. 1999, 48, 178–185.

[90]Ben-Jebria A, Chen D, Eskew ML, Vanbever R, Langer R, Edwards DA, Pharm. Res. 1999, 16, 555–561.

[91]Pillai RS, Yeates DB, Miller IF, Hickey AJ, J. Appl. Physiol. 1998, 84, 717–725.

[92]El-Baseir MM, Kellaway IW, Int. J. Pharm. 1998, 175, 135–145.

[93]Talton J, Fitz-Gerald J, Rajiv Singh, Hochhaus G, In: Respiratory Drug Delivery VII (Eds Dalby RN, Byron PR, Farr SJ, Peart J), pp. 67–81. Serentec Press, Raleigh, 2000.

[94]McAllister SM, Alpar HO, Teitelbaum Z, Bennet DB, Adv. Drug Deliv. Rev. 1996, 19, 89–110.

[95]Niven RW, Prestrelski SJ, Treuheit MJ, Ip AY, Arakawa T, Int. J. Pharm. 1996, 127, 191–201.

[96]Ip AY, Arakawa T, Silvers H, Ransone CM, Niven RW, J. Pharm. Sci. 1995, 84, 1210–1214.

[97]Williams RO, III, Liu J, Pharm. Res. 1997, 14, S634.

[98]Quinn EA, Forbes RT, Williams AC, Oliver MJ, McKenzie L, Purewal TS, Int. J. Pharm. 1999, 186, 31–41.

[99]Olsson B, Asking L, J. Aerosol Med. Deposition Clear. Eff. Lung 1994, 7, 201–204.

[100]Clark AR, Hollingworth AM, J. Aerosol Med. 1993, 6, 99–110.

[101]Svartengren K, Lindestad P, Svartengren M, Philipson K, Bylin G, Camner P, Am. J. Respir. Crit. Care Med. 1995, 152, 32–37.

[102]Brown PH, Ning ACWS, Greening AP, McLean A, Crompton GK, Eur. Respir. J. 1995, 8, 1940–1941.

[103]Meijer RJ, van der Mark ThW, Aalders BJ, Postma DS, Koëter GH, Thorax 1996, 51, 433–434.

[104]de Koning JP, van der Mark ThW, Rutgers SR, Coenegracht PMJ, Lerk CF, Am. J. Respir. Crit.

Care Med. 1998, 157, A635.

[105]Timsina M, Martin GP, Marriott C, Ganderton D, Lee KC, Suen KO, Yianneskis M, J. Aerosol Med. 1993, 6, 41.

[106]Sarinas PSA, Robinson TE, Clark AR, Canfield J, Chitkara RK, Fick Jr RB, Chest 1998, 114, 988–992.

[107]Engel T, Heinig JH, Madsen F, Nikander K, Eur. Respir. J. 1990, 3, 1037–1041.

[108]Newman SP, Morén F, Trofast E, Talaee N, Clarke SW, Eur. Respir. J. 1989, 2, 247–252.

[109]de Boer AH, Hagedoorn P, Gjaltema D, Eur. Respir. J. 1996, 23 (Suppl.), 206S.

[110]Olsson B, J. Aerosol Med. Deposition Clear. Eff. Lung 1995, 8, S13–S19.

[111]Ross DL, Schultz RK, J. Aerosol Med. Deposition Clear. Eff. Lung 1996, 9, 215–226.

[112]Prime D, Grant AC, Slater AL, Woodhouse RN, J. Aerosol Med. Deposition Clear. Eff. Lung

1999, 12, 75–84.

[113]de Boer AH, Bolhuis GK, Gjaltema D, Hagedoorn P, Int. J. Pharm. 1997, 153, 67–77.

[114]Everard ML, Devadason SG, Le Souëf PN, Respir. Med. 1997, 91, 624–628.

[115]Bonfig KW, Technische Durchflussmessung: mit Besonderer Berücksichtigung Neuartiger Durchflussmessverfahren. Vulkan-Verlag, Essen, 1977.

[116]Sullivan WJ, Peters GM, Enright PL, Respir. Care 1984, 29, 736–749.

[117]Holmann JCh, Schibler A, Kraemer R, Schweiz. Med. Wochenschr. 1989, 119, 1713–1718.

[118]Kreit JW, Sciurba FC, Am. J. Respir. Crit. Care Med. 1996, 154, 913–917.

[119]Perry RH, Chilton CH, Chemical Engineers’ Handbook. McGraw-Hill, New York, 1973.

[120]John W, J. Aerosol Sci. 1999, 30, 1317–1320.

[121]Physical tests and determinations on aerosols. In: United States Pharmacopoeia XXII, NF XVII,

Ninth Supplement, pp. 3584–3591, 1993.

[122]Preparations for inhalation: aerodynamic assessment of fine particles. In: European Pharmacopoeia, pp. 143–152. European Pharmacopoeia, Strasbourg, 1997.

[123]Asking L, Olsson B, Aerosol Sci. Technol. 1997, 27, 39–49.

[124]Müller RH, Schumann R, Teilchengrössenmessung in der Labor Praxis (Paperback APV). Wissenschaftliche Verlagsgesellschaft GmbH, Stuttgart, 1996.

[125]Heuer M, Leschonski K, Part. Charact. 1985, 2, 7–13.

[126]de Boer AH, Gjaltema D, Witt W, Frijlink HW, In: Respiratory Drug Delivery VII (Eds Dalby RN, Byron PR, Farr SJ, Peart J), pp. 585–587. Serentec Press, Raleigh, 2000.

[127]Le Brun PPH, de Boer AH, Gjaltema D, Hagedoorn P, Heijerman HGM, Frijlink HW, Int. J.

Pharm. 1999, 189, 205–214.

[128]Tzou T-Z, Int. J. Pharm. 1999, 186, 71–79.

[129]Stein SW, Int. J. Pharm. 1999, 186, 43–52.

[130]Bell JH, Brown K, Glasby J, J. Pharm. Pharmacol. 1973, 25, 32P–36P.

[131]Newman SP, Clarke SW, Chest 1993, 103, 1442–1446.

References 87

[132]Newman SP, Weisz AWB, Talaee N, Clarke SW, Thorax 1991, 46, 712–716.

[133]Leach CL, Respir. Med. 1998, 92, 3–8.

[134]Conway JH, Walker P, Eur. Respir. J. 1999, 14, 196s.

[135]Pauwels R, Newman S, Borgström L, Eur. Respir. J. 1997, 10, 2127–2138.

[136]Selroos O, Pietinalho A, Riska H, Clin. Immunother. 1996, 6, 273–299.

[137]Newman SP, Pitcairn GR, Hirst PH, Bacon RE, O’Keefe E, Reiners M, Hermann R, Eur. Respir. J. 2000, 16, 178–183.

[138]Griesenbach U, Chonn A, Cassady R, Hannam V, Ackerley C, Post M, Tanswell AK, Olek K, O’Brodovich H, Tsui L-C, Gene Ther. 1998, 5, 181–188.

[139]Kukowska–Latallo JF, Raczka E, Quintana A, Chen C, Rymaszewski M, Baker Jr JR, Hum Gene Ther. 2000, 11, 1385–1395.

[140]Orson FM, Kinsey BM, Hua PJ, Bhogal BS, Densmore CL, Barry MA, J. Immunol. 2000, 164, 6313–6321.

[141]Tyler RC, Fagan KA, Unfer RC, Gorman C, McClarrion M, Bullock C, Rodman DM, Am. J. Physiol. 1999, 277, L1199–L1204.

[142]Li S, Tan Y, Viroonchatapan E, Pitt BR, Huang L, Am. J. Physiol. Lung Cell. Mol. Physiol. 2000, 278, L504–L511.

[143]Christofidou-Solomidou M, Pietra GG, Solomides CC, Arguiris E, Harshaw D, Fitzgerald GA, Albelda SM, Muzykantov VR, Am. J. Physiol. Lung Cell. Mol. Physiol. 2000, 278, L794–L805.

[144]Olsson B, Asking L, J. Aerosol Med. 1994, 7, S43–S47.

[145]de Boer AH, In: Proceedings of The Second Annual Henry Stewart Update on Understanding Equivalence Testing for Inhaled Drugs, London, 22–23 June 1998, Russell House Publ., London,

1998.

Drug Targeting Organ-Specific Strategies. Edited by G. Molema, D. K. F. Meijer Copyright © 2001 Wiley-VCH Verlag GmbH ISBNs: 3-527-29989-0 (Hardcover); 3-527-60006-X (Electronic)

4Cell Specific Delivery of Anti-Inflammatory Drugs to Hepatic Endothelial and Kupffer Cells for the Treatment of Inflammatory Liver Diseases

Barbro N. Melgert, Leonie Beljaars, Dirk K. F. Meijer, Klaas Poelstra

4.1 Introduction

Fibrosis or scarring of the liver occurs after damage to liver tissue. Most chronic liver diseases eventually result in excess scarring leading to liver cirrhosis. This fatal disease, to date, can only be effectively treated with a liver transplantation. Since this is a costly procedure, hampered by the lack of donor organs among other technical factors, much effort has been put into developing new drugs. The drugs available are not sufficiently effective and/or cause too many adverse side-effects. Therefore drug targeting is an option in trying to maximize efficacy and minimize adverse drug reactions.

Chronic liver diseases are characterized by an inflammatory and a fibrotic component, both of which can be targets for pharmacological intervention. This chapter focuses on the treatment of liver fibrosis through the targeting of anti-inflammatory drugs. The target cells within the liver for anti-inflammatory treatment and possible entry mechanisms in these target cells will be identified. In addition, the different drug carriers and drug targeting preparations will be reviewed.

Since drug targeting implies the manipulation of drug distribution in the whole body, emphasis should be put on in vivo studies. In contrast to in vitro studies, studies in the intact organism will provide more definite insight into the cell specificity of carrier systems, the potential toxicity, immunogenicity, and the ability of the carrier system to pass anatomical barriers en route to the target cells. Moreover, it is of the utmost importance that these parameters are also studied in the diseased state, since the targeting potential of carriers can change dramatically under pathological conditions. In vitro studies with various liver preparations can be used to study endocytosis, carrier degradation and intracellular release of the targeted drug in more detail. In addition, the concept of drug targeting should also be tested in human tissue. Possibilities to include early (kinetic) screening in human tissue will also be discussed in this chapter.

4.2 The Liver

At the crossroads between the digestive tract and the rest of the body resides the largest solid organ of the body: the liver. Because of its interposition, the liver has a dual blood supply.

90 4 Cell Specific Delivery of Anti-Inflammatory Drugs to Hepatic Cells

Nutrient-rich blood arrives through the portal vein and oxygen-rich blood through the hepatic artery. Together these channels import a large variety of endobiotics and xenobiotics, ranging from nutrients to toxic substances derived from the digestive system. The main function of the liver, therefore, is to maintain the body’s metabolic homeostasis. This includes the efficient uptake of amino acids, carbohydrates, lipids and vitamins and their subsequent storage, metabolic conversion, and release into blood and bile; synthesis of serum proteins; hepatic biotransformation of circulating compounds, a process which converts hydrophobic substances into water-soluble derivatives that can be secreted into bile or urine, as well as phagocytosis of foreign macromolecules and particles such as bacteria.

Classically the liver has been divided into hexagonal lobules centred around the terminal hepatic venules. Blood enters the liver through the portal tracts that are situated at the corners of the hexagon. The portal tracts are triads of a portal vein, an hepatic artery, and a common hepatic bile duct. The vast expanse of hepatic tissue, mostly consisting of parenchymal cells (PC) or hepatocytes, is serviced via terminal branches of the portal vein and hepatic artery, which enters the tissue at intervals.The hepatocytes are organized into cords of cells radially disposed about the central hepatic venule. Between these cords are vascular sinusoids that transport the blood to the central hepatic venules. The blood is collected through the hepatic venules into the hepatic vein which exits the liver into the inferior vena cava (Figure 4.1).

Figure 4.1. Schematic representation of the architecture of the liver. Blood enters the liver through the portal vein (PV) and hepatic arteries (HA), flows through the sinusoids, and leaves the liver again via the central vein (CV). KC, Kupffer cells; SEC, sinusoidal endothelial cells; HSC, hepatic stellate cells; BD, bile duct. Modified from reference 98.

4.2 The Liver

91

The sinusoids are lined by the discontinuous and fenestrated sinusoidal endothelial cells (SEC) that demarcate the extrasinusoidal space of Disse. The abundant microvilli of the hepatocytes protrude into this space, which also contains the fat-containing lipocyte or hepatic stellate cell (HSC). At a strategic position along the luminal side of the endothelial cells are the resident tissue macrophages, the Kupffer cells (KC). Also located on the endothelial lining are the Pit cells, that correspond to large granular lymphocytes with natural killer activity. Between the abutting hepatocytes are bile canaliculi: channels in between the plasma membranes of facing hepatocytes, that are delineated from the vascular space by tight junctions. These intercellular spaces constitute the outermost reaches of the biliary tree. The canaliculi emanate from the centrilobular regions, progressively drain into the canals of Hering at the fringes of the portal tracts, and biliary fluid finally collects in the interlobular bile ducts.

4.2.1 The Parenchymal Cell (PC)

The liver consists mainly of parenchymal cells, or hepatocytes. Most drug-targeting preparations designed for liver targeting of therapeutic compounds are directed towards this cell type, generally aiming at the asialoglycoprotein receptor using galactose residues coupled to a core molecule for binding. This chapter, however, will not discuss this type of targeting, but further information can be found in several reviews [1–3].

Hepatocytes make up 60–70% of the total number of liver cells. They have a well-orga- nized intracellular structure with huge numbers of cell organelles to maintain the high metabolic profile. At the apical side or canalicular membrane the cell is specialized for the secretion of bile components. There are several ATP-dependent transport carriers located on this side of the membrane, which transport bile salts, lipids and xenobiotics into the canaliculus. On the sinusoidal side, the cells specialize in uptake and secretion of a wide variety of components.To increase the surface of the membrane for this exchange with the bloodstream, the sinusoidal domain of the membrane is equipped with irregular microvilli. The microvilli are embedded into the fluid and matrix components of the space of Disse and are in close contact with the sinusoidal blood because of the discontinuous and fenestrated SECs. To facilitate its metabolic functions numerous membrane transport mechanisms and receptors are situated in the membrane.

4.2.2 The Sinusoidal Endothelial Cell (SEC)

The endothelial lining of the sinusoids in the liver differs from the other capillaries in the body and is adapted to form a selective barrier between blood and hepatocytes. The basement membrane is composed of non-fibril-forming collagens including types IV,VI and XIV, glycoproteins and proteoglycans. The lining is discontinuous and the SECs are perforated by numerous fenestrae that lack diaphragms. This allows direct contact of the hepatocytes with most plasma proteins in the space of Disse, but prevents direct contact with blood cells, large chylomicrons, bacteria and viruses. SECs play an important role in the pathogenesis of sev-

92 4 Cell Specific Delivery of Anti-Inflammatory Drugs to Hepatic Cells

eral acute and chronic inflammatory liver diseases. Consequently they are attractive target cells for anti-inflammatory therapies.

The SECs account for 20% of all liver cells and are the first cells, together with the KCs, to encounter potentially harmful materials present in the portal blood. They are therefore equipped with scavenger capabilities and certain defence mechanisms to prevent damage to other cell types. The SECs have an active scavenging system for the majority of physiological and foreign soluble (waste) macromolecules [4,5]. Clearance mechanisms include receptormediated endocytosis, transcytosis, and phagocytosis. To regain local homeostasis after ingestion of injurious substances and after other detrimental events, the SECs can also produce cytokines, eicosanoids, and adhesion molecules for the mobilization of other hepatic cell types and cells of the immune system.

4.2.2.1 Receptor-mediated Endocytosis

Targeting to SECs should be directed at specific receptors present on this cell type. A wide range of proteins and other molecules can be taken up by SECs through receptor-mediated endocytosis. For example, SECs play an important role in the uptake of degradation products of the extracellular matrix. For this purpose they have hyaluronan [6], (pro)collagen, and fibronectin receptors [7]. The first two receptors are uniquely located on SECs. Elevated levels of serum hyaluronan and fibronectin, that are often found in liver disease [8], are usually the result of dysfunction of the clearance capacity of SECs combined with an increased production by HSCs [9].

Scavenger receptors on the SECs are instrumental in another important endocytic mechanism.They recognize and endocytose modified proteins that have a high net negative charge [9]. SECs predominantly express two types of scavenger receptors: the class AI and the class AII scavenger receptor [10]. Physiological substrates for these receptors were found to be the N-terminal propeptides of types I and III procollagen [11] and the lipid A moiety of endotoxin [12]. Most studies, however, have used non-physiological substrates such as nega- tively-charged albumins [13] and acetylated low-density lipoproteins (LDL) [14] to characterize these receptors.Yet, the binding of both physiological and non-physiological substrates is Ca2+-independent and is followed by rapid endocytosis and degradation in lysosomes.

The SECs are further equipped with a receptor that specifically interacts with mannoseand N-acetylglucosamine-terminated glycoproteins. Unlike the scavenger receptor, binding of ligands to this so-called mannose receptor is Ca2+-dependent, but is also followed by rapid endocytosis and degradation in lysosomes [15]. The receptor is thought to be involved in the uptake of micoorganisms like yeasts, bacteria, and parasites [16], but has also been shown to be involved in the uptake of tissue-type plasminogen activator [17]. In addition, the receptor is involved in antigen uptake for subsequent antigen presentation [18]. This indicates that SECs may also be involved in cell-mediated immune responses in the liver.

Other uptake-linked receptors found on the SECs are the Fc receptor for the uptake of immunoglobulins [19], the CD14 receptor for the binding of lipopolysaccharide (LPS) bound to LPS binding protein [20], the platelet derived growth factor AA receptor [21] and the glucagon receptor [22].

4.2 The Liver

93

4.2.2.2 Phagocytosis and Transcytosis

SECs are normally able to internalize only small particles (up to 0.23 µm). In conditions of impaired KC function, however, they have also been found to phagocytose larger particles [23]. They are also responsible for the receptor-mediated transcytosis of several compounds, such as insulin [24] and transferrin [25].

4.2.2.3 Regulation of the Inflammatory Process by SECs

Exposure of the SECs to pathogens or cytokines produced by other cells during stress induces activation of the SECs and subsequent production of cytokines, eicosanoids, and/or adhesion molecules. For instance, after activation with LPS, a main component of the walls of gramnegative bacteria and a major inducer of inflammation and non-specific immune functions [20], SECs produce a number of proand anti-inflammatory cytokines. Pro-inflammatory cytokines shown to be produced were: tumour necrosis factor alpha (TNFα) [26]; interleukin-1 alpha/beta(IL-1α/β) [27]; the major inducer of acute phase proteins interleukin-6 (IL-6) [28]; and the neutrophil chemo-attractant interleukin-8 (IL-8) [29]. Anti-inflammatory cytokines shown to be produced were: interleukin-10 (IL-10) [27] and hepatocyte growth factor (HGF) [30].

Eicosanoids are the oxidative metabolites derived from the cell membrane component arachidonic acid. Arachidonic acid is released from the cell membrane by phospholipase A2 and enzymatically converted to either prostaglandins (PGs) by cyclo-oxygenase or leukotrienes (LTs) by lipoxygenase. Eicosanoids is the collective name of prostaglandins and leukotrienes. SECs and KCs are the major sources of eicosanoids, whereas the PCs are considered to be the most important target cells for them. The main eicosanoid produced by SECs was found to be PGE2 [31], although PGD2 has also been reported to be a major product [32]. The type of PG released may be a result of the difference in the induction stimulus used. Eicosanoid production is induced by many circulating substances; LPS, interferon gamma (IFNγ), TNFα, and platelet activating factor (PAF). PGE2 is postulated to be involved in liver regeneration [33] and inhibition of hormone-stimulated glycogenolysis [31], PGD2 was found to induce glycogenolysis [34].

SECs, like the vascular endothelium, play an active part in the control of leucocyte recruitment in cases of acute and chronic inflammatory conditions. Leucocyte recruitment from the blood compartment is a crucial determinant for the induction of immunity and inflammation. SECs control this process by producing cytokines that activate leucocytes and by expressing adhesion molecules. Under inflammatory conditions upregulation of intracellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) was found [35;36], as well as expression of E-selectin and P-selectin [37]. Together with the expression of CD4 on SECs it has been postulated that these adhesion molecules might also be involved in the adhesion of KC cells to the sinusoidal wall [20].

4.2.3 The Kupffer Cell (KC)

Kupffer cells are the largest reservoir of fixed-tissue macrophages and are quantitatively the most important cell type for the removal of circulating microorganisms, LPS, tumour cells,

94 4 Cell Specific Delivery of Anti-Inflammatory Drugs to Hepatic Cells

immune complexes, and other circulating tissue and microbial debris [38]. They account for about 15% of the liver cell population in number and they are preferentially located in the periportal areas [39].

4.2.3.1 Receptor-mediated Endocytosis

Similar to the targeting of compounds to SECs, drug targeting preparations designed to modify KC functions have to be directed at KC-specific receptors. KCs are able to remove numerous soluble and particulate substances from the circulation and they possess many receptor systems that mediate this clearance, some of which have also been described for SECs. Like SECs, they possess fibronectin receptors, mannose receptors, Fc receptors, CD14 receptors, and the scavenger receptors class AI and AII [40]. In addition to these receptors, KCs also possess the novel member of the class A scavenger receptor family, the macrophage receptor with collagenous structure (MARCO) [41]. Besides these types of scavenger receptors, they also have macrosialin scavenger receptors for the uptake of oxidized LDL [10] and scavenger receptors class BI for the removal of high-density lipoproteins (HDL) [42]. For the uptake of unmodified LDL, KCs also have special LDL receptors [43].

Mannose receptors on KCs essentially recognize the same molecules as the mannose receptors present on SECs, but they exhibit different kinetics [44]. Besides the mannose receptors, KCs have two other carbohydrate-specific receptors. One is the galactose particle receptor, recognizing galactose-terminated oligosaccharides on particles and mediating endocytosis of desialylated erythrocytes [45]. The other is the fucose receptor which interacts not only with fucose-terminated glycoproteins, but also with galactose-exposing neoglycoproteins [46].

KCs also possess receptors for the complement components C1q and C3b [47;48]. The complement system is one of the main defence mechanisms of the body against invading pathogens. It is composed of a group of serum proteins that are part of a multienzymatic cascade. Activation of complement generates membranolytic components and protein fragments that enhance phagocytosis and mediate immune responses. KCs have the optimal capacity to remove complexes coated with complement from the circulation.

4.2.3.2 Phagocytosis

Not all KCs are phagocytic to the same extent; periportal KCs generally have a higher level of phagocytic activity than those in other regions of the liver [49]. Prior to phagocytosis, particulate material like viruses, bacteria and erythrocytes may be opsonized and bound by specific receptors, but this is not essential for phagocytosis [50].

4.2.3.3 Regulation of the Inflammatory Process by the KC

As is the case for SECs, endocytosis of substances represents more than just circulatory clearance mechanisms. The uptake of potentially toxic material can activate KCs to function as ei-