Drug delivery to the lymphatic system

Critical Reviews in Therapeutic Drug Carrier Systems

Volumn 14, Issue 4, 1997, Pages 333-393

  Porter, Christopher J H ^a  

^a MONASH UNIVERSITY   (Australia)

Author keywords

Gut associated lymphoid tissue; Lipoprotein; Liposome; Lymph; Lymphatic transport; Microsphere; Prodrug

Indexed keywords

3,7 DIMETHYL 9 [2 NONYLOXY 6 (TRIFLUOROMETHYL)PHENYL] 2,4,6,8 NONATETRAENOIC ACID; BLEOMYCIN; CHYLOMICRON; DEXTRAN; DIAZEPAM; DICLOFENSINE; FLUOROURACIL; LIPOSOME; MACROGOL; MITOMYCIN C; PEPLEOMYCIN; POVIDONE; RECOMBINANT ALPHA2 INTERFERON; SILICON DIOXIDE; TUMOR NECROSIS FACTOR; ZINOSTATIN;

DRUG DELIVERY SYSTEM; DRUG FORMULATION; DRUG SOLUBILITY; DRUG UPTAKE; HUMAN; INTESTINE ABSORPTION; INTESTINE LYMPHATIC TISSUE; INTRAMUSCULAR DRUG ADMINISTRATION; INTRAVENOUS DRUG ADMINISTRATION; LIPID SOLUBILITY; LYMPH FLOW; LYMPHATIC SYSTEM; MOLECULAR WEIGHT; NONHUMAN; ORAL DRUG ADMINISTRATION; REVIEW; STOMACH ABSORPTION; SUBCUTANEOUS DRUG ADMINISTRATION;

ANIMALS; BIOLOGICAL TRANSPORT; DRUG DELIVERY SYSTEMS; HUMANS; INTESTINES; LYMPHATIC SYSTEM; MACROMOLECULAR SUBSTANCES; MICROSPHERES; PRODRUGS;

EID: 0031455129     PISSN: 07434863     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (316)

1. Yoffey, J. M., and Courtice, F. C., Lymphatics, Lymph and the Lymphomyeloid Complex, Academic Press, London, 1970.
2. Embretson, T., Zupancic, M., Ribas, J. L., Burke, A., Racz, P., Tenner-Racz, K., and Haase, A. T., Massive covert infection of helper T lymphocytes and macrophages by HIV during the incubation period of AIDS, Nature, 362, 359, 1993.
3. Pantaleo, G., Graziosi, C., Butini, L., Pizzo, P. A., Schnittman, S. M., Kotler, D. P., and Fauci, A. S., Lymphoid organs function as major reservoirs for human immunodeficiency virus, Proc. Natl. Acad. Sci. USA., 88, 9838, 1991.
4. Pantaleo, G., Graziosi, C., Demarest, J. F., Butini, L., Montroni, M., Fox, C. H., Orenstein, J. M., Kotler, D. P., and Fauci, A. S., HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease, Nature, 362, 355, 1993.
5. Pantaleo, G., Graziosi, C., and Fauci, A. S., The role of lymphoid organs in the immunopathogenesis of HIV infection, AIDS, 7 (suppl 1), S19-23, 1993.
6. Pantaleo, G., Graziosi, C., Demarest, J. F., Cohen, O. J., Vaccarezza, M., Gantt, K., Muro-Cacho, C., and Fauci, A. S., Role of Lymphoid organs in the pathogenesis of human immunodeficiency virus (HIV) infection, Immunol. Rev., 140, 105, 1994.
7. O'Driscoll, C. M., Anatomy and physiology of the lymphatics, in Lymphatic Transport of Drugs, Charman, W. N., and Stella, V. J. Eds., CRC Press, Boca Raton, 1, 1992.
8. Bergstrom, K., and Werner, B., Proteins in human thoracic duct lymph. Studies on the distribution of some proteins between lymph and blood, Acta Chir. Scand., 131, 413, 1966.
9. Werner, B., The biochemical composition of the human thoracic duct lymph, Acta Chir. Scand., 132, 63, 1966.
10. Friedman, M., Byers, S. O., and Omoto, C., Some characteristics of hepatic lymph in the intact rat, Am. J. Physiol., 184, 11, 1965.
11. Order, S. E., Bloomer, W. D., Jones, A. G., Kaplan, W. D., Davis, M. A., Adelstein, S. J., and Hellman, S., Radionuclide immunoglobulin lymphangiography: A case report, Cancer, 35, 1487, 1975.
12. Order, S. E., Immunospecific radionuclide immunoglobulin lymphography, in Clinical Lymphography Vol 7, Clouse, M. E., Ed., Williams and Wilkins, Baltimore, 316, 1977.
13. Ariel, I. M., Resnick, M. I., and Galey, D., The intralymphatic administration of radioactive isotopes and cancer chemotherapeutic drugs, Surgery, 55, 355, 1964.
14. Kichen, G., and Garrett, M. J., A trial of intralymphatic cyclophosphamide in patients with arm lymphoedema due to metastatic breast carcinoma, Clin. Radiol., 22, 379, 1971.
15. 111In-T101 in patients with cutaneous T-cell lymphoma, Cancer Res., 51, 688, 1991.
16. Hawley, A. E., Davis, S. S., Illum, L., Targeting of colloids to lymph nodes: influence of lymphatic physiology and colloidal characteristics, Adv. Drug. Deliv. Rev., 17, 129, 1995.
17. Casley-Smith, J. R., The fine structure and functioning of tissue channels and lymphatics, Lymphology, 12, 183, 1980.
18. Takakura, Y., Matsumoto, S., Hashida, M., and Sezaki, H., Enhanced lymphatic delivery of mitomycin C conjugated with dextran, Cancer Res., 44, 2505, 1984.
19. Takakura, Y., Kitajima, M., Matsumototo, S., Hashida, M., and Sezaki, H., Development of a novel polymeric prodrug of mitomycin C-dextran conjugate with anionic charge. I. Physicochemical characteristics and in vivo and in vitro antitumour activities, Int. J. Pharmaceut., 37, 135, 1987.
20. Granger, D. N., and Taylor, A. E., Permeability of intestinal capillaries to endogenous macromolecules, Am. J. Physiol, 238, H457, 1980.
21. Casley-Smith, J. R., Are the initial lymphatics normally pulled open by the anchoring filaments? Lymphology, 13, 120, 1980.
22. Leak, L. V., Lymphatic removal of fluids and particles in the mammalian lung, Environ. Health Perspect., 35, 55, 1980.
23. Leak, L. V., and Burke, J. F., Ultrastructural studies on the lymphatic anchoring filaments, J. Cell. Biol., 36, 129, 1968.
24. Yang, V. V., O'Morchoe, P. J., and O'Morchoe, C. C., Transport of protein across lymphatic eudothelium in the rat kidney, Microvasc. Res., 21, 75, 1981.
25. O'Morchoe, P. J., Yang, V. V., and O'Morchoe, C. C., Lymphatic transport during volume expansion, Microvasc. Res., 20, 275, 1980.
26. O'Morchoe, C. C., Albertine, K. H., and O'Morchoe, P. J., The rate of translymphatic endothelial fluid movement in the canine kidney, Microvasc. Res., 23, 180, 1982.
27. Leak, L. V., Studies on the permeability of lymphatic capillaries, J. Cell. Biol., 50, 300, 1971.
28. Dobbins, W. O., and Rollins, E. L., Intestinal mucosal lymphatic permeability: an electron microscopic study of endothelial vesicles and cell functions, J. Ultrastruct. Res., 33, 29, 1970.
29. O'Morchoe, C. C., Jones, W. R., Jarosz, H. M., O'Morchoe, P. J., and Fox, L. M., Temperature dependence of protein transport across lymphatic endothelium in vitro, J. Cell Biol., 98, 629, 1984.
30. Lamka, J., Jindrova, O., Ruisar, L., Kohoutek, P., Gallova, S., and Kvetina, J., The pharmacokinetics of intraduodenally administered diazepam in rats as influenced by composition of the central lymph, Physiol. Bohemoslov., 38, 441, 1989.
31. Lamka, J., Gallova, S., Pharmacokinetics of ortho-I-hippurate in the blood and central lymph of the rat., Physiol. Res., 40, 543, 1991.
32. Lamka, J., Rudisar, L., Kvetina, J., On the limiting factors affecting the distribution of model drugs from blood into the lymphatic system, Eur.J. Drug. Metab. Pharmacokin., 3, 47, 1991.
33. Lamka, J., Pharmacokinetics of inulin in blood and central lymph in the rat., Pol. J. Pharmacol. Pharm., 44, 147, 1992.
34. Lamka, J., Jindrova, O., Gallova, S., Uhrova, R., and Kvetina, J. Influence of the composition of rat central lymph on the pharmacokinetics (the steady state during infusion, bioavailability, absorption) of diazepam, studied in the blood and lymph, Physiol. Bohemoslov., 39, 403, 1990.
35. Deak, S. T., and Csaky, T. Z. Factors regulating the exchange of nutrients and drugs between lymph and blood in the small intestine, Microcirc. Endothelium Lymphatics, 1, 569, 1984.
36. Nix, J. T., Mann, F. C., Bollman, J. L., Grindlay, J. H., and Flock, E. V., Alterations of protein constituents of lymph by specific injury to the liver, Am. J. Physiol., 164, 119, 1951.
37. Takakura, Y., Fujita, T., Hashida, M., and Seaki, H., Disposition characteristics of macromolecules in tumor-bearing mice, Pharm. Res., 7, 339, 1990.
38. Papisov, M. I., Weissleder, R., and Schaffer, B., Intravenous carriers for drug delivery to lymph nodes, J. Cont. Rel., 28, 293, 1994.
39. Allen, T. M., Hansen, C. B., and Guo, L. S. S., Subcutaneous administration of liposomes: a comparison with the intravenous and intraperitoneal routes of injection, Biochim. Biophys. Acta, 1150, 9, 1993.
40. 3H] methotrexate-encapsulated neutral large unilamellar vesicles and immunoliposomes, Int. J. Pharmaceut., 98, 9, 1993.
41. Harvie, P., Desormeaux, A., Gagne, N., Tremblay, M., Poulin, L., Beauchamp, D., and Bergeron, M. G., Lymphoid tissue targeting of liposome-encapsulated 2′3′-dideoxyinosine, AIDS 9, 701, 1995.
42. Malek, P., Kolc, J., Herold, M., and Hoffman, J., Lymphotropic antibiotics - "antibiolymphins," in Antibiotics Manual, 1957/1958, Medical Encyclopedia, N. Y., 546, 1958.
43. Weinstein, J. N., Antibody lymphoscintigraphy, Cancer Treat. Res., 51, 365, 1990.
44. 111In-labeled T 101 monoclonal antibody in patients with cutaneous T-cell lymphoma, Cancer Res., 47, 6093, 1987.
45. Weinstein, J. N., Parker, R. J., Keenan, A. M., Dower, S. K., Morse, H. C., and Sieber, S. M., Monoclonal antibodies in the lymphatics: towards the diagnosis and therapy of tumour metastases, Science, 218, 1334, 1982.
46. Mulshine, J. L., Keenan, A. M., Carrasquillo, J. A., Walsh, T., Linnoila, R. I., Holton, O. D., Harwell, J., Larson, S. M., Bunn, P. A., and Weinstein, J. N., Immunolymphoscintigraphy of pulmonary and mediastinal lymph nodes in dogs: a new approach to lung cancer imaging, Cancer Res., 47, 3572, 1987.
47. Parker, R. J., Keenan, A. M., Dower, S. K., Steller, M. A., Holton, O. D., Sieber, S. M., and Weinstein, J. N., Targeting of murine radiolabeled monoclonal antibodies in the lymphatics, Cancer Res., 47, 2073, 1987.
48. Keenan, A. M., Weinstein, J. N., Mulshire, J. L., Carrasquillo, J. A., Bunn, P. A., Reynolds, J. C., and Larson, S. M., Immunolymphoscintigraphy in patients with lymphoma after subcutaneous injection with indium 111 labeled T 101 monoclonal antibody, J. Nucl. Med., 28, 42, 1987.
49. Lotze, M. T., Carrasquillo, J. A., Weinstein J. N., Bryant, G. J., Perentesis, P., Reynolds, J. C., Matis, L. A., Eger, R. R., Keenean, A. M., Hellstrom, I., Hellstrom, K. E., and Larson, S. M., Monoclonal antibody imaging of human melanoma. Radioimmunodetection by subcutaneous or systemic injection, Ann. Surg. 204, 223, 1986.
50. Steller, M. A., Parker, R. J., Covell, D. G., Holton, O. D., Keenan, A. M., Sieber, S. M., and Weinstein, J. N., Optimization of monoclonal antibody delivered via the lymphatics: the dose dependence, Cancer, Res., 46, 1830, 1986.
51. Weinstein, J. N., Steller, M. A., Covell, D. G., Holton, O. D., Keenan, A. M., Sieber, S. M., and Parker, R. J., Monoclonal antitumour antibodies in the lymphatics, Cancer, Treat. Rep., 68, 257, 1984.
52. Weinstein, J. N., Steller, M. A., Keenan, A. M., Covell, D. G., Key, M. E., Sieber, S. M., Oldham, R. K., Hwang, K. M., and Parker, R. J., Monoclonal antibodies in the lymphatics: selective delivery to lymph node metastases of a solid tumour, Science, 222, 423, 1983.
53. Shah, S. A., Gallagher, B. M., and Sands, H., Lymphoscintigraphy of human colorectal carcinoma metastases in athymic mice by use of radioiodinated B72. 3 monoclonal antibody, J. Natl. Cancer. Inst. 78, 1069, 1987.
54. Wahl, R. L., Geatti, O., Liebert, M., Wilson, B., Shreve, P., Beers, B. A., Kinetics of interstitially administered monoclonal antibodies for purposes of lymphoscintigraphy, J. Nucl. Med. 28, 1736, 1987.
55. Yoshikawa, H., Sutoh, Y., Naruse, N., Takada, K., and Muranishi, S., Comparison of dissappearance from blood and lymphatic delivery of human fibroblast interferon in rat by different routes, J. Pharmacobio-Dyn, 8, 206, 1985.
56. Bocci, V., Evaluation of routes of administration of interferon in cancer: A review and a proposal, Cancer Drug Delivery, 1, 337, 1984.
57. Bocci, V., Muscettola, M., Grasso, G., Magyar, Zs., Naldini, A., Szabo, G., The lymphatic route. I. Albumin and hyaluronidase modify the normal distribution of interferon in lymph and plasma, Experientia, 42, 432, 1986.
58. Kojima, K., Takahashi, T., and Nakanishi, Y., Lymphatic transport of recombinant human tumour necrosis factor in rats, J. Pharmacobiodyn., 11, 700, 1988.
59. Supersaxo, A., Hein, W., Gallati, H., and Steffen, H., Recombinant human interferon alpha 2a: Delivery to lymphoid tissue by selected mode of application, Pharm. Res., 5, 472, 1988.
60. Supersaxo, A., Hein, W. R., and Steffen, H., Effect of molecular weight on the lymphatic absorption of water soluble compounds following subcutaneous administration, Pharm. Res., 7, 167, 1990.
61. Supersaxo, A., Hein, W. R., and Steffen, H., Mixed micelles as a proliposomal lymphotropic drug carrier, Pharm. Res., 8, 1286, 1991.
62. 99mTc and its evaluation for lymphoscintigraphy, Nucl. Med. Biol., 20, 701, 1993.
63. Freeman, D. O., deAlmeida-Filho, P. J., Besh, S., Maia-e-Silva, M. E., Braga, C., and Maciel, A., Lymphoscintigraphic analysis of lymphatic abnormalities in symptomatic and asymptomatic human filariasis, J. Infect. Dis. 170, 427, 1994.
64. m hydroxyethylstarch: a potential radiopharmaceutical for lymphoscintigraphy, Nucl. Med. Commun., 8, 395, 1987.
65. Sadek, S., Owunwanne, A., Abdel Dayem, H. M., and Yacoub, T., Preparation and evaluation of Tc-99m hydroxyethylstarch as a potential radiopharmaceutical for lymphoscintigraphy: comparison with Tc-99m human serum albumin, Tc-99m dextran and Tc-99m sulfur colloid, Lymphology, 22, 157, 1989.
66. Strand, S. E., and Bergqvist, L., Radiolabeled colloids and macromolecules in the lymphatic system, Crit. Rev. Ther. Drug. Carrier Syst., 6, 211, 1989.
67. Muranishi, S., Takahashi, Y., Hashida, M., and Sezaki, H., Effect of complexation with dextran sulphate on the lymphatic delivery of bleomycin following interstitial administration, J. Pharmacobio-Dyn., 2, 383, 1979.
68. Takakura, Y., Matsumoto, S., Hashida, M., and Sezaki, H., Enhanced lymphatic delivery of mitomycin C conjugated with dextran, Cancer Res., 44, 2505, 1984.
69. Takakura, Y., Kitajima, M., Matsumoto, S., Hashida, M., and Sezaki, H., Development of a novel polymeric prodrug of mitomycin C-dextran conjugate with anionic charge. I. Physicochemical characteristics and in vivo and in vitro antitumour activities, Int. J. Pharmaceut., 37, 135, 1987.
70. Takakura, Y., Atsumi, M., Hashida, M., and Sezaki, H., Development of a novel polymeric prodrug of mitomycin C-dextran conjugate with anionic charge. II. Disposition and pharmacokinetics following intravenous and intramuscular administration, Int. J. Pharmaceut., 37, 145, 1987.
71. Maeda, H., Takeshita, Y., Kanamaru, R., Sato, H., Khatoh, J., and Sato, H., Antimetastatic and antitumour activity of a derivative of neocarzinostatin: an organic solvent and water-soluble polymer conjugated protein, Gann, 70, 601, 1979.
72. Takeshita, Y., Maeda, H., and Kanamaru, R., In vitro mode of action, pharmacokinetics, and organ specificity of poly(maleic acid-styrene)-conjugated neocarzinostatin, SMANCS, Gann, 73, 278, 1982.
73. Nakamoto, Y., Hashida, M., Muranishi, S., and Sezaki, H., Studies on pharmaceutical modification of anticancer agents. II. Enhanced delivery of bleomycin into lymph by emulsions and drying emulsions, Chem. Pharm. Bull., 23, 3125, 1975.
74. Nakamoto, Y., Fujiwara, M., Noguchi, T., Kimura, T., Muranishi, S., and Sezaki, H., Studies on pharmaceutical modification of anticancer agents. I. Enhancement of lymphatic transport of mitomycin C by parenteral emulsions, Chem. Pharm. Bull., 23, 3125, 1975.
75. Hashida, M., Muranishi, S., and Sezaki, H., Evaluation of water in oil and microsphere in oil emulsions as a specific delivery system of 5-fluorouracil into the lymphatics, Chem. Pharm. Bull, 25, 2410, 1977.
76. Takahashi, T., Mizuno, M., Fujita, Y., Ueda, S., Nishioka, B., and Majima, S., Increased concentration of anticancer agents in regional lymph nodes by fat emulsions, with special reference to chemotherapy of metastases, Gann, 64, 345, 1973.
77. Takahashi, T., Kono, K., Yamaguchi, T., Watanabe, S., and Majima, S., Enhancement of chemotherapeutic effect on lymph node metastasis by anticancer agents in fat emulsion, Gann, 20, 195, 1977.
78. Ohta, H., Takagi, K., Noguchi, Y., Ohashi, I., Takahashi, T., Watanabe, S., Takekoshi, T., Ohashi, K., and Kato, Yo., Endoscopic intramural injection of anti-neoplastic emulsion, Gann, 75, 641, 1984.
79. Hashida, M., Egawa, M., Muranishi, S., and Sezaki, H., Role of intramuscular administration of water-in-oil emulsions as a method for increasing the delivery of anticancer agents to regional lymphatics, J. Pharmacokinet. Biopharm., 5, 225, 1977.
80. Hashida, M., Takahashi, Y., Muranishi, S., and Sezaki, H., An application of water-in-oil and gelatin microsphere-in-oil emulsions to specific delivery of anticancer agent into stomach lymphatics. J. Pharmacokinet. Biopharm., 5, 241, 1977.
81. Muranishi, S., Drug targeting towards the lymphatics, Adv. Drug. Res., 21, 1, 1991.
82. Davis, S. S., Hadgraft, J., and Palin, K. J., Medical applications of emulsions, in Encyclopedia of Emulsion Technology, Vol 2: Applications, Becher, P., Ed., Marcel Dekker, New York, 196, 1985.
83. O'Hagan, D. T., Christy, N. M., Davis, S. S., Particulates and lymphatic drug delivery, in Lymphatic Transport of Drugs, Charman, W. N., and Stella, V. J., Eds., CRC Press, Boca Raton, 279, 1992.
84. Arrowsmith, M., Hadgraft, J., Kellaway, I. W., The in vivo release of cortisone esters from liposomes and the intramuscular clearance of liposomes, Int. J. Pharm., 20, 347, 1984.
85. Zierenberg, O., and Betzing, H., Pharmacokinetics and metabolism of i. m. injected polyenylphosphatidylcholine liposomes, Arzneim-Forsch., 29 494, 1979.
86. Kim, S., and Howell, S. B., Multivesicular liposomes containing cytaribine for slow release s. c. administration, Cancer Treat. Rep., 71, 447, 1987.
87. Roy, R., and Kim, S., Multivesicular liposomes containing bleomycin for subcutaneous administration, Cancer Chemother. Pharmacol., 28, 105, 1991.
88. Daoud, S. S., Fetouh, M. I., and Giovanella, B. C., Antitumour effect of liposome-incorporated camptothecin in human malignant xenografts, Anti-Cancer Drugs, 6, 83, 1995.
89. Patel, H. M., Fate of liposomes in the lymphatics, in Liposomes as Drug Cariers, Gregoriadis, G., Ed., Wiley, N. Y. 51, 1988.
90. Kadir, F., Zuidema, J., Crommelin, D. J. A., Liposomes as intramuscular and subcutaneous injection drug delivery systems, in Pharmaceutical Particulate Carriers, Rolland, A., Ed., Marcel Dekker, N. Y., 165, 1993.
91. Osborne, M. P., Richardson, V. J., Jeyasingh, K., and Ryman, B. E., Radionuclide-labeled liposomes: A new lymph node imaging agent, Int. J. Nucl. Med. Biol., 6, 75, 1979.
92. Jackson, A. J., Intramuscular absorption and regional lymphatic uptake of liposome entrapped inulin, Drug Metab. Dispos., 9, 535, 1981.
93. Hirano, K., and Hunt, C. A., Lymphatic transport of liposome encapsulated agents: effect of liposome size following intraperitoneal administration, J. Pharm. Sci., 9, 915, 1985.
94. 99mTc marker to represent intact liposomes in lymph nodes, Biochim. Biophys. Acta, 801, 76, 1984.
95. Akamo, Y., Yotsuyanagi, T., Mizuno, I., Ichino, T., Noritaka, T., Kurahashi, S., Saito, T., Yamamoto, T., Yasui, T., Itabashi, Y., and Yura, J., Delivery of lymph node targeted adriamycin by gastric submucosal liposomal injection in rabbits, Jpn. J. Cancer Res., 84, 208, 1993.
96. Akamo, Y., Mizuno, I., Yotsuyangi, T., Ichino, T., Tanimoto, N., Yamamoto, T., Nagata, M., Takeyama, H., Shinagawa, N., Yura, J., and Manabe, T., Chemotherapy targeting regional lymph nodes by gastric submucosal injection of liposomal adriamycin in patients with gastric carcinoma, Jpn. J. Cancer Res., 85, 652, 1994.
97. Ohsawa, T., Matsukawa, Y., Takakura, Y., Hashida, M., and Sezaki, H., Fate of lipid and encapsulated drugs after intramuscular administration of liposomes prepared by the freeze thawing method in rats, Chem. Pharm. Bull., 33, 5013, 1985.
98. Allen, T. M., Hansen, C. B., Guo, L. S., Subcutaneous administration ofliposomes: a comparison with the intravenous and intraperitoneal routes of injection, Biochim. Biophys. Acta, 1150, 9, 1993
99. Moghimi, S. M., Hawley, A. E., Christy, N. M., Gray, T., Illum, L., and Davis, S. S., Surface engineered nanospheres with enhanced drainage into lymphatics and uptake by macrophages of the regional lymph nodes, FEBS Lett., 344, 25, 1994.
100. Gabizon, A., and Papahadjopoulos, D., Liposome formulations with prolonged circulation time in blood and enhanced uptake by tumours, Proc. Natl. Acad. Sci. (USA), 85, 6949, 1988.
101. Allen, T. M., Hancen, C., Martin, F., Redeman, C., Yau-Young, A., Liposomes containing synthetic lipid derivatives of poly(ethylene gycol) show prolonged circulation half lives in vivo, Biochim. Biophys. Acta, 1066, 29, 1991.
102. Trubetskoy, V. S., Cannillo, J. A., Milshtein, A., Wolf, G. L., and Torchilin, V. P., Controlled delivery of Gd-containing liposomes to lymph nodes: surface modification may enhance MRI contrast properties, Magn. Reson. Imaging, 13, 31, 1995.
103. Torchilin, V. P., Immunoliposomes and PEGylated immunoliposomes: possible use for targeted delivery of imaging agents, Immunomethods, 4, 244, 1994.
104. Mangat, S., and Patel, H. M., Lymph node localization of non-specific antibody coated liposomes, Life Sci, 36, 1917, 1985.
105. Gregoriadis, G., Immunological adjuvents: a role for liposomes, Immun. Today, 11, 89, 1990.
106. Wassef, N. M., Roerdink, F., Richardson, E. C., and Alving, C. R.., Suppression of phagocytic function and phospholipid metabolism in macrophages by phosphatidylinositol liposomes, Proc. Natl. Acad. Sci. U. S. A., 81, 2655, 1984.
107. Therien, H. M., and Gruda, J., Pleiotropic effects of positively charged liposomes on immune functions, In Vitro Cell Dev. Biol., 26, 511, 1990.
108. Yui, S., and Yamazaki, M., Induction of macrophage growth by lipids, J. Immun., 136, 1334, 1986.
109. Desjardins, R., Krzystyniak, K., Therien, H. M., Banska, W., Tancrede, P., and Fournier, M., Immunoactivating potential of multilamellar liposome vesicles in murine popliteal lymph node (PLN) test, Int. J. Immunopharmacol., 17, 367, 1995.
110. Krzystyniak, K., Desjardins, R., Therien, H. M., Banska, W., Tancrede, P., and Descotes, J., Lymphcyte activation by liposome trapped streptozocin in murine popliteal lymph node (PLN) test, Int. J. Immunopharmacol. 16, 817, 1994.
111. Gregoriadis, G., and Panagiotidi, C., Immunoadjuvent action of liposomes: comparison with other adjuvents, Immun. Lett., 20, 237, 1989.
112. Therien, H. M., Shahum, E., and Fortin, A., Liposome adjuvanticity: influence of dose and protein : lipid ratio on the humoral response to encapsulated and surface linked antigen, Cell. Immun., 136, 402, 1991.
113. Gluck, R., Liposomal presentation of antigen for human vaccines, Pharm. Biotechnol, 6, 325, 1995.
114. Wassef, N. M., Alving, C. R., and Richards, R. L., Liposomes as carriers for vaccines, Immunomethods, 4, 217, 1994.
115. Christy, N. M., Moghimi, S. M., Ilium, L., and Davis, S. S., Effect of size on the lymphatic uptake of a model colloid system, Proc. Int. Symp. Control. Release Bioact. Mater., 19, 355, 1992.
116. Maincent, P., Thouvenot, P., Amicabile, C., Hoffman, M., Kreuter, J., Couvreur, P., and Devissaguet, J. P., Lymphatic targeting of polymeric nanoparticles after intraperitoneal administration to rats, Pharm. Res., 9, 1534, 1992.
117. Yoshikawa, H., Nakao, Y., Takada, K., Muranishi, S., Wada. R., Rabata, Y., Hyon, S. H., and Ikada, Y., Targeted and sustained delivery of aclarubicin to lymphatics by lactic acid oligomer in rat, Chem Pharm. Bull., 37, 802, 1989.
118. Greenway, T. E., Eldridge, J. H., Ludwig, G., Staas, J. K., Smith, J. F., Gilley, R. M., and Michalek, S. M. Enhancement of protective immune response to venezuelan equine encephalitis (VEE) virus with microencapsulated vaccine, Vaccine, 13, 1411, 1995.
119. Kreuter, J., Nanoparticles as adjuvants for vaccines, Pharm. Biotechnol., 6, 463, 1995.
120. Nakoda, R., Tabata, Y., and Ikada, Y., Potentiality of gelatin microspheres as immunological adjuvant, Vaccine, 13, 653, 1995.
121. Shahin, R., Leef, M., Eldridge, J., Hudson, M., and Gilley, R., Adjuvanticity and protective immunity elicited by Bordetella pertussis antigens encapsulated in poly(DL-lactide-co-glycolide) microspheres, Infect. Immun., 63, 1195, 1995.
122. Morris, W., Steinhoff, M. C., and Russell, P. K., Potential of polymer microencapsulation technology for vaccine innovation, Vaccine, 12, 5, 1994.
123. Eldridge, J. H., Staas, J. K., Chen, D., Marx, P. A., Tice, T. R., and Gilley, R. M., New advances in vaccine delivery systems, Semin. Hematol., 30, suppl 4, 16, 1993.
124. Eldridge, J. H., Staas, J. K., Meulbroek, J. A., Tice, T. R., and Gilley, R. M., Biodegradable and biocompatible poly(DL-lactide-co-glycolide) microspheres as an adjuvant for staphylococcal enterotoxin B toxoid which enhances the level of toxin neutralizing antibodies, Infect. Immun., 59, 2978, 1991,
125. Uchida, Y., Martin, S., Foster, T. p., Wardley, R. C., and Grimm, S., Dose and load studies for subcutaneous and oral delivery of poly(lactide-co-glycolide) microspheres containing ovalbumin, Pharm. Res., 11, 1009, 1994.
126. O'Hagan, D. T., Jeffery, H., Davis, S. S., Long term antibody response in mice following subcutaneous immunization with ovalbumin entrapped in biodegradable microparticles, Vaccine, 11, 965, 1993.
127. O'Hagan, D. T., Jeffery, H., Roberts, M. J. J., McGee, J. P., and Davis, S. S., Controlled release microparticles for vaccine development, Vaccine, 9, 768, 1991.
128. Maloy, K. J., Donachie, A. M., O'Hagan, D. T., and Mowat, A. McI., Induction of mucosal and systemic immune responses by immunization with ovalbumin entrapped in poly(lactide-co-glycolide) microparticles, Immunology, 81, 661, 1994.
129. O'Hagan, D. T., Rahman, D., McGee, J. P., Jeffery, H., Davies, M. C., Williams, P., and Davis, S. S., Biodegradable microparticles as controlled release antigen delivery systems, Immunology, 73, 239, 1991.
130. Jones, D. H., McBride, B. W., Jeffrey, H., O'Hagan, D. T., Robinson, A., and Farrar, G. H., Protection of mice from Bordetella pertussis, Vaccine, 13, 675, 1995.
131. Vordermeier, H. M., Coomber, A. G. A., Jenkins, P., McGee, J. P., O'Hagan, D. T., Davis, S. S., and Singh, M., Synthetic delivery system for tuberculosis vaccines: immunological evaluation of the M. tuberculosis 38 kDa protein entrapped in biodegradable PLG microparticles, Vaccine, 13, 1576, 1995.
132. Hagiwara, A., Takahashi, T., Ueda, T., Iwamoto, A., and Torii, T., Activated carbon particles as anti-cancer drug carrier into regional lymph nodes, Anti-Cancer Drug Design, 1, 313, 1987.
133. Hagiwara, A., Takahashi, T., Ueda, T., Iwamoto, A., Yamashita, H., and Maeda, T., Enhanced therapeutic efficacy on lymph node metastsis by the use of peplomycin adsorbed on small activated carbon particles, Anticancer Res., 8, 287, 1988.
134. Hagiwara, A., Takahashi, T., Kojima, O., Kitamura, K., Sakakura, C., Shoubayashi, S., Osaki, K., Iwamoto, A., Lee, M., and Fujita, K., Endoscopic local injection of a new drug-delivery format of peplomycin for superficial esophageal cancer: a pilot study, Gastroenterology, 104, 1037, 1993.
135. Natsugoe, S., Shimada, M., Kumanohoso, T., Tokuda, K., Baba, M., Yoshinaka, H., Fukumoto, T., Nakamura, K., Yamada, K., Nakashima, T., Aikou, T., Enhanced efficacy of bleomycin adsorbed on silica particles against lymph node metastasis in patients with esophageal cancer: A pilot study, Surgery, 117, 636, 1995.
136. Barrowman, J. A., Transport of absorbed lipids, in Physiology of the Gastrointestinal Lymphatic System, Barrowman, J. A., Ed., Cambrdge University Press, Cambridge, 165, 1978.
137. Granger, D. N., Mortillaro, N. A., Kvietys, R., Rutili, G., Parker, J. C., and Taylor, A. E., Role of the interstitial matrix during intestinal volume absorption, Am. J. Physiol, 238, G183, 1980.
138. Lee, J. S., Lymphatic contractility, in Physiology of the Lymphatic Circulation, Shepherd, A. P., and Granger, D. N., Eds., Raven Press, N. Y., 201, 1984.
139. Reininger, E. J., and Saperstein, L. A., Effect of digestion on the distribution of blood flow in the rat, Science, 126, 1176, 1957.
140. Rubas, W., and Grass, G. M., Gastrointestinal lymphatic absorption of peptides and proteins, Adv. Drug. Deliv. Rev., 7, 15, 1991.
141. Alexander, H. L., Shirley, K., and Allen, D., The route of ingested egg white to the systemic circulation, J. Clin. Invest. 15, 163, 1936.
142. May, A. T., and Whaler, B.C., The absorption of clostridium botulinum type A toxin from the alimentary canal, Br. J. Exp. Pathol., 39, 307, 1958.
143. Lamanna, C., and Carr, C. J., The botulinum, tetanal and enterostaphylococcal toxins: a review. Clin. Pharmacol. Ther., 8, 286, 1967.
144. Gans, H., and Matsumoto, K., Are enteric toxins able to escape from the intestine, Proc. Soc. Exp. Bio. Med., 147, 736, 1974.
145. Warshaw, A. L., Walker, W. A., Cornell, R., and Isselbacher, K. J., Small intestinal permeability to macromolecules. Transmission of horseradish peroxidase into mesenteric lymph and portal blood. Lab Inv., 25, 675, 1971.
146. Warshaw, A. L., Walker, W. A., and Isselbacher, K. J., Protein uptake by the intestine: evidence for absorption of intact macromolecules, Gastroenterology, 66, 987, 1974.
147. 131I labeled elastase in vivo, Biochim. Biophys. Acta, 288, 181, 1972.
148. Muranishi, S., Absorption enhancers, Crit. Rev. Ther. Drug Carrier Syst., 7, 1, 1990.
149. Yoshikawa, H., Takada, K., and Muranishi, S., Molecular weight dependence of permselectivity of to rat small intestine blood lymph barrier for exogenous macromolecules absorbed from lumen. J. Pharmacobio-Dyn, 7, 1, 1984.
150. Muranishi, S., Characterization of drug absorption via the rectal route, in Rectal Therapy, Glas, B., and de Blaey, C. J., Eds., J. R. Prous Publishers, Barcelona, 35, 1984.
151. Yoshikawa, H., Takada, K., Muranishi, S., Satoh, Y., and Naruse, N., A method to potentiate enteral absorption of interferon and selective delivery into lymphatics, J. Pharmacobio-Dyn., 7, 59, 1984.
152. Yoshikawa, H., Takada, K., Satoh, Y., Naruse, N., and Muranishi, S., Potentiation of enteral absorption of human interferon alpha and selective transfer into lymphatics in rats, Pharm. Res., 2, 250, 1985.
153. Yoshikawa, H., Takada, K., Satoh, Y., Narus, N., and Muranishi, S., Development of interferon suppositories I. Enhanced rectal absorption of human fibroblast interferon by fusogenic lipid via lymphotropic delivery in rats, Pharm. Res., 3, 116, 1986.
154. Yoshikawa, H., Muranishi, S., Kato, C., and Sezaki, H., Bifunctional delivery system for selective transfer of bleomycin into lymphatics via enteral route, Int. J. Pharmaceut., 8, 291, 1981.
155. Yoshikawa, H., Sezaki, H., and Muranishi, S., Mechanism for selective transfer of bleomycin into lymphatics by a bifunctional delivery system via the lumen of the large intestine, Int. J. Pharmaceut., 13, 321, 1983.
156. Yoshikawa, H., Muranishi, S., Sugihira, N., and Sezaki, H., Mechanism of transfer of bleomycin into lymphatics by bifunctional delivery system via lumen of small intestine, Chem. Pharm. Bull., 31, 1726, 1983.
157. Kuroda, D., Hamabe, Y., Ikuta, H., Katoh, M., Saitoh, Y., Yoshikawa, H., and Muranishi, S., Study of esophageal cancer chemotherapy on promoted mucosal absorption and lymphotrophy by lipid-surfactant mixed micelles and macromolecular dextran sulfate, Drug Delivery Syst., 2, 107, 1987.
158. Kuroda, D., Hamabe, Y., Ikuta, H., Katoh, M., Saitoh, Y., Yoshikawa, H., and Muranishi, S., Study of esophageal cancer chemotherapy ar enhanced antitumour effect by lipid surfactant mixed micelles and a macromolecular dextran sulphate, Drug Delivery Syst., 4, 20, 1989.
159. Fukui, H., Murakami, M., Yoshikawa, H., Takada, K., and Muranishi, S., Studies on the promoting effect of lipid surfactant mixed micelle (MM) on intestinal absorption of colloidal particle. Dependence on particle size and administration site, J. Pharmacobio-Dyn., 10, 236, 1987.
160. Charman, W. N., and Porter, C. J. H., Lipophilic prodrugs designed for intestinal lymphatic transport. Adv. Drug Deliv. Rev., 19, 149, 1996.
161. Porter, C. J. H., and Charman, W. N., Uptake of drugs into the intestinal lymphatics after oral administration. Adv. Drug. Deliv. Rev., 25, 71, 1997.
162. Charman, W. N., Lipid vehicle and formulation effects on intestinal lymphatic drug transport, in Lymphatic Transport of Drugs, Charman, W. N., and Stella, V. J. Eds., CRC Press, Boca Raton, 113, 1992.
163. Staggers, J. E., Hernell, O., Stafford R. J., and Carey, M. C., Physical-chemical behaviour of dietary and biliary lipids during intestinal digestion and absorption. 1. Phase behaviour and aggregation states of model lipid systems patterned after aqueous duodenal contents of healthy adult human beings, Biochemistry, 29, 2028, 1990.
164. Hernell, O., Staggers, J. E., and Carey, M. C., Physical-chemical behaviour of dietary and biliary lipids during intestinal digestion and absorption. 2. Phase analysis and aggregation states of luminal lipids during duodenal fat digestion in healthy adult human beings, Biochemistry, 29, 2041, 1990.
165. Tso, P., Intestinal lipid absorption, in Physiology of the Gastrointestinal Tract, Johnson, L. R., Ed., Raven Press, New York, 867, 1994.
166. Hoffman, N. E., The relationship between uptake in vitro of oleic acid and micellar solubilization, Biochim. Biophys. Acta, 196, 193, 1970.
167. Simmonds, W. J., The role of micellar solubilization in lipid absorption. Aust. J. Exp. Biol. Med. Sci., 50, 403, 1972.
168. Westergaard, H., and Dietschy, J. M., The mechanism whereby bile acid micelles increase the rate of fatty acid and cholesterol uptake into the mucosal cell, J. Clin. Invest. 58, 97, 1976.
169. Lucas, M. L., Schneider, W., Haberich, F. J., and Blair, J. A., Direct measurement by pH microelectrode of the pH microclimate in rat proximal jejunum, Proc. Royal Soc. B., 192, 39, 1975.
170. Shiau, Y-F., Fernandez, P., Jackson M. J., and McMonagle, S., Mechanisms maintaining a low pH microclimate in the intestine, Am. J. Physiol, 248, G608, 1985.
171. Shiau, Y-F., Mechanism of intestinal fatty acid uptake in the rat: the role of an acidic microclimate, J. Physiol., 421, 463, 1990.
172. Stremmel, W., Lotz, G., Strohmeyer G., and Berk, P. D., Identification, isolation and partial characterization of a fatty acid binding protein from rat jejunal microvillus membranes, J. Clin. Invest., 75, 1068, 1985.
173. Stremmel, W., Uptake of fatty acids by jejunal mucosal cells is mediated by a fatty acid binding membrane protein. J. Clin. Invest., 82, 2001, 1988.
174. McDonald, G. B., and Weidman, M., Partitioning of polar fatty acids into lymph and portal vein after intestinal absorption in the rat, Quart. J. Exp. Physiol, 72, 153, 1987.
175. McDonald, G. B., Saunders, D. R., Weidman, M., and Fisher, L., Portal venous transport of long-chain fatty acids absorbed from rat intestine, Am. J. Physiol, 239, G141, 1980.
176. Bugaut, M., and Carlier, H., Role of intestinal hydrolases, endogenous substrates, and chyloportal partition in fat absorption, in Fat Absorption, Vol. 1, Kuksis, A. Ed., CRC Press, Boca Raton, 197, 1987.
177. Senior, J. R., and Isselbacher, K. J., Direct esterification of monoglycerides with palmityl coenzyme A by intestinal epithelial subcellular fractions, J Biol. Chem., 237, 1454, 1962.
178. Johnson, J. M., Triglyceride biosynthesis in the intestinal mucosa, in Lipid Absorption: Biochemical and Clinical Aspects, Rommel, K., Goebell, H., and Bohmer, R., Eds., MTP Press, Lancaster, 85, 1976.
179. Zilversmit, D. B., The composition and structure of lymph chylomicrons in dog, rat and man, J. Clin. Invest., 44, 1610, 1965.
180. Shiau, Y-F., Mechanism of intestinal fat absorption, Am. J. Physiol., 240,G1-G9, 1981.
181. Bisgaier, C. L., and Glickman, R. M., Intestinal synthesis, secretion and transport of lipoproteins, Annu. Rev. Physiol., 45, 625, 1983.
182. Thomson, A. B. R., Keelan, M., Garg, M. L., and Clandinin, M. T., Intestinal aspects of lipid absorption: in review, Can. J. Physiol. Pharmacol., 67, 179, 1989.
183. Carey, M. C., Small, D. M., and Bliss, C. M., Lipid digestion and absorption, Annu. Rev. Physiol., 45, 651, 1983.
184. Ueda, C. T., Lemaire, M., Gsell, G., and Nussbaumer, K., Intestinal lymphatic absorption of cyclosporin A following oral administration in an olive oil solution to rats, Biopharm. Drug. Dispos., 4, 113, 1983.
185. Grimus, R. G., and Schuster, I., The role of the lymphatic transport in the enteral absorption of naftifine by the rat, Xenobiotica, 14, 287, 1984.
186. Palin, K. J., and Wilson, C. J., The effect of different oils on the absorption of probucol in the rat. J. Pharm. Pharmacol., 36, 641, 1984.
187. Ichihashi, T., Kinoshita, H., Shimamura, K., and Yamada, H., Absorption and disposition of epithiosteroids in rats (1): Route of administration and plasma levels of epitiostanol, Xenobiotica, 21, 865, 1991.
188. Ichihashi, T., Kinoshita, H., and Yamada, H., Absorption and disposition of epithiosteroids in rats (2): Avoidance of first-pass metabolism of mepitiostane by lymphatic absorption, Xenobiotica, 21, 873, 1991.
189. Kuksis, A., Absorption of fat-soluble vitamins, in Fat Absorption, Vol. 2, Kuksis, A., Ed., CRC Press, Boca Raton, 65, 1987.
190. Porter, C. J. H., Charman, S. A., and Charman W. N., Lymphatic transport of halofantrine in the triple-cannulated anaesthetized rat model: Effect of lipid vehicle dispersion, J. Pharm. Sci., 85, 351, 1996.
191. Sieber, S. M., The lymphatic absorption of p,p-DDT and some structurally-related compounds in the rat., Pharmacology, 14, 443, 1976.
192. Charman, W. N., Noguchi, T., and Stella, V. J., An experimental system designed to study the in situ intestinal lymphatic transport of drugs in anaesthetized rats, Int. J. Pharmaceut., 33, 155, 1986.
193. Charman, W. N., and Stella, V. J., Effect of lipid class and lipid vehicle volume on the intestinal lymphatic transport of DDT, Int. J. Pharmaceut., 33, 165, 1986.
194. Laher, J. M., Rigler, M. W., Vetter, R. D., Barrowman, J. A., and Patton, J. S., Similar bioavailability and lymphatic transport of benzo(a)pyrene when administered to rats in different amounts of dietary fat, J. Lipid Res., 25, 1337, 1984.
195. Busbee, D. L., Yoo, J-S, H., Norman, J. O., and Joe, C. O., Polychlorinated biphenyl uptake and transport by lymph and plasma components, Proc. Soc. Exp. Biol. Med., 179, 116, 1985.
196. Charman, W. N., and Stella, V. J., Estimating the maximal potential for intestinal lymphatic transport of lipophilic drug molecules, Int. J. Pharmaceut, 34, 175, 1986.
197. Bollman, J. L., Cava, J. C., and Grindley, J. H., Techniques for the collection of lymph from the liver, small intestine and thoracic duct of the rat, J. Lab. Clin. Med., 33, 1349, 1948.
198. Aramaki, Y., Tomizawa, H., Hara, T., Yachi, K., Kikuchi, H., and Tsuchiya, S., Stability of liposomes in vitro and their uptake by rat Peyer's patches following oral administration, Pharm. Res., 10, 1228, 1993.
199. Tomizawa, H., Aramaki, Y., Fujii, Y., Hara, T., Suzuki, N., Yachi, K., Kikuchi, H., and Tsuchiya, S., Uptake of phosphatidylserine liposomes by rat Peyer's patches following intraluminal administration, Pharm. Res., 10, 549, 1993.
200. Childers, N. K., Denys, F. R., McGee, N. F., and Michalek, S. M., Ultrastructural study of liposome uptake by M cells of rat Peyer's patch: an oral vaccine system for delivery of purified antigen, Reg. Immun., 3, 8, 1990.
201. Fernandez, E., and Borgstrom, B., Intestinal absorption of retinol and retinyl palmitate. Effects of tetrahydrolipstatin, Lipids, 25, 549, 1990.
202. Fernandez, E., and Borgstrom, B., Effects of tetrahydrolipistatin, a lipase inhibitor on absorption of fat from the rat intestine, Biochim. Biophys. Acta, 1001, 249, 1989.
203. Fukui, E., Kurohara, H., Kareyu, A., Kurisaki, Y., Nakayaman T., and Kimura, T., Enhancing effect of medium-chain triglycerides on intestinal absorption of d-α-tocopherol acetate from lecithin-dispersed preparations in the rat, J. Pharmacobio-Dyn., 12, 80, 1989.
204. Noguchi, T., Charman, W. N., and Stella, V. J., The effect of drug lipophilicity and lipid vehicles on the lymphatic absorption of various testosterone esters, Int. J. Pharmaceut., 24, 173, 1985.
205. Nishigaki, R., Awazu, S., Hanano, M., and Fuwa, T., The effect of dosage form on absorption of vitamin A into lymph, Chem. Pharm. Bull., 24, 3207, 1976.
206. Takada, K., Yoshimura, H., Yoshikawa, H., Muranishi, S., Yasumura, T., and Oka, S., Enhanced lymphatic delivery of cyclosporin A by solubilisers and intensified immunosuppressive activity against mice skin allograft, Pharm. Res., 3, 48, 1986.
207. Ichihashi, T., Kinoshita, H., Takagishi, Y., and Yamada, H., Effect of oily vehicles on absorption of mepitiostane by the lymphatic system in rats, J. Pharm. Pharmacol., 44, 560, 1992.
208. Adachi, I., Liu, H., Horkoshi, I., and Ueno, M., Possibility of lymphatic absorption of epidermal growth factor from intestine, Yakugaku Zasshi, 113, 256, 1993.
209. Moriwaki, T., Yoshikawa, H Takada, K., and Muranishi, S., DDS with MFGM (milk fat globule membrane): Gastrointestinal absorption of vitamin A acetate, Yakuzaikaku, 50, 263, 1990.
210. Honda, T., Okamoto, M., Maeda, M., Kawagoshi, T., Nihonmatsu, H., Yamashita, I., Yoshida, M., Tazawa, K., and Fujimaki, M., DDS with MFGM (milk fat globule membrane): Intestinal absorption of MFGM-insulin emulsion, Drug Deliv. Sys., 7, 43, 1992.
211. Liu, H., Adachi, I., Horikoshi, I., and Ueno, M., Promotion of intestinal drug absorption by milk fat globule membrane, Yakugaku Zasshi, 111, 510, 1991.
212. Liu, H-X., Adachi, I., Horikoshi, I., and Ueno, M., Mechanism of promotion of lymphatic drug absorption by milk fat globule membrane, Int. J. Pharmaceut., 118, 55, 1995.
213. Porter, C. J. H., Charman, S. A., Humberstone, A. J., and Charman, W. N., Lymphatic transport of halofantrine in the conscious rat when administered as either the free base or the hydrochloride salt: effect of lipid class and lipid vehicle dispersion. J. Pharm. Sci., 85, 357, 1996.
214. Hauss, D. J., Mehta, S., Radebaugh, G. W., Targeted lymphatic transport and modified systemic distribution of CI-976, a lipophilic lipid-regulator drug, via a formulation approach, Int. J. Pharmaceut., 108, 85, 1994.
215. Nankervis, R., Davis, S. S., Day, N. H., and Shaw, P. N., Intestinal lymphatic transport of three retinoids in the rat after oral administration: effect of lipophilicity and lipid vehicle, Int. J. Pharmaceut., 130, 57, 1996.
216. Stella, V. J., and Pochopin, N. L., Lipophilic prodrugs and the promotion of intestinal lymphatic drug transport, in Lymphatic Transport of Drugs, Charman, W. N., and Stella, V. J., Eds., CRC Press, Boca Raton, 181, 1992.
217. 2-α-tocopheryl esters in the rat, Lipids, 10, 627, 1975.
218. Gallo-Torres, H. E., Obligatory role of bile for the intestinal absorption of vitamin E, Lipids, 5, 379, 1970.
219. 2-α-tocopheryl nicotinate in the rat, Int. J. Vitam. Nutr. Res., 40, 505, 1970.
220. Hasegawa, J., Tomono, Y., Fujita, T., Sugiyama, K., and Hamamura, K., The effect of food on the absorption of α-tocopheryl nicotinate in beagle dogs and human volunteers, Int. J. Clin. Pharmacol. Ther. Tox., 19, 216, 1981.
221. Mishima, M., Kobayashi, S., Abe, S., and Yamato, C., Metabolic fate of indometacin farnesil, a prodrug of indomethacin: characteristic biotransformation of indometacin farnesil in rats, Xenobiotica, 20, 135, 1990.
222. Ichihashi, T., Kinoshita, H., Takagishi, Y., and Yamada, H., Effect of bile on absorption of mepitiostane by the lymphatic system in rats, J. Pharm. Pharmacol., 44, 566, 1992.
223. Ichihashi, T., Kinoshita, H., Takagishi, Y., and Yamada, H., Intrinsic lymphatic partition rate of mepitiostane, epitiostanol, and oleic acid absorbed from rat intestine, Pharm. Res., 8, 1302, 1991.
224. Tauber, U., Schroder, K., Dusterberg, B., and Matthes, H., Absolute bioavailability of testosterone after oral administration of testosterone-undecanoate and testosterone, Eur. J. Drug Metab. Pharmacokin., 11, 145, 1986.
225. Garzon-Abureh, A., Poupaert, J. H., Claesen, M., and Dumont, P., A lymphotropic prodrug of L-Dopa: Synthesis, pharmacological properties, and pharmacokinetic behavior of 1,3-Dihexadecanoyl-2-[(S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl] propane-1,2,3-triol, J. Med. Chem., 29, 687, 1986.
226. Sugihara, J., Furuuchi, S., Ando, H., Takashima, K., and Harigaya, S., Studies on the intestinal lymphatic absorption of drugs. II. Glyceride prodrugs for improving the lymphatic absorption of naproxen and nicotinic acid, J. Pharmacobio-Dyn., 11, 555, 1988.
227. Sugihara, J., Furuuchi, S., Nakano, K., and Harigaya, S., Studies on the intestinal lymphatic absorption of drugs. I. Lymphatic absorption of alkyl ester derivatives and α-monoglyceride derivatives of drugs, J. Pharmacobio-Dyn, 11, 369, 1988.
228. Mizobe, M., Matsuda, S., Yoneyama, T., and Kohno, K., Evaluation of the bioavailability of hypolipidemic compound, LK-903, Chem. Pharm. Bull., 31, 2424, 1983.
229. Sugihara, J., and Furuuchi, S., Lymphatic absorption of hypolipidemic compound, 1-O-[p-(myristyloxy)-α-methylcinnamoyl]glycerol (LK-903), J. Pharmacobio-Dyn., 11, 121, 1988.
230. Deverre, J. R., Gulik, A., Letourneux, Y., Couvreur, P., and Benoit, J. P., Synthesis and aqueous organization of 1,3-dipalmitoyl-2-(4-aminobutyryl)glycerol. HCl: A diglyceride prodrug. Chem. Phys. Lipids, 59, 75, 1991.
231. Deverre, J. R., Loiseau, P., Couvreur, P., Letourneux, Y., Gayral, P., and Benoit, J. P., In vitro evaluation of filaricidal activity of GABA and 1,3-dipalmitoyl-2-(4-aminobutyryl)glycerol. HCl: a diglyceride prodrug. J. Pharm. Pharmacol, 41, 191, 1989.
232. Jacob, J. N., Hesse, G. W., and Shashoua, V. E., Synthesis, brain uptake, and pharmacological properties of a glyceryl lipid containing GABA and the GABA-T inhibitor, g-vinyl-GABA, J. Med. Chem., 33, 733, 1990.
233. Deverre, J. R., Loiseau, P., Puisieux, F., Gayral, P., Letourneux, Y., Couvreur, P., and Benoit, J. P., Synthesis of the orally macofilaricidal and stable glycerolipidic prodrug of melphalan, 1,3-dipalmitoyl-2-(4′(bis(2″-chloroethyl)amino)phenylalaninoyl) glycerol. Arzneim.-Forsch., 42, 1153, 1992.
234. Elkihel, L., Loiseau, P. M., Bourass, J., Gayral, P., and Letourneux, Y., Synthesis and orally macrofilaricidal evaluation of niclosamide lymphotropic prodrugs, Arzneim.-Forsch, 44, 1259, 1994.
235. Garzon-Abureh, A., Poupaert, J. H., Claesen, M., Dumont, P., and Atassi, G., 1,3-Dipalmitoylglycerol ester of chlorambucil as a lymphotropic, orally administrable antineoplastic agent, J. Med. Chem., 26, 1200, 1983.
236. Sakai, A., Mori, N., Shuto, S., and Suzuki, T., Deacylation-reacylation cycle: A possible absorption mechanism for the novel lymphotropic antitumor agent dipalmitoyl-phosphatidylfluorouridine in rats, J. Pharm. Sci. 82, 575, 1993.
237. Hostetler, K. Y., Richman, D. D., Sridhar, C. N., Felgner, P. L., Felgner, J., Ricci, J., Gardner, M. F., Selleseth, D. W., and Ellis, M. N., Phosphatidylazidothymidine and phosphatidyl-ddC: Assessment of uptake in mouse lymphoid tissues and antiviral activities in human immunodeficiency virus infected cells and in Rauscher leukemia virus infected mice, Antimicrob. Agents Chemother., 38, 2792, 1994.
238. Maccoss, M., Edwards, J. J., Seed, T. M., and Spragg, S. P., Phospholipid-nucleoside conjugates. The aggregation characteristics and morphological aspects of selected 1-β-D-arabinofuranosylcytosine 5′-diphosphate-L-1,2-diacylglycerols, Biochim. Biophys. Acta, 719, 544, 1982.
239. Hong, C. I., An, S-E., Buchheit, D. J., Nechaev, A., Kiristis, A. J., West, C. R., and Berdel, W. E., Nucleoside conjugates. 7. Synthesis and antitumour activity of 1-β-D-arabinofuranosylcytosine conjugates of ether lipids, J. Med. Chem., 29, 2038, 1986.
240. Lavelle, E. C., Sharif, S., Thomas, N. W., Holland, J., and Davis, S. S., The importance of gastrointestinal uptake of particles in the design of oral delivery systems, Adv. Drug Deliv. Rev., 18, 5, 1995.
241. Wilding, I. R., Davis, S. S., O'Hagan, D. T., Targeting of drugs and vaccines to the gut, Pharmac. Ther., 62, 97, 1994.
242. O'Hagan, D. T., Oral delivery of vaccines, formulation and clinical pharmacokinetic considerations, Clin. Pharmacokinet., 22, 1, 1992.
243. Florence, A. T., Hillery, A. M., Hussain, N., and Jani, P. U., Factors affecting the oral uptake and translocation of polystyrene nanoparticles: histological and analytical evidence, J. Drug Targeting, 3, 65, 1995.
244. Worthington, B. S., and Syrotuck, J., Intestinal permeability to large particles in normal and protein deficient adult rats, J. Nutr., 106, 20, 1976.
245. Barbour, W., and Hopwood, D., Uptake of cationized ferritin by colonic epithelium, J. Pathol., 139, 167, 1983.
246. Matsumo, K., Schafner, T., Gerber, H. A., Ruchti, C., Hess, M. W., and Cottier, H., Uptake by enterocytes and subsequent translocation to internal organs, e.g., the thymus of percoll microspheres administered per os to suckling mice, J. Reticuloendothel. Soc., 33, 263, 1983.
247. Clark, S. L., The ingestion of proteins and colloidal materials by columnar cells of the small intestine in suckling rats and mice, Biophys. Biochem. Cytol., 5, 41, 1959.
248. Rehnberg, G. L., Hein, J. F., Carter, S. D., Laskey, J. W., Age dependent changes in gastrointestinal transport of particulate manganese oxide in the rat, J. Toxicol. Environ. Health, 16, 887, 1985.
249. Wells, C. L., Maddaus, M. A., Erlandsen, S. L., and Simmons, R. L., Evidence for the phagocytic transport of intestinal particles in dogs and rats, Infec. Immun., 56, 278, 1988.
250. Wells, C. L., Maddaus, M. A., and Simmons, R. L., Role of the macrophage in the translocation of intestinal bactria, Arch. Surg., 122, 48, 1987.
251. Owen, R. L., Allen, C. L., and Stevens, D. P., Phagocytosis of Giardia muris by macrophages in Peyer's patches epithelium in mice, Infec. Immun., 33, 591, 1981.
252. Aprahamian, M., michel, C., Humbert, W., Devisaguet, J. P., and Damge, C., Transmucosal passage of polyalkylcyanoacrylate nanocapsules as a new drug carrier, Biol. Cell., 61, 69, 1987.
253. Damge, C., Michel, C., Aprahamian, M., and Couvreur, P., New approach for oral administration of insulin with polyalkylcyanoacrylate nanocapsules as drug carriers, Diabetes, 37, 246, 1988.
254. Michel, C., Aprahamian, M., Defontaine, L., Couvreur, P., and Damge, C., The effect of site of administration in the gastrointestinal tract on the absorption of insulin from nanoparticles in diabetic rats. J. Pharm. Pharmacol., 43, 1, 1991.
255. Volkheimer, G., Persorption of particles: physiology and pharmacology, Adv. Pharmacol. Chemother., 14, 163, 1977.
256. Volkheimer, G., Hematogenous dissemination of ingested polyvinyl chloride particles, Ann. N. Y. Acad. Sci., 409, 164, 1983.
257. Santiago, N., Haas, S., Baughman, R. A., Vehicles for oral immunization, in Vaccine Design: the Subunit and Adjuvant Approach, Powell, M. F., and Newman, M. J., Eds., Plenum Press, N. Y., 413, 1995.
258. LeFevre, M. E., Hancock, D. C., and Joel, D. D., Intestinal barrier to large particulates in mice, J. Toxicol. Environ. Health, 6, 691, 1980.
259. LeFevre, M. E., and Joel, D. D., Peyer's patch epithelium, an imperfect barrier, in Intestinal Toxicology, Schiller, C. M., Ed., Raven Press, N. Y., 45, 1984.
260. Joel, D. D., Laissue, J. A., and Lefevre, M. E., Distribution and fate of ingested carbon particles in mice, J. Reticulaendothel. Soc. 24, 477, 1978.
261. LeFevre, M. E., Joel, D. D., and Schidlovsky, G., Retention of ingested latex particles in Peyer's patches of germfree and conventional mice (42133), Proc. Soc. Exp. Biol. Med., 179, 522, 1985.
262. LeFevre, M. E., and Joel, D. D., Distribution of label after intragatric administration of 7Be-labeled carbon to weanling and aged mice (42318), Proc. Soc. Exp. Biol. Med., 182, 112, 1986.
263. LeFevre, M. E., Warren, J. B., and Joel, D. D., Particles and macrophages in murine Peyer's patches, Expl. Cell. Biol., 53, 121, 1985.
264. LeFevre, M. E., Boccio, A. M., and Joel, D. D., Intestinal uptake of fluorescent microspheres in young and aged mice (4825), Proc. Soc. Exp. Biol. Med., 190, 23, 1989.
265. Pappo, J., and Ermak, T. H., Uptake and translocation of fluorescent latex particles by rabbit Peyer's patch follicle epithelium: a quantitative model for M cell uptake, Clin. Exp. Immunol., 76, 144, 1989.
266. Jepson, M. A., Simmons, N. L., O'Hagan, D. T., and Hurst, B. H., Comparison of poly(DL-lactide-co-glycolide) and polystyrene microsphere targeting to intestinal M cells, J. Drug Targeting, 1, 245, 1993.
267. Jepson, M. A., Simmons, N. L., Savidge, T. C., James, P. S., and Hirst, B. H., Selective binding and transcytosis of latex microspheres by rabbit intestinal M cells, Cell. Tissue Res., 271, 399, 1993.
268. Sass, W., Dreyer, H-P., and Seifert, J., Rapid insorption of small particles in the gut, Am. J. Gastroenterol., 85, 255, 1990.
269. Ebel, J. D., A method for quantifying particle absorption from the mouse small intestine, Pharm. Res., 7, 848, 1990.
270. Jenkins, P. G., Howard, K. A., Blackhall, N. W., Thomas, N. W., Davis, S. S., and O'Hagan, D. T., Microparticulate absorption from the rat intestine, J. Controlled Release, 29, 339, 1994.
271. Jenkins, P. G., Howard, K. A., Blackhall, N. W., Thomas, N. W., Davis, S. S., and O'Hagan, D. T., The quantitation of the absorption of microparticles into the intestinal lymph of Wistar rats, Int. J. Pharmaceut., 102, 261, 1994.
272. Jani, P., Halbert, G. W., Langridge, J., and Florence, A. T., The uptake and translocation of latex nanospheres and microspheres after oral administration to rats, J. Pharm. Pharmacol., 41, 809, 1989.
273. Jani, P., Halbert, G. W., Langridge, J., and Florence, A. T., Nanaoparticle uptake by the rat gastrointestinal mucosa: Quantitation and particle size dependency, J. Pharm. Pharmacol., 42, 821, 1990.
274. Alpar, H. O., Field, W. N., Hyde, R., and Lewis, D. A., The transport of microspheres from the gastrointestinal tract to inflammatory air pouches in the rat, J. Pharm. Pharmacol., 41, 194, 1989.
275. Alpar, H. O., Field, W. N., Hayes, K., and Lewis, D. A., A possible use of orally administered microspheres in the treatment of inflammation, J. Pharm. Pharmacol., 41, 50P, 1989.
276. Jani, P. U., Florence, A. T., and McCarthy, D. E., Further histological evidence of the gastrointestinal absorption of polystyrene nanospheres in the rat, Int. J. Pharmaceut., 84, 245, 1992.
277. Jani, P. U., McCarthy, D. E., and Florence, A. T., Nanosphere and microsphere uptake via Peyer's patches: observation of the rate of uptake in the rat after a single oral dose, Int. J. Pharmaceut., 86, 239, 1992.
278. Eldridge, J. H., Hammond, C. J., Meulbroeck, J. A., Staas, J. K., Gilley, R. M., and Tice, T. R., Controlled vaccine release in the gut-associated lymphoid tissues. I. Orally administered biodegradable microspheres to target the Peyer's patches, J. Control. Rel., 11, 205, 1990.
279. Hillery, A. N., Jani, P. U., and Florence, A. T., Comparative, quantitative study of lymphoid and non-lymphoid uptake of 60 nm polystyrene particles, J. Drug Target., 2, 151, 1994.
280. Porta, C., James, P. S., Phillips, A. D., Savidge, T. C., Smith, M. W., and Cremaschi, D., Confocal analysis of fluorescent bead uptake by mouse Peyer's patch follicle associated M cells, Exp. Physiol., 77, 929, 1992
281. Smith, M. W., Thomas, N. W., Jenkins, P. G., Miller, N. G. A., Cremaschi, D., and Porta, C., Selective transport of microparticles across Peyer's patch follicle-associated M cells from mice and rats, Exp. Physiol., 80, 735, 1995.
282. Pappo, J., Ermak, T. H., and Steger, H. J., Monoclonal antibody-directed targeting of fluorescent polystyrene microspheres to Peyer's patch M cells, Immunology, 73, 277, 1991.
283. Artursson, P., Johansson, D., Sjoholm, I., Receptor mediated uptake of starch and mannan microparticles by macrophages: relative contribution of receptors for complement immunoglobulins and carbohydrates, Biomaterials, 9, 241, 1988.
284. Illum, L., and Davis, S. S., The organ uptake of intravenously administered colloidal particles can be altered using a non-ionic surfactant (Poloxamer 338), FEBS Lett., 167, 79, 1984.
285. Ilium, L., Hunneyball, I. M., and Davis, S. S., The effect of hydrophilic coatings on the uptake of colloidal particles by the liver and by peritoneal macrophages, Int. J. Pharmaceut., 29, 53, 1986.
286. Santiago, N., Haas, S., Baughman, R. A., Vehicles for oral immunization, Pharm. Biotechnol, 6, 413, 1995.
287. Jenkins, P. G., Coombes, A. G. A., Yeh, M. K., Thomas, N. W., and Davis, S. S., Aspects of the design and delivery of microparticles for vaccine applications, J. Drug Target., 3, 79, 1995.
288. O'Hagan, D. T., Palin, K. J., and Davis, S. S., Intestinal absorption of proteins and macromolecules and the immunological response, Crit. Rev. Ther. Drug Carrier Sys., 4, 197, 1987.
289. Challacome, S. J., Rahman, D., Jeffrey, H., Davis, S. S., and O'Hagan, D. T., Enhanced secretory IgA and systemic IgG antibody responses after oral administration with biodegradable microparticles containing antigen, Immunology, 76, 164, 1992.
290. O'Hagan, D. T., Palin, K. J., and Davis, S. S., Poly(butyl-2-cyanoacrylate) particles as adjuvants for oral administration, Vaccine, 7, 213, 1989.
291. O'Hagan, D. T., Palin, K., Davis, S. S., Artursson, P., and Sjoholm, I., Microparticles as potentially orally active immunological adjuvants, Vaccine, 7, 421, 1989.
292. McQueen, C. E., Boedeker, E. C., Reid, R., Jarboe, D., Wolf, M., Le, M., and Brown, W. R., Pili in microspheres protect rabbits from diarrhoea induced by E. coli strain RDEC-1, Vaccine, 11, 201, 1993.
293. Edelman, R., Russell, R. G., Losonsky, G., Tall, B. D., Tacket, C. O., Levine, M. M., and Lewis, D. H., Immunization of rabbits with enterotoxigenic E. coli colonization factor antigen (CFA/I) encapsulated in biodegradable microspheres of poly (lactide-co-glycolide), Vaccine, 11, 155, 1993.
294. Reid, R. H., Boedeker, E. C., McQueen, C. E., Davis, D., Tseng, L.-Y., Kodak, J., Sau, K., Wilhelmsen, C. L., Nellore, R., Dalal, P., and Bhagat, H. R., Preclinical evaluation of microencapsulated CFA/II oral vaccine against enterotoxigenic E. coli, Vaccine, 2, 159, 1993.
295. O'Hagan, D. T., Rahman, D., Jeffery, H., Sharif, S., and Challacombe, S. J., Controlled release microparticles for oral immunization, Int. J. Pharmaceut., 108, 133, 1994.
296. Sau, K., Reid, R. H., McQueen, C., Boedeker, E. C., Nellore, R., Dalal, P., and Bhagat, H. R., Intraduodenal immunization with microencapsulated CFA/II induces a delayed, anti-CFA/II, IgG antibody-secreting spleen cell response, Adv. Exp. Med. Biol., 371B, 1469, 1995.
297. Eldridge, J. H., Staas, J. K., Meulbroek, J. A., McGhee, J. R., Tice, T. R., and Gilley, R. M., Biodegradable microspheres as a vaccine delivery system, Mol. Immunol., 28, 287, 1991.
298. McGee, J. P., Davis, S. S., and O'Hagan, D. T., The immunogenicity of a model protein entrapped in poly(lactide-co-glycolide) microparticles prepared by a novel phase separation technique, J. Control. Rel., 31, 55, 1994.
299. O'Hagan, D. T., McGee, J. P., Holmgren, J., Mowat, A. MCl., Donachie, A. M., Mills, K. H. G., Gaisford, W., Rahman, D., and Challacombe, S. J., Biodegradable microparticles for oral immunization, Vaccine, 11, 149, 1993.
300. Santiago, N., Milstein, S., Rivera, T., Garcia, G., Zaidi, T., Hong, H., and Bucher, D., Oral immunization of rats with proteinoid microspheres encapsulating influenza virus antigens, Pharm. Res., 10, 1243, 1993.
301. Jones, D. H., McBride, B. W., Thornton, C., O'Hagan, D. T., Robinson, A., and Farrar, G. H., Orally administered microencapsulated Bordetella pertussis fimbriae protect mice from B. pertussis respiratory infection, Infect. Immun., 2, 489, 1996.
302. Alpar, H. O., Almeida, A. J., Identification of some of the physico-chemical characteristics of microspheres which influence the induction of the immune response following mucosal delivery, Eur. J. Pharm. Biopharm., 40, 198, 1994.
303. O'Hagan, D. T., Intestinal translocation of particulates - implications for drug and antigen delivery, Adv. Drug Deliv. Rev., 5, 265, 1990.
304. O'Hagan, D. T., Jeffery, H., Maloy, K. J., Mowat, A. MCI., Rahman, D., and Challacombe, S. J., Biodegradable microparticles as oral vaccines, Adv. Exp. Med. Biol., 371B, 1463, 1995.
305. Hanaue, H., Kurosawa, T., Kitano, Y., Miyakawa, S., Horie, F., Nemoto, A., Shikata, J., N1-(2 tetrahydrofuryl)-5-fluorouracil (FT-207) in the postoperative adjuvant chemotherapy of gastric cancer, Cancer, 57, 693, 1986.
306. Oba, N., Sugimura, H., Umehara, Y., Yoshida, M., Kimura, T., and Yamaguchi, T., Evaluation of an oleic acid water-in-oil-in-water type multiple emulsion as potential drug carrier via the enteral route, Lipids, 27, 701, 1992.
307. Nakamoto, Y., Takeeda, T., Sakikawa, F., Morimoto, K., Morisaka, K., Muranishi, S., and Sezaki, H., Enhancement of lymphatic transport of 1-(2-tetrahydrofuryl)-5-fluorouracil by water in oil emulsion, J. Pharm. Dyn., 2, 45, 1979.
308. Omotosho, J. A., Florence, A. T., and Whateley, T. L., Absorption and lymphatic uptake of 5-fluorouracil in the rat following oral administration of W/O/W multiple emulsions, Int. J. Pharmaceut., 61, 51, 1990.
309. Chiang, C.-M., and Weiner, N., Gastrointestinal uptake of liposomes, Int. J. Pharmaceut., 37, 75, 1987.
310. Wachsmann, D., Klein, J. P., Scholler, M., Ogier, J., Ackermans, F., and Frank, R. M., Serum and salivary antibody responses in rats orally immunised with streptococcus mutans carbohydrate protein conjugate associated with liposomes, Infect. Immun., 52, 408, 1986.
311. Gregory, R. L., Michalek, S. M., Richardson, G., Harmon, C., Hilton, T., and McGhee, J. R., Characterization of immune response to oral administration of streptococcus sobrinus ribosomal preparations in liposomes, Infect. Immun., 54, 780, 1986.
312. Jackson, S., Mestecky, J., Childers, N. K., and Michalek, S. M., Liposomes containing anti-idiotypic antibodies: an oral vaccine to induce protective secretory immune responses specific for pathogens of mucosal surfaces, Infect. Immun., 58, 1932, 1990.
313. Laing, G. D., and Theakston, R. D. G., Immunization against Echis ocellatus (carpet viper) venom using liposomes incorporating immunostimulants: role of lipopolysaccharide in conferring protection in a mouse model, Toxicon, 31, 615, 1993.
314. Childers, N. K., Michalek, S. M., Pritchard, D. G., and McGhee, J. R., Mucosal and systemic responses to an oral liposome-streptococcus mutans carbohydrate vaccine in humans, Reg. Immun., 3, 289, 1991.
315. Wachsmann, D., Klein, J. P., Scholler, M., Frank, R. M., Local and systemic immune response to orally administered liposome associated soluble S. mutans cell wall antigens, Immunology, 54, 189, 1985.
316. Michalek, S. M., Childers, N. K., Katz, J., Dertzbaugh, M., Zhang, S., Russell, M. W., Macrina, F. L., Jackson, S., and Mestecky, J., Liposomes and conjugate vaccines for antigen delivery and induction of mucosal immune responses, Adv. Exp. Med. Biol., 327, 191, 1992.