From sewer to saviour-targeting the lymphatic system to promote drug exposure and activity

Nature Reviews Drug Discovery

Volumn 14, Issue 11, 2015, Pages 781-803

  Trevaskis, Natalie L ^a   Kaminskas, Lisa M ^a   Porter, Christopher J H ^a  

^a MONASH UNIVERSITY   (Australia)

Author keywords

[No Author keywords available]

Indexed keywords

DENDRIMER; LIPID; LIPOPROTEIN; LIPOSOME; METHYLESTRENOLONE; NANOMATERIAL; SUPERPARAMAGNETIC IRON OXIDE; TESTOSTERONE UNDECANOATE; NANOPARTICLE; PRODRUG;

ANTIGEN PRESENTING CELL; ATHEROSCLEROSIS; DRUG ACTIVITY; DRUG BIOAVAILABILITY; DRUG DELIVERY SYSTEM; DRUG EXPOSURE; DRUG METABOLISM; EXOCYTOSIS; FIRST PASS EFFECT; GASTROINTESTINAL MUCOSA; GASTROINTESTINAL TRACT; HOMEOSTASIS; HUMAN; IMMUNE RESPONSE; IMMUNOLOGICAL TOLERANCE; INTERSTITIAL FLUID; LIPID ABSORPTION; LIPID METABOLISM; LIPID STORAGE; LIPID TRANSPORT; LYMPH VESSEL; LYMPHATIC SYSTEM; MACROMOLECULE; MESENTERY LYMPH NODE; METASTASIS; NANOTECHNOLOGY; OBESITY; OSMOTIC PRESSURE; PRIORITY JOURNAL; RECOGNITION; REVIEW; VACCINATION; ANIMAL; DRUG EFFECTS; METABOLISM; NEOPLASMS; PATHOLOGY; PHYSIOLOGY; PROCEDURES; TRANSPORT AT THE CELLULAR LEVEL; TRENDS;

ANIMALS; BIOLOGICAL TRANSPORT; DRUG DELIVERY SYSTEMS; HUMANS; LYMPHATIC SYSTEM; LYMPHATIC VESSELS; NANOPARTICLES; NEOPLASMS; PRODRUGS;

EID: 84946486670     PISSN: 14741776     EISSN: 14741784     Source Type: Journal    
DOI: 10.1038/nrd4608     Document Type: Review

References (280)

1. Girard, J. P., Moussion, C., & Forster, R. HEVs, lymphatics, and homeostatic immune cell trafficking in lymph nodes. Nat. Rev. Immunol. 12, 762-773 (2012
2. Randolph, G. J., & Miller, N. E. Lymphatic transport of high-density lipoproteins, and chylomicrons. J. Clin. Invest. 124, 929-935 (2014
3. Miller, N. E., et al. Secretion of adipokines by human adipose tissue in vivo: partitioning between capillary, and lymphatic transport. Am. J. Physiol. Endocrinol. Metab. 301, E659-E667 (2011
4. Wiig, H., & Swartz, M. A. Interstitial fluid, and lymph formation, and transport: physiological regulation, and roles in inflammation, and cancer. Physiol. Rev. 92, 1005-1060 (2012
5. Starling, E. H. On the absorption of fluids from the connective tissue spaces. J. Physiol. 19, 312-326 (1896
6. Levick, J. R., & Michel, C. C. Microvascular fluid exchange, and the revised Starling principle. Cardiovasc. Res. 87, 198-210 (2010
7. Mortimer, P. S., & Rockson, S. G. New developments in clinical aspects of lymphatic disease. J. Clin. Invest. 124, 915-921 (2014
8. Card, C. M., Yu, S. S., & Swartz, M. A. Emerging roles of lymphatic endothelium in regulating adaptive immunity. J. Clin. Invest. 124, 943-952 (2014
9. Pabst, O., & Mowat, A. M. Oral tolerance to food protein. Mucosal Immunol. 5, 232-239 (2012
10. Lichtenstein, L., et al. Angptl4 protects against severe proinflammatory effects of saturated fat by inhibiting fatty acid uptake into mesenteric lymph node macrophages. Cell. Metabolism 12, 580-592 (2010
11. Macpherson, A. J., & Smith, K. Mesenteric lymph nodes at the center of immune anatomy. J. Exp. Med. 203, 497-500 (2006
12. Dixon, J. B. Lymphatic lipid transport: sewer or subway? Trends Endocrinol. Metab. 21, 480-487 (2010
13. Martel, C., et al. Lymphatic vasculature mediates macrophage reverse cholesterol transport in mice. J. Clin. Invest. 123, 1571-1579 (2013
14. Lim, H. Y., et al. Lymphatic vessels are essential for the removal of cholesterol from peripheral tissues by SR BI mediated transport of HDL. Cell. Metabolism 17, 671-684 (2013
15. Harvey, N. L. The link between lymphatic function, and adipose biology. Ann. NY Acad. Sci. 1131, 82-88 (2008
16. Pond, C. M. Adipose tissue, and the immune system. Prostaglandins Leukot. Essent. Fatty Acids 73, 17-30 (2005
17. Harvey, N. L., et al. Lymphatic vascular defects promoted by Prox1 haploinsufficiency cause adult-onset obesity. Nat. Genet. 37, 1072-1081 (2005
18. Sawane, M., et al. Apelin inhibits diet-induced obesity by enhancing lymphatic, and blood vessel integrity. Diabetes 62, 1970-1980 (2013
19. Blum, K. S., et al. Chronic high-fat diet impairs collecting lymphatic vessel function in mice. PLoS ONE 9, e94713 (2014
20. Arngrim, N., Simonsen, L., Holst, J. J., & Bulow, J. Reduced adipose tissue lymphatic drainage of macromolecules in obese subjects: a possible link between obesity, and local tissue inflammation? Int. J. Obes. 37, 748-750 (2013
21. Savetsky, I. L., et al. Obesity increases inflammation, and impairs lymphatic function in a mouse model of lymphedema. Am. J. Physiol. Heart Circ. Physiol. 307, H165-H172 (2014
22. Weitman, E. S., et al. Obesity impairs lymphatic fluid transport, and dendritic cell migration to lymph nodes. PLoS ONE 8, e70703 (2013
23. Kim, C. S., et al. Visceral fat accumulation induced by a high-fat diet causes the atrophy of mesenteric lymph nodes in obese mice. Obesity 16, 1261-1269 (2008
24. Alitalo, K. The lymphatic vasculature in disease. Nat. Med. 17, 1371-1380 (2011
25. Kesler, C. T., Liao, S., Munn, L. L., & Padera, T. P. Lymphatic vessels in health, and disease. Wiley Interdiscip. Rev. Syst. Biol. Med. 5, 111-124 (2013
26. Wang, Y., & Oliver, G. Current views on the function of the lymphatic vasculature in health, and disease. Genes Dev. 24, 2115-2126 (2010
27. Swartz, M. A., & Lund, A. W. Lymphatic, and interstitial flow in the tumour microenvironment: linking mechanobiology with immunity. Nat. Rev. Cancer 12, 210-219 (2012
28. Dieterich, L. C., Seidel, C. D., & Detmar, M. Lymphatic vessels: new targets for the treatment of inflammatory diseases. Angiogenesis 17, 359-371 (2014
29. Proulx, S. T., et al. Expansion of the lymphatic vasculature in cancer, and inflammation: new opportunities for in vivo imaging, and drug delivery. J. Control. Release 172, 550-557 (2013
30. von der Weid, P. Y., Rehal, S., & Ferraz, J. G. Role of the lymphatic system in the pathogenesis of Crohn's disease. Curr. Opin. Gastroenterol. 27, 335-341 (2011
31. Alessio, S., et al. VEGF C-dependent stimulation of lymphatic function ameliorates experimental inflammatory bowel disease. J. Clin. Invest. 124, 3863-3878 (2014
32. Huggenberger, R., et al. An important role of lymphatic vessel activation in limiting acute inflammation. Blood 117, 4667-4678 (2011
33. Zhang, Q., et al. Increased lymphangiogenesis in joints of mice with inflammatory arthritis. Arthritis Res. Ther. 9, R118 (2007
34. Baluk, P., et al. TNF α drives remodeling of blood vessels, and lymphatics in sustained airway inflammation in mice. J. Clin. Invest. 119, 2954-2964 (2009
35. Machnik, A., et al. Macrophages regulate salt-dependent volume, and blood pressure by a vascular endothelial growth factor-C dependent buffering mechanism. Nat. Med. 15, 545-552 (2009
36. Ribera, J., et al. Increased nitric oxide production in lymphatic endothelial cells causes impairment of lymphatic drainage in cirrhotic rats. Gut 62, 138-145 (2012
37. Jones, D., & Min, W. An overview of lymphatic vessels, and their emerging role in cardiovascular disease. J. Cardiovasc. Dis. Res. 2, 141-152 (2011
38. Fletcher, C. V., et al. Persistent HIV 1 replication is associated with lower antiretroviral drug concentrations in lymphatic tissues. Proc. Natl Acad. Sci. USA 111, 2307-2312 (2014
39. Pantaleo, G., et al. Lymphoid organs function as major reservoirs for human-immunodeficiency-virus. Proc. Natl Acad. Sci. USA 88, 9838-9842 (1991
40. Giannini, C., et al. Association between persistent lymphatic infection by hepatitis C virus after antiviral treatment, and mixed cryoglobulinemia. Blood 111, 2943-2945 (2008
41. Bennuru, S., & Nutman, T. B. Lymphangiogenesis, and lymphatic remodeling induced by filarial parasites: implications for pathogenesis. PLoS Pathog. 5, e1000688 (2009
42. Feldmann, H., & Geisbert, T. W. Ebola haemorrhagic fever. Lancet 377, 849-862 (2011
43. Deitch, E. A. Gut lymph, and lymphatics: a source of factors leading to organ injury, and dysfunction. Ann. NY Acad. Sci. 1207, E103-E111 (2010
44. Kerjaschki, D., et al. Lymphatic endothelial progenitor cells contribute to de novo lymphangiogenesis in human renal transplants. Nat. Med. 12, 230-234 (2006
45. Wang, X., et al. Mechanism of oral tolerance induction to therapeutic proteins. Adv. Drug Deliv. Rev. 65, 759-773 (2013
46. Swartz, M. A., Hirosue, S., & Hubbell, J. A. Engineering approaches to immunotherapy. Sci. Transl. Med. 4, 148rv9 (2012
47. Trevaskis, N. L., Charman, W. N., & Porter, C. J. Lipid-based delivery systems, and intestinal lymphatic drug transport: a mechanistic update. Adv. Drug Deliv. Rev. 60, 702-716 (2008
48. Ryan, G. M., Kaminskas, L. M., & Porter, C. J. Nano-chemotherapeutics: maximising lymphatic drug exposure to improve the treatment of lymph-metastatic cancers. J. Control. Release 193, 241-256 (2014
49. Yáñez, J. A., Wang, S. W. J., Knemeyer, I. W., Wirth, M. A., & Alton, K. B. Intestinal lymphatic transport for drug delivery. Adv. Drug Deliv. Rev. 63, 923-942 (2011
50. Supersaxo, A., Hein, W. R., & Steffen, H. Effect of molecular-weight on the lymphatic absorption of water-soluble compounds following subcutaneous administration. Pharm. Res. 7, 167-169 (1990
51. Irvine, D. J., Swartz, M. A., & Szeto, G. L. Engineering synthetic vaccines using cues from natural immunity. Nat. Mater. 12, 978-990 (2013
52. Charman, S. A., McLennan, D. N., Edwards, G. A., & Porter, C. J. H. Lymphatic absorption is a significant contributor to the subcutaneous bioavailability of insulin in a sheep model. Pharm. Res. 18, 1620-1626 (2001
53. Charman, S. A., Segrave, A. M., Edwards, G. A., & Porter, C. J. H. Systemic availability, and lymphatic transport of human growth hormone administered by subcutaneous injection. J. Pharm. Sci. 89, 168-177 (2000
54. Kota, J., et al. Lymphatic absorption of subcutaneously administered proteins: influence of different injection sites on the absorption of darbepoetin alfa using a sheep model. Drug Metab. Dispos. 35, 2211-2217 (2007
55. McLennan, D., et al. Pharmacokinetic model to describe the lymphatic absorption of r methu-leptin after subcutaneous injection to sheep. Pharm. Res. 20, 1156-1162 (2003
56. McLennan, D., et al. The absorption of darbepoetin alfa occurs predominantly via the lymphatics following subcutaneous administration to sheep. Pharm. Res. 23, 2060-2066 (2006
57. McLennan, D. N., et al. Lymphatic absorption is the primary contributor to the systemic availability of epoetin alfa following subcutaneous administration to sheep. J. Pharmacol. Exp. Ther. 313, 345-351 (2005
58. Oussoren, C., Zuidema, J., Crommelin, D. J., & Storm, G. Lymphatic uptake, and biodistribution of liposomes after subcutaneous injection. II. Influence of liposomal size, lipid composition, and lipid dose. Biochim. Biophys. Acta 1328, 261-272 (1997
59. Reddy, S. T., et al. Exploiting lymphatic transport, and complement activation in nanoparticle vaccines. Nat. Biotech. 25, 1159-1164 (2007
60. Reed, A. L., Rowson, S. A., & Dixon, J. B. Demonstration of ATP-dependent, transcellular transport of lipid across the lymphatic endothelium using an in vitro model of the lacteal. Pharm. Res. 30, 3271-3280 (2013
61. Laakkonen, P., et al. Antitumor activity of a homing peptide that targets tumor lymphatics, and tumor cells. Proc. Natl Acad. Sci. USA 101, 9381-9386 (2004
62. Laakkonen, P., Porkka, K., Hoffman, J. A., & Ruoslahti, E A tumor-homing peptide with a targeting specificity related to lymphatic vessels. Nat. Med. 8, 751-755 (2002
63. Parker, J. C., Gilchrist, S., & Cartledge, J. T. Plasma-lymph exchange, and interstitial distribution volumes of charged macromolecules in the lung. J. Appl. Physiol. 59, 1128-1136 (1985
64. Stylianopoulos, T., et al. Diffusion of particles in the extracellular matrix: the effect of repulsive electrostatic interactions. Biophys. J. 99, 1342-1349 (2010
65. Kaminskas, L. M., et al. PEGylation of polylysine dendrimers improves absorption, and lymphatic targeting following SC administration in rats. J. Control. Release 140, 108-116 (2009
66. Rao, D. A., Forrest, M. L., Alani, A. W., Kwon, G. S., & Robinson, J. R. Biodegradable PLGA based nanoparticles for sustained regional lymphatic drug delivery. J. Pharm. Sci. 99, 2018-2031 (2010
67. Harvey, A. J., et al. Microneedle-based intradermal delivery enables rapid lymphatic uptake, and distribution of protein drugs. Pharm. Res. 28, 107-116 (2011
68. Lambert, P. H., & Laurent, P. E. Intradermal vaccine delivery: will new delivery systems transform vaccine administration? Vaccine 26, 3197-3208 (2008
69. Nicolas, J. F., & Guy, B. Intradermal, epidermal, and transcutaneous vaccination: from immunology to clinical practice. Expert Rev. Vaccines 7, 1201-1214 (2008
70. Bocci, V., Pessina, G. P., Paulesu, L., & Nicoletti, C. The lymphatic route. VI. Distribution of recombinant interferon-α2 in rabbit, and pig plasma, and lymph. J. Biolog. Response Mod. 7, 390-400 (1988
71. Feng, L., et al. Roles of dextrans on improving lymphatic drainage for liposomal drug delivery system. J. Drug Target. 18, 168-178 (2010
72. Pessina, G. P., Bocci, V., Carraro, F., Naldini, A., & Paulesu, L. The lymphatic route. IX. Distribution of recombinant interferon-α 2 administered subcutaneously with oedematogenic drugs. Physiol. Res. 42, 243-250 (1993
73. Liu, H., et al. Structure-based programming of lymph-node targeting in molecular vaccines. Nature 507, 519-522 (2014
74. Jiang, G., et al. Hyaluronic acid-polyethyleneimine conjugate for target specific intracellular delivery of siRNA. Biopolymers 89, 635-642 (2008
75. Fogal, V., Zhang, L., Krajewski, S., & Ruoslahti, E. Mitochondrial/cell-surface protein p32/gC1qR as a molecular target in tumor cells, and tumor stroma. Cancer Res. 68, 7210-7218 (2008
76. Karmali, P. P., et al. Targeting of albumin-embedded paclitaxel nanoparticles to tumors. Nanomedicine 5, 73-82 (2009
77. Luo, G., et al. LyP 1 conjugated nanoparticles for targeting drug delivery to lymphatic metastatic tumors. Int. J. Pharm. 385, 150-156 (2010
78. Yan, Z., et al. LyP 1 conjugated PEGylated liposomes: a carrier system for targeted therapy of lymphatic metastatic tumor. J. Control. Release 157, 118-125 (2012
79. Desgrosellier, J. S., & Cheresh, D. A. Integrins in cancer: biological implications, and therapeutic opportunities. Nat. Rev. Cancer 10, 9-22 (2010
80. Andorko, J., Hess, K., & Jewell, C. Harnessing biomaterials to engineer the lymph node microenvironment for immunity or tolerance. AAPS J. 17, 323-338 (2014
81. Zeng, Q., et al. Cationic micelle delivery of Trp2 peptide for efficient lymphatic draining, and enhanced cytotoxic T lymphocyte responses. J. Control. Release 200, 1-12 (2015
82. Wang, C., et al. Lymphatic-Targeted cationic liposomes: a robust vaccine adjuvant for promoting long-Term immunological memory. Vaccine 32, 5475-5483 (2014
83. Azad, A. K., Rajaram, M. V., & Schlesinger, L. S. Exploitation of the macrophage mannose receptor (CD206) in infectious disease diagnostics, and therapeutics. J. Cytol. Mol. Biol. 1, 1000003 (2014
84. Kwon, Y. J., James, E., Shastri, N., & Fr?chet, J. M. J. In vivo targeting of dendritic cells for activation of cellular immunity using vaccine carriers based on pH responsive microparticles. Proc. Natl Acad. Sci. USA 102, 18264-18268 (2005
85. Dahlberg, A. M., et al. The lymphatic system plays a major role in the intravenous, and subcutaneous pharmacokinetics of trastuzumab in rats. Mol. Pharm. 11, 496-504 (2014
86. Ryan, G. M., et al. PEGylated polylysine dendrimers increase lymphatic exposure to doxorubicin when compared to PEGylated liposomal, and solution formulations of doxorubicin. J. Control. Release 172, 128-136 (2013
87. Tseng, Y. C., Xu, Z., Guley, K., Yuan, H., & Huang, L. Lipid-calcium phosphate nanoparticles for delivery to the lymphatic system, and SPECT/CT imaging of lymph node metastases. Biomaterials 35, 4688-4698 (2014
88. Iliff, J. J., et al. Brain-wide pathway for waste clearance captured by contrast-enhanced MRI. J. Clin. Invest. 123, 1299-1309 (2013
89. Iliff, J. J., et al A paravascular pathway facilitates CSF flow through the brain parenchyma, and the clearance of interstitial solutes, including amyloid β. Sci. Transl. Med. 4, 147ra111 (2012
90. Iliff, J. J., et al. Cerebral arterial pulsation drives paravascular CSF-interstitial fluid exchange in the murine brain. J. Neurosci. 33, 18190-18199 (2013
91. Xie, L., et al. Sleep drives metabolite clearance from the adult brain. Science 342, 373-377 (2013
92. Yang, L., et al. Evaluating glymphatic pathway function utilizing clinically relevant intrathecal infusion of CSF tracer. J. Transl. Med. 11, 107 (2013
93. Aspelund, A., et al A dural lymphatic vascular system that drains brain interstitial fluid, and macromolecules. J. Exp. Med. 212, 991-999 (2015
94. Louveau, A., et al. Structural, and functional features of central nervous system lymphatic vessels. Nature 523, 337-341 (2015
95. Shackleford, D., Porter, C. H., & Charman, W. in Prodrugs Vol. 5 (eds Stella, V., et al.) 653-682 (Springer, 2007
96. Lambert, D. M. Rationale, and applications of lipids as prodrug carriers. Eur. J. Pharm. Sci. 11 (Suppl. 2), S15-S27 (2000
97. Kunisawa, J., Kurashima, Y., & Kiyono, H. Gut-Associated lymphoid tissues for the development of oral vaccines. Adv. Drug Deliv. Rev. 64, 523-530 (2012
98. Bakhru, S. H., Furtado, S., Morello, A. P., & Mathiowitz, E. Oral delivery of proteins by biodegradable nanoparticles. Adv. Drug Deliv. Rev. 65, 811-821 (2013
99. Florence, A. T. Nanoparticle uptake by the oral route: fulfilling its potential? Drug Discov. Today Technol. 2, 75-81 (2005
100. Khoo, S. M., Shackleford, D. M., Porter, C. J., Edwards, G. A., & Charman, W. N. Intestinal lymphatic transport of halofantrine occurs after oral administration of a unit-dose lipid-based formulation to fasted dogs. Pharm. Res. 20, 1460-1465 (2003
101. Caliph, S. M., Charman, W. N., & Porter, C. J. Effect of short-, medium-, and long-chain fatty acid-based vehicles on the absolute oral bioavailability, and intestinal lymphatic transport of halofantrine, and assessment of mass balance in lymph-cannulated, and non-cannulated rats. J. Pharm. Sci. 89, 1073-1084 (2000
102. Trevaskis, N. L., et al A mouse model to evaluate the impact of species, sex, and lipid load on lymphatic drug transport. Pharm. Res. 30, 3254-3270 (2013
103. Charman, W. N., & Stella, V. J. Estimating the maximum potential for intestinal lymphatic transport of lipophilic drug molecules. Int. J. Pharm. 34, 175-178 (1986
104. Myers, R. A., & Stella, V. J. Factors affecting the lymphatic transport of penclomedine (NSC 338720), a lipophilic cytotoxic drug-comparison to DDT, and hexachlorobenzene. Int. J. Pharm. 80, 51-62 (1992
105. Trevaskis, N. L., Shanker, R. M., Charman, W. N., & Porter, C. J. The mechanism of lymphatic access of two cholesteryl ester transfer protein inhibitors (CP524,515, and CP532,623), and evaluation of their impact on lymph lipoprotein profiles. Pharm. Res. 27, 1949-1964 (2010
106. Choo, E. F., et al. The role of lymphatic transport on the systemic bioavailability of the Bcl 2 protein family inhibitors navitoclax (ABT 263), and ABT 199. Drug Metab. Dispos. 42, 207-212 (2014
107. Gershkovich, P., et al. The role of molecular physicochemical properties, and apolipoproteins in association of drugs with triglyceride-rich lipoproteins: in silico prediction of uptake by chylomicrons. J. Pharm. Pharmacol. 61, 31-39 (2009
108. Gershkovich, P., & Hoffman, A. Uptake of lipophilic drugs by plasma derived isolated chylomicrons: linear correlation with intestinal lymphatic bioavailability. Eur. J. Pharm. Sci. 26, 394-404 (2005
109. Lawless, E., Griffin, B., O'Mahony, A., & O'Driscoll, C. Exploring the impact of drug properties on the extent of intestinal lymphatic transport-in vitro, and in vivo studies. Pharm. Res. 32, 1817-1829 (2014
110. Lu, Y., et al. Biomimetic reassembled chylomicrons as novel association model for the prediction of lymphatic transportation of highly lipophilic drugs via the oral route. Int. J. Pharm. 483, 69-76 (2015
111. Holm, R., & Hoest, J. Successful in silico predicting of intestinal lymphatic transfer. Int. J. Pharm. 272, 189-193 (2004
112. Lipinski, C. A., Lombardo, F., Dominy, B. W., & Feeney, P. J. Experimental, and computational approaches to estimate solubility, and permeability in drug discovery, and development settings. Adv. Drug Deliv. Rev. 46, 3-26 (2001
113. Hopkins, A. L., Keseru, G. M., Leeson, P. D., Rees, D. C., & Reynolds, C. H. The role of ligand efficiency metrics in drug discovery. Nat. Rev. Drug Discov. 13, 105-121 (2014
114. Han, S., et al. Targeted delivery of a model immunomodulator to the lymphatic system: comparison of alkyl ester versus triglyceride mimetic lipid prodrug strategies. J. Control. Release 177, 1-10 (2014
115. Sugihara, J., Furuuchi, S., Nakano, K., & Harigaya, S. Studies on intestinal lymphatic absorption of drugs. I. Lymphatic absorption of alkyl ester derivatives, and alpha-monoglyceride derivatives of drugs. J. Pharmacobiodyn. 11, 369-376 (1988
116. Sugihara, J., Furuuchi, S., Ando, H., Takashima, K., & Harigaya, S. Studies on intestinal lymphatic absorption of drugs. II. Glyceride prodrugs for improving lymphatic absorption of naproxen, and nicotinic-Acid. J. Pharmacobiodyn. 11, 555-562 (1988
117. Dahan, A., et al. The oral absorption of phospholipid prodrugs: in vivo, and in vitro mechanistic investigation of trafficking of a lecithin-valproic acid conjugate following oral administration. J. Control. Release 126, 1-9 (2008
118. Sakai, A., Mori, N., Shuto, S., & Suzuki, T. Deacylation-reacylation cycle: a possible absorption mechanism for the novel lymphotropic antitumor agent dipalmitoylphosphatidylfluorouridine in rats. J. Pharm. Sci. 82, 575-578 (1993
119. Hussain, N., Jaitley, V., & Florence, A. T. Recent advances in the understanding of uptake of microparticulates across the gastrointestinal lymphatics. Adv. Drug Deliv. Rev. 50, 107-142 (2001
120. Yun, Y., Cho, Y. W., & Park, K. Nanoparticles for oral delivery: targeted nanoparticles with peptidic ligands for oral protein delivery. Adv. Drug Deliv. Rev. 65, 822-832 (2013
121. Pasetti, M. F., Simon, J. K., Sztein, M. B., & Levine, M. M. Immunology of gut mucosal vaccines. Immunol. Rev. 239, 125-148 (2011
122. Attili-Qadri, S., et al. Oral delivery system prolongs blood circulation of docetaxel nanocapsules via lymphatic absorption. Proc. Natl Acad. Sci. USA 110, 17498-17503 (2013
123. Pridgen, E. M., et al. Transepithelial transport of Fc targeted nanoparticles by the neonatal Fc receptor for oral delivery. Sci. Transl. Med. 5, 213ra167 (2013
124. Neutra, M. R., & Kozlowski, P. A. Mucosal vaccines: the promise, and the challenge. Nat. Rev. Immunol. 6, 148-158 (2006
125. Schulz, O., et al. Intestinal CD103+, but not CX3CR1+, antigen sampling cells migrate in lymph, and serve classical dendritic cell functions. J. Exp. Med. 206, 3101-3114 (2009
126. Rescigno, M. Intestinal dendritic cells. Adv. Immunol. 107, 109-138 (2010
127. Niess, J. H., et al. CX3CR1 mediated dendritic cell access to the intestinal lumen, and bacterial clearance. Science 307, 254-258 (2005
128. Clark, M. A., Hirst, B. H., & Jepson, M. A. Lectin-mediated mucosal delivery of drugs, and microparticles. Adv. Drug Deliv. Rev. 43, 207-223 (2000
129. Hussain, N., & Florence, A. Utilizing bacterial mechanisms of epithelial cell entry: invasin-induced oral uptake of latex nanoparticles. Pharm. Res. 15, 153-156 (1998
130. Fievez, V., et al. Targeting nanoparticles to M cells with non-peptidic ligands for oral vaccination. Eur. J. Pharm. Biopharm. 73, 16-24 (2009
131. Jin, Y., et al. Goblet cell-Targeting nanoparticles for oral insulin delivery, and the influence of mucus on insulin transport. Biomaterials 33, 1573-1582 (2012
132. Reineke, J. J., et al. Unique insights into the intestinal absorption, transit, and subsequent biodistribution of polymer-derived microspheres. Proc. Natl Acad. Sci. USA 110, 13803-13808 (2013
133. Desai, M. P., Labhasetwar, V., Amidon, G. L., & Levy, R. J. Gastrointestinal uptake of biodegradable microparticles: effect of particle size. Pharm. Res. 13, 1838-1845 (1996
134. Jani, P., Halbert, G. W., Langridge, J., & Florence, A. T. Nanoparticle uptake by the rat gastrointestinal mucosa: quantitation, and particle size dependency. J. Pharm. Pharmacol. 42, 821-826 (1990
135. Ebel, J. A. Method for quantifying particle absorption from the small intestine of the mouse. Pharm. Res. 7, 848-851 (1990
136. Jenkins, P. G., et al. The quantitation of the absorption of microparticles into the intestinal lymph of Wistar rats. Int. J. Pharm. 102, 261-266 (1994
137. Lefevre, M. E., Joel, D. D., & Schidlovsky, G. Retention of ingested latex particles in Peyer's patches of germfree, and conventional mice. Proc. Soc. Exp. Biol. Med. 179, 522-528 (1985
138. Hussain, N., Jani, P. U., & Florence, A. T. Enhanced oral uptake of tomato lectin-conjugated nanoparticles in the rat. Pharm. Res. 14, 613-618 (1997
139. Ralay-Ranaivo, B., et al. Novel self assembling nanoparticles for the oral administration of fondaparinux: synthesis, characterization, and in vivo evaluation. J. Control. Release 194, 323-331 (2014
140. Zhang, N., et al. Lectin-modified solid lipid nanoparticles as carriers for oral administration of insulin. Int. J. Pharm. 327, 153-159 (2006
141. Florence, A. T., Sakthivel, T., & Toth, I. Oral uptake, and translocation of a polylysine dendrimer with a lipid surface. J. Control. Release 65, 253-259 (2000
142. Ryan, G. M., et al. Pulmonary administration of PEGylated polylysine dendrimers: absorption from the lung versus retention within the lung is highly size-dependent. Mol. Pharm. 10, 2986-2995 (2013
143. Lycke, N. Recent progress in mucosal vaccine development: potential, and limitations. Nat. Rev. Immunol. 12, 592-605 (2012
144. Meeusen, E. N. Exploiting mucosal surfaces for the development of mucosal vaccines. Vaccine 29, 8506-8511 (2011
145. Stano, A., et al. PPS nanoparticles as versatile delivery system to induce systemic, and broad mucosal immunity after intranasal administration. Vaccine 29, 804-812 (2011
146. Stano, A., Nembrini, C., Swartz, M. A., Hubbell, J. A., & Simeoni, E. Nanoparticle size influences the magnitude, and quality of mucosal immune responses after intranasal immunization. Vaccine 30, 7541-7546 (2012
147. Rytting, E., Nguyen, J., Wang, X., & Kissel, T. Biodegradable polymeric nanocarriers for pulmonary drug delivery. Expert Opin. Drug Deliv. 5, 629-639 (2008
148. Patton, J. S., Fishburn, C. S., & Weers, J. G. The lungs as a portal of entry for systemic drug delivery. Proc. Am. Thorac. Soc. 1, 338-344 (2004
149. Schraufnagel, D. E. Lung lymphatic anatomy, and correlates. Pathophysiology 17, 337-343 (2010
150. Pabst, R., & Tschernig, T. Bronchus-Associated lymphoid tissue. Am. J. Respir. Cell. Mol. Biol. 43, 137-141 (2010
151. Geiser, M. Update on macrophage clearance of inhaled micro-, and nanoparticles. J. Aerosol Med. Pulm. Drug Deliv. 23, 207-217 (2010
152. Wanner, A., Salathe, M., & O'Riordan, T. G. Mucociliary clearance in the airways. Am. J. Respir. Crit. Care Med. 154, 1868-1902 (1996
153. Kambouchner, M., & Bernaudin, J. F. Intralobular pulmonary lymphatic distribution in normal human lung using D2 40 antipodoplanin immunostaining. J. Histochem. Cytochem. 57, 643-648 (2009
154. Botelho, M. F., et al. Visualization of deep lung lymphatic network using radioliposomes. Rev. Port. Pneumol. 17, 124-130 (in Portuguese) (2011
155. Hanatani, K., et al. Molecular weight-dependent lymphatic transfer of fluorescein isothiocyanate-labeled dextrans after intrapulmonary administration, and effects of various absorption enhancers on the lymphatic transfer of drugs in rats. J. Drug Target 3, 263-271 (1995
156. Choi, H. S., et al. Rapid translocation of nanoparticles from the lung airspaces to the body. Nat. Biotech. 28, 1300-1303 (2010
157. Li, A. V., et al. Generation of effector memory T cell-based mucosal, and systemic immunity with pulmonary nanoparticle vaccination. Sci. Transl. Med. 5, 204ra130 (2013
158. Videira, M. A., et al. Lymphatic uptake of pulmonary delivered radiolabelled solid lipid nanoparticles. J. Drug Target 10, 607-613 (2002
159. Latimer, P., et al. Aerosol delivery of liposomal formulated paclitaxel, and vitamin E analog reduces murine mammary tumor burden, and metastases. Exp. Biol. Med. (Maywood) 234, 1244-1252 (2009
160. Mohammad, A. K., Amayreh, L. K., Mazzara, J. M., & Reineke, J. J. Rapid lymph accumulation of polystyrene nanoparticles following pulmonary administration. Pharm. Res. 30, 424-434 (2013
161. Mackay, C. R., Marston, W. L., & Dudler, L. Naive, and memory T cells show distinct pathways of lymphocyte recirculation. J. Exp. Med. 171, 801-817 (1990
162. Braun, A. Afferent lymph-derived T cells, and DCs use different chemokine receptor CCR7 dependent routes for entry into the lymph node, and intranodal migration. Nat. Immunol. 12, 879-887 (2011
163. Moghimi, S. M., & Bonnemain, B. Subcutaneous, and intravenous delivery of diagnostic agents to the lymphatic system: applications in lymphoscintigraphy, and indirect lymphography. Adv. Drug Deliv. Rev. 37, 295-312 (1999
164. Sensken, S. C., Bode, C., & Gräler, M. H. Accumulation of fingolimod (FTY720) in lymphoid tissues contributes to prolonged efficacy. J. Pharmacol. Exp. Ther. 328, 963-969 (2009
165. Manolova, V., et al. Nanoparticles target distinct dendritic cell populations according to their size. Eur. J. Immunol. 38, 1404-1413 (2008
166. Moghimi, S. M., et al. Surface engineered nanospheres with enhanced drainage into lymphatics, and uptake by macrophages of the regional lymph nodes. FEBS Lett. 344, 25-30 (1994
167. Oussoren, C., et al. Lymphatic uptake, and biodistribution of liposomes after subcutaneous injection: IV. Fate of liposomes in regional lymph nodes. Biochim. Biophys. Acta 1370, 259-272 (1998
168. Reddy, S. T., Rehor, A., Schmoekel, H. G., Hubbell, J. A., & Swartz, M. A. In vivo targeting of dendritic cells in lymph nodes with poly(propylene sulfide) nanoparticles. J. Control. Release 112, 26-34 (2006
169. Sixt, M., et al. The conduit system transports soluble antigens from the afferent lymph to resident dendritic cells in the T cell area of the lymph node. Immunity 22, 19-29 (2005
170. Caserta, S., Alessi, P., Guarnerio, J., Basso, V., & Mondino, A. Synthetic CD4+ T cell-Targeted antigen-presenting cells elicit protective antitumor responses. Cancer Res. 68, 3010-3018 (2008
171. Moon, J. J., et al. Enhancing humoral responses to a malaria antigen with nanoparticle vaccines that expand Tfh cells, and promote germinal center induction. Proc. Natl Acad. Sci. USA 109, 1080-1085 (2012
172. Oussoren, C., & Storm, G. Liposomes to target the lymphatics by subcutaneous administration. Adv. Drug Deliv. Rev. 50, 143-156 (2001
173. Takakura, Y., Matsumoto, S., Hashida, M., & Sezaki, H. Enhanced lymphatic delivery of mitomycin C conjugated with dextran. Cancer Res. 44, 2505-2510 (1984
174. Kim, C. K., & Han, J. H. Lymphatic delivery, and pharmacokinetics of methotrexate after intramuscular injection of differently charged liposome-entrapped methotrexate to rats. J. Microencapsul. 12, 437-446 (1995
175. Kaminskas, L. M., et al. Methotrexate-conjugated PEGylated dendrimers show differential patterns of deposition, and activity in tumor-burdened lymph nodes after intravenous, and subcutaneous administration in rats. Mol. Pharm. 12, 432-443 (2015
176. Nune, S. K., Gunda, P., Majeti, B. K., Thallapally, P. K., & Forrest, M. L. Advances in lymphatic imaging, and drug delivery. Adv. Drug Deliv. Rev. 63, 876-885 (2011
177. Shackleford, D. M., et al. Contribution of lymphatically transported testosterone undecanoate to the systemic exposure of testosterone after oral administration of two andriol formulations in conscious lymph duct-cannulated dogs. J. Pharmacol. Exp. Ther. 306, 925-933 (2003
178. White, K. L., et al. Lymphatic transport of methylnortestosterone undecanoate (MU), and the bioavailability of methylnortestosterone are highly sensitive to the mass of coadministered lipid after oral administration of MU. J. Pharmacol. Exp. Ther. 331, 700-709 (2009
179. Surampudi, P., et al. Single, escalating dose pharmacokinetics, safety, and food effects of a new oral androgen dimethandrolone undecanoate in man: a prototype oral male hormonal contraceptive. Andrology 2, 579-587 (2014
180. Khoo, S. M., Edwards, G. A., Porter, C. J. H., & Charman, W. N A conscious dog model for assessing the absorption, enterocyte-based metabolism, and intestinal lymphatic transport of halofantrine. J. Pharm. Sci. 90, 1599-1607 (2001
181. Trevaskis, N. L., et al. Intestinal lymphatic transport enhances the post-prandial oral bioavailability of a novel cannabinoid receptor agonist via avoidance of first-pass metabolism. Pharm. Res. 26, 1486-1495 (2009
182. Trevaskis, N. L., Porter, C. J., & Charman, W. N. An examination of the interplay between enterocyte-based metabolism, and lymphatic drug transport in the rat. Drug Metab. Dispos. 34, 729-733 (2006
183. Zhang, Z., et al A self-Assembled nanocarrier loading teniposide improves the oral delivery, and drug concentration in tumor. J. Control. Release 166, 30-37 (2013
184. Garzonaburbeh, A., Poupaert, J. H., Claesen, M., Dumont, P., & Atassi, G. 1,3 dipalmitoylglycerol ester of chlorambucil as a lymphotropic, orally administrable anti-neoplastic agent. J. Med. Chem. 26, 1200-1203 (1983
185. Kaminskas, L. M., et al. PEGylation of interferon α2 improves lymphatic exposure after subcutaneous, and intravenous administration, and improves antitumour efficacy against lymphatic breast cancer metastases. J. Control. Release 168, 200-208 (2013)
186. Li, S., Goins, B., Hrycushko, B. A., Phillips, W. T., & Bao, A. Feasibility of eradication of breast cancer cells remaining in postlumpectomy cavity, and draining lymph nodes following intracavitary injection of radioactive immunoliposomes. Mol. Pharm. 9, 2513-2522 (2012
187. Cai, S., Xie, Y., Davies, N. M., Cohen, M. S., & Forrest, M. L. Carrier-based intralymphatic cisplatin chemotherapy for the treatment of metastatic squamous cell carcinoma of the head, and neck. Ther. Delivery 1, 237-245 (2010
188. Qin, L., et al. Polymeric micelles for enhanced lymphatic drug delivery to treat metastatic tumors. J. Control. Release 171, 133-142 (2013
189. Rafi, M., et al. Polymeric micelles incorporating (1,2 diaminocyclohexane)platinum (II) suppress the growth of orthotopic scirrhous gastric tumors, and their lymph node metastasis. J. Control. Release 159, 189-196 (2012
190. Kourtis, I. C., et al. Peripherally administered nanoparticles target monocytic myeloid cells, secondary lymphoid organs, and tumors in mice. PLoS ONE 8, e61646 (2013
191. Liu, R., et al. Prevention of nodal metastases in breast cancer following the lymphatic migration of paclitaxel-loaded expansile nanoparticles. Biomaterials 34, 1810-1819 (2013
192. Cai, S., Xie, Y., Bagby, T. R., Cohen, M. S., & Forrest, M. L. Intralymphatic chemotherapy using a hyaluronan-cisplatin conjugate. J. Surg. Res. 147, 247-252 (2008
193. Akamo, Y., et al. Chemotherapy targeting regional lymph nodes by gastric submucosal injection of liposomal adriamycin in patients with gastric carcinoma. Jpn J. Cancer Res. 85, 652-658 (1994
194. Khullar, O. V., et al. Nanoparticle migration, and delivery of paclitaxel to regional lymph nodes in a large animal model. J. Am. Coll. Surg. 214, 328-337 (2012
195. Ling, R., et al. Lymphatic chemotherapy induces apoptosis in lymph node metastases in a rabbit breast carcinoma model. J. Drug Target. 13, 137-142 (2005
196. Yang, F., et al. Magnetic functionalised carbon nanotubes as drug vehicles for cancer lymph node metastasis treatment. Eur. J. Cancer 47, 1873-1882 (2011
197. Zhao, C., et al. Local targeted therapy of liver metastasis from colon cancer by galactosylated liposome encapsulated with doxorubicin. PLoS ONE 8, e73860 (2013
198. Dane, K. Y., et al. Nano-sized drug-loaded micelles deliver payload to lymph node immune cells, and prolong allograft survival. J. Control. Release 156, 154-160 (2011
199. Trevaskis, N. L., Charman, W. N., & Porter, C. J. Targeted drug delivery to lymphocytes: a route to site-specific immunomodulation? Mol. Pharm. 7, 2297-2309 (2010
200. Okanobo, A., Chauhan, S. K., Dastjerdi, M. H., Kodati, S., & Dana, R. Efficacy of topical blockade of interleukin 1 in experimental dry eye disease. Am. J. Ophthalmol. 154, 63-71 (2012
201. Shinriki, S., et al. Interleukin 6 signalling regulates vascular endothelial growth factor C synthesis, and lymphangiogenesis in human oral squamous cell carcinoma. J. Pathol. 225, 142-150 (2011
202. Polzer, K., et al. Tumour necrosis factor blockade increases lymphangiogenesis in murine, and human arthritic joints. Ann. Rheum. Dis. 67, 1610-1616 (2008
203. Pal, I., & Ramsey, J. D. The role of the lymphatic system in vaccine trafficking, and immune response. Adv. Drug Deliv. Rev. 63, 909-922 (2011
204. Woodruff, M. C., et al. Trans-nodal migration of resident dendritic cells into medullary interfollicular regions initiates immunity to influenza vaccine. J. Exp. Med. 211, 1611-1621 (2014
205. Senti, G., Johansen, P., & Kundig, T. M. Intralymphatic immunotherapy. Curr. Opin. Allergy Clin. Immunol. 9, 537-543 (2009
206. Senti, G., et al. Intralymphatic allergen administration renders specific immunotherapy faster, and safer: a randomized controlled trial. Proc. Natl Acad. Sci. USA 105, 17908-17912 (2008
207. Jewell, C. M., Bustamante López, S. C., & Irvine, D. J. In situ engineering of the lymph node microenvironment via intranodal injection of adjuvant-releasing polymer particles. Proc. Natl Acad. Sci. USA 108, 15745-15750 (2011
208. Maloy, K. J., et al. Intralymphatic immunization enhances DNA vaccination. Proc. Natl Acad. Sci. USA 98, 3299-3303 (2001
209. De Titta, A., et al. Nanoparticle conjugation of CpG enhances adjuvancy for cellular immunity, and memory recall at low dose. Proc. Natl Acad. Sci. USA 110, 19902-19907 (2013
210. Xu, Z., et al. Multifunctional nanoparticles co delivering Trp2 peptide, and CpG adjuvant induce potent cytotoxic T lymphocyte response against melanoma, and its lung metastasis. J. Control. Release 172, 259-265 (2013
211. Moon, J. J., et al. Interbilayer-crosslinked multilamellar vesicles as synthetic vaccines for potent humoral, and cellular immune responses. Nat. Mater. 10, 243-251 (2011
212. St John, A. L., Chan, C. Y., Staats, H. F., Leong, K. W., & Abraham, S. N. Synthetic mast-cell granules as adjuvants to promote, and polarize immunity in lymph nodes. Nat. Mater. 11, 250-257 (2012
213. Jeanbart, L., et al. Enhancing efficacy of anticancer vaccines by targeted delivery to tumor-draining lymph nodes. Cancer Immunol. Res. 2, 436-447 (2014
214. Thomas, S. N., Vokali, E., Lund, A. W., Hubbell, J. A., & Swartz, M. A. Targeting the tumor-draining lymph node with adjuvanted nanoparticles reshapes the anti-Tumor immune response. Biomaterials 35, 814-824 (2014
215. Kim, S. H., Lee, K. Y., & Jang, Y. S. Mucosal immune system, and M cell-Targeting strategies for oral mucosal vaccination. Immune Netw. 12, 165-175 (2012
216. Zhu, Q., et al. Large intestine-Targeted, nanoparticle-releasing oral vaccine to control genitorectal viral infection. Nat. Med. 18, 1291-1296 (2012
217. Ballester, M., et al. Nanoparticle conjugation, and pulmonary delivery enhance the protective efficacy of Ag85B, and CpG against tuberculosis. Vaccine 29, 6959-6966 (2011
218. Nembrini, C., et al. Nanoparticle conjugation of antigen enhances cytotoxic T cell responses in pulmonary vaccination. Proc. Natl Acad. Sci. USA 108, E989-E997 (2011
219. Faria, A. M. C., & Weiner, H. L. Oral tolerance: therapeutic implications for autoimmune diseases. Clin. Dev. Immunol. 13, 143-157 (2006
220. Miller, S. D., Turley, D. M., & Podojil, J. R. Antigen-specific tolerance strategies for the prevention, and treatment of autoimmune disease. Nat. Rev. Immunol. 7, 665-677 (2007
221. Weiner, H. L., da Cunha, A. P., Quintana, F., & Wu, H. Oral tolerance. Immunol. Rev. 241, 241-259 (2011
222. Scandling, J. D., Busque, S., Shizuru, J. A., Engleman, E. G., & Strober, S. Induced immune tolerance for kidney transplantation. N. Engl. J. Med. 365, 1359-1360 (2011
223. Faria, A. M. C., & Weiner, H. L. Oral tolerance. Immunol. Rev. 206, 232-259 (2005
224. Burks, A. W., Laubach, S., & Jones, S. M. Oral tolerance, food allergy, and immunotherapy: implications for future treatment. J. Allergy Clin. Immunol. 121, 1344-1350 (2008
225. Worbs, T., et al. Oral tolerance originates in the intestinal immune system, and relies on antigen carriage by dendritic cells. J. Exp. Med. 203, 519-527 (2006
226. Spahn, T. W., et al. Mesenteric lymph nodes are critical for the induction of high-dose oral tolerance in the absence of Peyer's patches. Eur. J. Immunol. 32, 1109-1113 (2002
227. Spahn, T. W., et al. Induction of oral tolerance to cellular immune responses in the absence of Peyer's patches. Eur. J. Immunol. 31, 1278-1287 (2001
228. Kraus, T. A., et al. Induction of mucosal tolerance in Peyer's patch-deficient, ligated small bowel loops. J. Clin. Invest. 115, 2234-2243 (2005
229. Fujihashi, K., et al. Peyer's patches are required for oral tolerance to proteins. Proc. Natl Acad. Sci. USA 98, 3310-3315 (2001
230. Suzuki, H., et al. Ovalbumin-protein sigma 1 M cell targeting facilitates oral tolerance with reduction of antigen-specific CD4+ T cells. Gastroenterology 135, 917-925 (2008
231. Masuda, K., Horie, K., Suzuki, R., Yoshikawa, T., & Hirano, K. Oral delivery of antigens in liposomes with some lipid compositions modulates oral tolerance to the antigens. Microbiol. Immunol. 46, 55-58 (2002
232. Kim, W., et al. Suppression of collagen-induced arthritis by single feeding of poilylactic-poilyglycolic acid entrapping immunodominant peptide of type II collagen: involvement of CD4+ IL 10+ T cells in Peyer's pathces. Ann. Rheum. Dis. 62, 168-168 (2003
233. Goldmann, K., Hoffmann, J., Eckl, S., Spriewald, B. M., & Ensminger, S. M. Attenuation of transplant arteriosclerosis by oral feeding of major histocompatibility complex encoding chitosan-DNA nanoparticles. Transplant Immunol. 28, 9-13 (2013
234. Pecquet, S., et al. Oral tolerance elicited in mice by β-lactoglobulin entrapped in biodegradable microspheres. Vaccine 18, 1196-1202 (2000
235. Shirali, A. C., et al. Nanoparticle delivery of mycophenolic acid upregulates PD L1 on dendritic cells to prolong murine allograft survival. Am. J. Transplant. 11, 2582-2592 (2011
236. Maldonado, R. A., et al. Polymeric synthetic nanoparticles for the induction of antigen-specific immunological tolerance. Proc. Natl Acad. Sci. USA 112, E156-E165 (2015
237. Capini, C., et al. Antigen-specific suppression of inflammatory arthritis using liposomes. J. Immunol. 182, 3556-3565 (2009
238. Getts, D. R., et al. Microparticles bearing encephalitogenic peptides induce T cell tolerance, and ameliorate experimental autoimmune encephalomyelitis. Nat. Biotech. 30, 1217-1224 (2012
239. Kinman, L., et al. Lipid-drug association enhanced HIV 1 protease inhibitor indinavir localization in lymphoid tissues, and viral load reduction: a proof of concept study in HIV 2287 infected macaques. J. Acquir. Immune Defic. Syndr. 34, 387-397 (2003
240. Freeling, J. P., Koehn, J., Shu, C., Sun, J., & Ho, R. J. Y. Long-Acting three-drug combination anti-HIV nanoparticles enhance drug exposure in primate plasma, and cells within lymph nodes, and blood. AIDS 28, 2625-2627 (2014
241. Freeling, J. P., & Ho, R. J. Y. Anti-HIV drug particles may overcome lymphatic drug insufficiency, and associated HIV persistence. Proc. Natl Acad. Sci. USA 111, E2512-E2513 (2014
242. das Neves, J., Amiji, M. M., Bahia, M. F., & Sarmento, B. Nanotechnology-based systems for the treatment, and prevention of HIV/AIDS. Adv. Drug Deliv. Rev. 62, 458-477 (2010
243. Edagwa, B. J., Zhou, T., McMillan, J. M., Liu, X. M., & Gendelman, H. E. Development of HIV reservoir targeted long acting nanoformulated antiretroviral therapies. Curr. Med. Chem. 21, 4186-4198 (2014
244. Sosnik, A., Chiappetta, D. A., & Carcaboso, Á. M. Drug delivery systems in HIV pharmacotherapy: what has been done, and the challenges standing ahead. J. Control. Release 138, 2-15 (2009
245. Lalanne, M., et al. Synthesis, and biological evaluation of two glycerolipidic prodrugs of didanosine for direct lymphatic delivery against HIV. Bioorg. Med. Chem. Lett. 17, 2237-2240 (2007
246. Skanji, R., et al A new nanomedicine based on didanosine glycerolipidic prodrug enhances the long term accumulation of drug in a HIV sanctuary. Int. J. Pharm. 414, 285-297 (2011
247. Puligujja, P., et al. Pharmacodynamics of long-Acting folic acid-receptor targeted ritonavir-boosted atazanavir nanoformulations. Biomaterials 41, 141-150 (2015
248. Horst, H. J., et al. Lymphatic absorption, and metabolism of orally administered testosterone undecanoate in man. Klin. Wochenschr. 54, 875-879 (1976
249. Edwards, G. A., Porter, C. J., Caliph, S. M., Khoo, S. M., & Charman, W. N. Animal models for the study of intestinal lymphatic drug transport. Adv. Drug Deliv. Rev. 50, 45-60 (2001
250. Seeger, M., & Bewig, B. Ultrasound imaging of the thoracic duct. N. Engl. J. Med. 359, e28 (2008
251. Nadolski, G., & Itkin, M. Thoracic duct embolization for the management of chylothoraces. Curr. Opin. Pulm. Med. 19, 380-386 (2013
252. Thomas, S. N., & Schudel, A. Overcoming transport barriers for interstitial-, lymphatic-, and lymph node-Targeted drug delivery. Curr. Opin. Chem. Engineer. 7, 65-74 (2015
253. Miteva, D. O. Transmural flow modulates cell, and fluid transport functions of lymphatic endothelium. Circ. Res. 106, 920-931 (2010
254. Banerji, S., et al. LYVE 1, a new homologue of the CD44 glycoprotein, is a lymph-specific receptor for hyaluronan. J. Cell Biol. 144, 789-801 (1999
255. Dixon, J. B., Raghunathan, S., & Swartz, M. A A tissue-engineered model of the intestinal lacteal for evaluating lipid transport by lymphatics. Biotechnol. Bioengineer. 103, 1224-1235 (2009
256. John, T. A., Vogel, S. M., Tiruppathi, C., Malik, A. B., & Minshall, R. D. Quantitative analysis of albumin uptake, and transport in the rat microvessel endothelial monolayer. Am. J. Physiol. Lung Cell. Mol. Physiol. 284, L187-L196 (2003
257. Schubert, W., et al. Caveolae-deficient endothelial cells show defects in the uptake, and transport of albumin in vivo. J. Biol. Chem. 276, 48619-48622 (2001
258. Mendelsohn, A. R., & Larrick, J. W. Sleep facilitates clearance of metabolites from the brain: glymphatic function in aging, and neurodegenerative diseases. Rejuven. Res. 16, 518-523 (2013
259. Thrane, V. R., et al. Paravascular microcirculation facilitates rapid lipid transport, and astrocyte signaling in the brain. Sci. Rep. 3, 2582 (2013
260. Florence, A. T., & Hussain, N. Transcytosis of nanoparticle, and dendrimer delivery systems: evolving vistas. Adv. Drug Deliv. Rev. 50 (Suppl. 1), 69-89 (2001
261. des Rieux, A., Fievez, V., Garinot, M., Schneider, Y. J., & Preat, V. Nanoparticles as potential oral delivery systems of proteins, and vaccines: A mechanistic approach. J. Control. Release 116, 1-27 (2006
262. Hunter, A. C., Elsom, J., Wibroe, P. P., & Moghimi, S. M. Polymeric particulate technologies for oral drug delivery, and targeting: a pathophysiological perspective. Nanomedicine 8, S5-S20 (2012
263. Ravi, P. R., Aditya, N., Kathuria, H., Malekar, S., & Vats, R. Lipid nanoparticles for oral delivery of raloxifene: optimization, stability, in vivo evaluation, and uptake mechanism. Eur. J. Pharm. Biopharm. 87, 114-124 (2014
264. Sun, M., et al. Intestinal absorption, and intestinal lymphatic transport of sirolimus from self-microemulsifying drug delivery systems assessed using the single-pass intestinal perfusion (SPIP) technique, and a chylomicron flow blocking approach: Linear correlation with oral bioavailabilities in rats. Eur. J. Pharm. Sci. 43, 132-140 (2011
265. Zhang, Z., et al. Bile salts enhance the intestinal absorption of lipophilic drug loaded lipid nanocarriers: mechanism, and effect in rats. Int. J. Pharm. 452, 374-381 (2013
266. Fu, C., et al. The absorption, distribution, excretion, and toxicity of mesoporous silica nanoparticles in mice following different exposure routes. Biomaterials 34, 2565-2575 (2013
267. Dahan, A., & Hoffman, A. Evaluation of a chylomicron flow blocking approach to investigate the intestinal lymphatic transport of lipophilic drugs. Eur. J. Pharm. Sci. 24, 381-388 (2005
268. Bernard, A., Carlier, H., & Caselli, C. Biochemical, and ultrastructural study of actidione-cycloheximide effect on fat intestinal absorption in the rat (author's transl). J. Physiol. (Paris). 76, 147-157 (1980) (in French
269. Alitalo, A., & Detmar, M. Interaction of tumor cells, and lymphatic vessels in cancer progression. Oncogene 31, 4499-4508 (2012
270. Hwee, Y. L., et al. Hypercholesterolemic mice exhibit lymphatic vessel dysfunction, and degeneration. Am. J. Pathol. 175, 1328-1337 (2009
271. Liao, S., et al. Impaired lymphatic contraction associated with immunosuppression. Proc. Natl Acad. Sci. USA 108, 18784-18789 (2011
272. Bagby, T. R., et al. Lymphatic trafficking kinetics, and near-infrared imaging using star polymer architectures with controlled anionic character. Eur. J. Pharm. Sci. 47, 287-294 (2012
273. Karlsson, M., et al. Tolerosomes are produced by intestinal epithelial cells. Eur. J. Immunol. 31, 2892-2900 (2001
274. Menard, S., Cerf-Bensussan, N., & Heyman, M. Multiple facets of intestinal permeability, and epithelial handling of dietary antigens. Mucosal Immunol. 3, 247-259 (2010
275. Wang, Y. H., et al. Chylomicrons promote intestinal absorption, and systemic dissemination of dietary antigen (ovalbumin) in mice. PLoS ONE 4, e8442 (2009
276. Jang, M. H., et al. Intestinal villous M cells: an antigen entry site in the mucosal epithelium. Proc. Natl Acad. Sci. USA 101, 6110-6115 (2004
277. Neutra, M. R., & Kraehenbuhl, J. P. in Mucosal Immunology 3rd edn (eds Mestecky, J., et al.) 111-130 (Elsevier, 2005
278. Caliph, S. M., et al. The impact of lymphatic transport on the systemic disposition of lipophilic drugs. J. Pharm. Sci. 102, 2395-2408 (2013
279. Carrasco, Y. R., & Batista, F. D. B cells acquire particulate antigen in a macrophage-rich area at the boundary between the follicle, and the subcapsular sinus of the lymph node. Immunity 27, 160-171 (2007
280. Junt, T. Subcapsular sinus macrophages in lymph nodes clear lymph-borne viruses, and present them to antiviral B cells. Nature 450, 110-114 (2007