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Annual Review of Medicine

Volume 72, 2021

Lymphatic Vasculature: An Emerging Therapeutic Target and Drug Delivery Route

Abstract

The lymphatic system has received increasing scientific and clinical attention because a wide variety of diseases are linked to lymphatic pathologies and because the lymphatic system serves as an ideal conduit for drug delivery. Lymphatic vessels exert heterogeneous roles in different organs and vascular beds, and consequently, their dysfunction leads to distinct organ-specific outcomes. Although studies in animal model systems have led to the identification of crucial lymphatic genes with potential therapeutic benefit, effective lymphatic-targeted therapeutics are currently lacking for human lymphatic pathological conditions. Here, we focus on the therapeutic roles of lymphatic vessels in diseases and summarize the promising therapeutic targets for modulating lymphangiogenesis or lymphatic function in preclinical or clinical settings. We also discuss considerations for drug delivery or targeting of lymphatic vessels for treatment of lymphatic-related diseases. The lymphatic vasculature is rapidly emerging as a critical system for targeted modulation of its function and as a vehicle for innovative drug delivery.

Keyword(s): adrenomedullin, drug delivery, lymphangiogenesis, lymphatics, VEGF-C
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2021-01-27
2024-04-24
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Literature Cited

  1. 1. 
    Petrova TV, Koh GY. 2020. Biological functions of lymphatic vessels. Science369eaax4063
     [Google Scholar]
  2. 2. 
    Breslin JW, Yang Y, Scallan JP et al. 2018. Lymphatic vessel network structure and physiology. Compr. Physiol. 9:207–99
     [Google Scholar]
  3. 3. 
    Girard JP, Moussion C, Förster R 2012. HEVs, lymphatics and homeostatic immune cell trafficking in lymph nodes. Nat. Rev. Immunol. 12:762–73
     [Google Scholar]
  4. 4. 
    Randolph GJ, Miller NE. 2014. Lymphatic transport of high-density lipoproteins and chylomicrons. J. Clin. Investig. 124:929–35
     [Google Scholar]
  5. 5. 
    Trevaskis NL, Kaminskas LM, Porter CJH 2015. From sewer to saviour—targeting the lymphatic system to promote drug exposure and activity. Nat. Rev. Drug Discov. 14:781–803
     [Google Scholar]
  6. 6. 
    Wiig H, Swartz MA. 2012. Interstitial fluid and lymph formation and transport: physiological regulation and roles in inflammation and cancer. Physiol. Rev. 92:1005–60
     [Google Scholar]
  7. 7. 
    Oliver G, Kipnis J, Randolph GJ, Harvey NL 2020. The lymphatic vasculature in the 21st century: novel functional roles in homeostasis and disease. Cell 182:270–96
     [Google Scholar]
  8. 8. 
    Dejana E, Orsenigo F. 2013. Endothelial adherens junctions at a glance. J. Cell Sci. 126:2545–49
     [Google Scholar]
  9. 9. 
    Dejana E, Orsenigo F, Molendini C et al. 2009. Organization and signaling of endothelial cell-to-cell junctions in various regions of the blood and lymphatic vascular trees. Cell Tissue Res 335:17–25
     [Google Scholar]
  10. 10. 
    Schmid-Schönbein GW. 1990. Microlymphatics and lymph flow. Physiol. Rev. 70:987–1028
     [Google Scholar]
  11. 11. 
    von der Weid P-Y. 2019. Lymphatic vessel pumping. Smooth Muscle Spontaneous Activity: Physiological and Pathological Modulation H Hashitani, RJ Lang 357–77 Singapore: Springer Singapore
     [Google Scholar]
  12. 12. 
    Brouillard P, Boon L, Vikkula M 2014. Genetics of lymphatic anomalies. J. Clin. Investig. 124:898–904
     [Google Scholar]
  13. 13. 
    Gordon K, Varney R, Keeley V et al. 2020. Update and audit of the St George's classification algorithm of primary lymphatic anomalies: a clinical and molecular approach to diagnosis. J. Med. Genet. 57:653–59
     [Google Scholar]
  14. 14. 
    Mendola A, Schlogel MJ, Ghalamkarpour A et al. 2013. Mutations in the VEGFR3 signaling pathway explain 36% of familial lymphedema. Mol. Syndromol. 4:257–66
     [Google Scholar]
  15. 15. 
    Karkkainen MJ, Saaristo A, Jussila L et al. 2001. A model for gene therapy of human hereditary lymphedema. PNAS 98:12677–82
     [Google Scholar]
  16. 16. 
    Hartiala P, Lahdenperä O, Vuolanto A, Saarikko A 2020. Lymfactin, an investigational adenoviral gene therapy expressing VEGF-C, is currently studied in a double-blind, randomized, placebo-controlled, multicenter, phase 2 clinical study in patients suffering from breast cancer associated secondary lymphedema (BCAL). Cancer Res 80:OT1–06-01 (Abstr.)
     [Google Scholar]
  17. 17. 
    Hartiala P, Suominen S, Suominen E et al. 2020. Phase 1 Lymfactin® study: short-term safety of combined adenoviral VEGF-C and lymph node transfer treatment for upper extremity lymphedema. J. Plast. Reconstr. Aesthet. Surg. 73:1612–21
     [Google Scholar]
  18. 18. 
    Akamo Y, Mizuno I, Yotsuyanagi T et al. 1994. Chemotherapy targeting regional lymph nodes by gastric submucosal injection of liposomal adriamycin in patients with gastric carcinoma. Jpn. J. Cancer Res. 85:652–58
     [Google Scholar]
  19. 19. 
    Van Balkom ID, Alders M, Allanson J et al. 2002. Lymphedema-lymphangiectasia-mental retardation (Hennekam) syndrome: a review. Am. J. Med. Genet. 112:412–21
     [Google Scholar]
  20. 20. 
    Jeltsch M, Jha SK, Tvorogov D et al. 2014. CCBE1 enhances lymphangiogenesis via A disintegrin and metalloprotease with thrombospondin motifs-3-mediated vascular endothelial growth factor-C activation. Circulation 129:1962–71
     [Google Scholar]
  21. 21. 
    Bui HM, Enis D, Robciuc MR et al. 2016. Proteolytic activation defines distinct lymphangiogenic mechanisms for VEGFC and VEGFD. J. Clin. Investig. 126:2167–80
     [Google Scholar]
  22. 22. 
    Le Guen L, Karpanen T, Schulte D et al. 2014. Ccbe1 regulates Vegfc-mediated induction of Vegfr3 signaling during embryonic lymphangiogenesis. Development 141:1239–49
     [Google Scholar]
  23. 23. 
    Fritz-Six KL, Dunworth WP, Li M, Caron KM 2008. Adrenomedullin signaling is necessary for murine lymphatic vascular development. J. Clin. Investig. 118:40–50
     [Google Scholar]
  24. 24. 
    Mackie DI, Al Mutairi F, Davis RB et al. 2018. hCALCRL mutation causes autosomal recessive nonimmune hydrops fetalis with lymphatic dysplasia. J. Exp. Med. 215:2339–53
     [Google Scholar]
  25. 25. 
    Hoopes SL, Willcockson HH, Caron KM 2012. Characteristics of multi-organ lymphangiectasia resulting from temporal deletion of calcitonin receptor-like receptor in adult mice. PLOS ONE 7:e45261
     [Google Scholar]
  26. 26. 
    Xu W, Wittchen ES, Hoopes SL et al. 2018. Small GTPase Rap1A/B is required for lymphatic development and adrenomedullin-induced stabilization of lymphatic endothelial junctions. Arterioscler. Thromb. Vasc. Biol. 38:2410–22
     [Google Scholar]
  27. 27. 
    Brakenhielm E, Alitalo K. 2019. Cardiac lymphatics in health and disease. Nat. Rev. Cardiol. 16:56–68
     [Google Scholar]
  28. 28. 
    Brakenhielm E, González A, Díez J 2020. Role of cardiac lymphatics in myocardial edema and fibrosis: JACC review topic of the week. J. Am. Coll. Cardiol. 76:735–44
     [Google Scholar]
  29. 29. 
    Telinius N, Vibeke EH. 2019. Role of the lymphatic vasculature in cardiovascular medicine. Heart 105:1777–84
     [Google Scholar]
  30. 30. 
    Vivien CJ, Pichol-Thievend C, Sim CB et al. 2019. Vegfc/d-dependent regulation of the lymphatic vasculature during cardiac regeneration is influenced by injury context. npj Regen. Med. 4:18
     [Google Scholar]
  31. 31. 
    Brice G, Child AH, Evans A et al. 2005. Milroy disease and the VEGFR-3 mutation phenotype. J. Med. Genet. 42:98–102
     [Google Scholar]
  32. 32. 
    Vuorio T, Tirronen A, Yla-Herttuala S 2017. Cardiac lymphatics—a new avenue for therapeutics. Trends Endocrinol. Metab. 28:285–96
     [Google Scholar]
  33. 33. 
    Klotz L, Norman S, Vieira JM et al. 2015. Cardiac lymphatics are heterogeneous in origin and respond to injury. Nature 522:62–67
     [Google Scholar]
  34. 34. 
    Henri O, Pouehe C, Houssari M et al. 2016. Selective stimulation of cardiac lymphangiogenesis reduces myocardial edema and fibrosis leading to improved cardiac function following myocardial infarction. Circulation 133:1484–97
     [Google Scholar]
  35. 35. 
    Houssari M, Dumesnil A, Tardif V et al. 2020. Lymphatic and immune cell cross-talk regulates cardiac recovery after experimental myocardial infarction. Arterioscler. Thromb. Vasc. Biol. 40:1722–37
     [Google Scholar]
  36. 36. 
    Zhang HF, Wang YL, Tan YZ et al. 2019. Enhancement of cardiac lymphangiogenesis by transplantation of CD34+VEGFR-3+ endothelial progenitor cells and sustained release of VEGF-C. Basic Res. Cardiol. 114:43
     [Google Scholar]
  37. 37. 
    Wada H, Suzuki M, Matsuda M et al. 2018. VEGF-C and mortality in patients with suspected or known coronary artery disease. J. Am. Heart Assoc. 7:e010355
     [Google Scholar]
  38. 38. 
    Tsuruda T, Kato J, Kuwasako K, Kitamura K 2019. Adrenomedullin: continuing to explore cardioprotection. Peptides 111:47–54
     [Google Scholar]
  39. 39. 
    Trincot CE, Xu W, Zhang H et al. 2019. Adrenomedullin induces cardiac lymphangiogenesis after myocardial infarction and regulates cardiac edema via connexin 43. Circ. Res. 124:101–13
     [Google Scholar]
  40. 40. 
    Kataoka Y, Miyazaki S, Yasuda S et al. 2010. The first clinical pilot study of intravenous adrenomedullin administration in patients with acute myocardial infarction. J. Cardiovasc. Pharmacol. 56:413–19
     [Google Scholar]
  41. 41. 
    Davis KL, Mehlhorn U, Laine GA, Allen SJ 1995. Myocardial edema, left ventricular function, and pulmonary hypertension. J. Appl. Physiol. 1985 78:132–37
     [Google Scholar]
  42. 42. 
    Desai KV, Laine GA, Stewart RH et al. 2008. Mechanics of the left ventricular myocardial interstitium: effects of acute and chronic myocardial edema. Am. J. Physiol. Heart Circ. Physiol. 294:H2428–34
     [Google Scholar]
  43. 43. 
    Laine GA. 1988. Microvascular changes in the heart during chronic arterial hypertension. Circ. Res. 62:953–60
     [Google Scholar]
  44. 44. 
    Laine GA, Allen SJ. 1991. Left ventricular myocardial edema. Lymph flow, interstitial fibrosis, and cardiac function. Circ. Res. 68:1713–21
     [Google Scholar]
  45. 45. 
    Mehlhorn U, Davis KL, Laine GA et al. 1996. Myocardial fluid balance in acute hypertension. Microcirculation 3:371–78
     [Google Scholar]
  46. 46. 
    Song D, Yang Y, He N et al. 2018. The involvement of AQP1 in myocardial edema induced by pressure overload in mice. Eur. Rev. Med. Pharmacol. Sci. 22:4969–74
     [Google Scholar]
  47. 47. 
    Leeds SE, Uhley HN, Sampson JJ, Friedman M 1970. The cardiac lymphatics after ligation of the coronary sinus. Proc. Soc. Exp. Biol. Med. 135:59–62
     [Google Scholar]
  48. 48. 
    Nielsen NR, Rangarajan KV, Mao L et al. 2020. A murine model of increased coronary sinus pressure induces myocardial edema with cardiac lymphatic dilation and fibrosis. Am. J. Physiol. Heart Circ. Physiol. 318:H895–H907
     [Google Scholar]
  49. 49. 
    Schwager S, Detmar M. 2019. Inflammation and lymphatic function. Front. Immunol. 10:308
     [Google Scholar]
  50. 50. 
    Kita T, Kaji Y, Kitamura K 2020. Safety, tolerability, and pharmacokinetics of adrenomedullin in healthy males: a randomized, double-blind, phase 1 clinical trial. Drug Des. Devel. Ther. 14:1–11
     [Google Scholar]
  51. 51. 
    Pedersen MS, Muller M, Rulicke T et al. 2020. Lymphangiogenesis in a mouse model of renal transplant rejection extends life span of the recipients. Kidney Int 97:89–94
     [Google Scholar]
  52. 52. 
    Cui Y, Liu K, Monzon-Medina ME et al. 2015. Therapeutic lymphangiogenesis ameliorates established acute lung allograft rejection. J. Clin. Investig. 125:4255–68
     [Google Scholar]
  53. 53. 
    Kress BT, Iliff JJ, Xia M et al. 2014. Impairment of paravascular clearance pathways in the aging brain. Ann. Neurol. 76:845–61
     [Google Scholar]
  54. 54. 
    Iliff JJ, Wang M, Liao Y et al. 2012. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Sci. Transl. Med. 4:147ra11
     [Google Scholar]
  55. 55. 
    Da Mesquita S, Louveau A, Vaccari A et al. 2018. Functional aspects of meningeal lymphatics in ageing and Alzheimer's disease. Nature 560:185–91
     [Google Scholar]
  56. 56. 
    Ostergaard P, Simpson MA, Connell FC et al. 2011. Mutations in GATA2 cause primary lymphedema associated with a predisposition to acute myeloid leukemia (Emberger syndrome). Nat. Genet. 43:929–31
     [Google Scholar]
  57. 57. 
    Kazenwadel J, Betterman KL, Chong CE et al. 2015. GATA2 is required for lymphatic vessel valve development and maintenance. J. Clin. Investig. 125:2979–94
     [Google Scholar]
  58. 58. 
    Mahamud MR, Geng X, Ho YC et al. 2019. GATA2 controls lymphatic endothelial cell junctional integrity and lymphovenous valve morphogenesis through miR-126. Development146dev184218
     [Google Scholar]
  59. 59. 
    Rockson SG, Tian W, Jiang X et al. 2018. Pilot studies demonstrate the potential benefits of antiinflammatory therapy in human lymphedema. JCI Insight 3:e123775
     [Google Scholar]
  60. 60. 
    Tian W, Rockson SG, Jiang X et al. 2017. Leukotriene B4 antagonism ameliorates experimental lymphedema. Sci. Transl. Med. 9:eaal3920
     [Google Scholar]
  61. 61. 
    Choong I. 2018. Eiger BioPharmaceuticals announces phase 2 ULTRA results of ubenimex in lower leg lymphedema: study did not meet primary or secondary endpoint Press Release, Eiger Biopharmaceuticals Oct. 16
  62. 62. 
    Roh K, Cho S, Park JH et al. 2017. Therapeutic effects of hyaluronidase on acquired lymphedema using a newly developed mouse limb model. Exp. Biol. Med. 242:584–92
     [Google Scholar]
  63. 63. 
    Jackson DG. 2019. Hyaluronan in the lymphatics: the key role of the hyaluronan receptor LYVE-1 in leucocyte trafficking. Matrix Biol 78–79:219–35
     [Google Scholar]
  64. 64. 
    Brown M, Assen FP, Leithner A et al. 2018. Lymph node blood vessels provide exit routes for metastatic tumor cell dissemination in mice. Science 359:1408–11
     [Google Scholar]
  65. 65. 
    Shimizu K, Kubo H, Yamaguchi K et al. 2004. Suppression of VEGFR-3 signaling inhibits lymph node metastasis in gastric cancer. Cancer Sci 95:328–33
     [Google Scholar]
  66. 66. 
    Roberts N, Kloos B, Cassella M et al. 2006. Inhibition of VEGFR-3 activation with the antagonistic antibody more potently suppresses lymph node and distant metastases than inactivation of VEGFR-2. Cancer Res 66:2650–57
     [Google Scholar]
  67. 67. 
    Shibata MA, Shibata E, Tanaka Y et al. 2020. Soluble Vegfr3 gene therapy suppresses multi-organ metastasis in a mouse mammary cancer model. Cancer Sci 111:2837–49
     [Google Scholar]
  68. 68. 
    Lin J, Lalani AS, Harding TC et al. 2005. Inhibition of lymphogenous metastasis using adeno-associated virus-mediated gene transfer of a soluble VEGFR-3 decoy receptor. Cancer Res 65:6901–9
     [Google Scholar]
  69. 69. 
    Yang H, Kim C, Kim MJ et al. 2011. Soluble vascular endothelial growth factor receptor-3 suppresses lymphangiogenesis and lymphatic metastasis in bladder cancer. Mol. Cancer 10:36
     [Google Scholar]
  70. 70. 
    Takahashi K, Mizukami H, Saga Y et al. 2013. Suppression of lymph node and lung metastases of endometrial cancer by muscle-mediated expression of soluble vascular endothelial growth factor receptor-3. Cancer Sci 104:1107–11
     [Google Scholar]
  71. 71. 
    Yao J, Da M, Guo T et al. 2013. RNAi-mediated gene silencing of vascular endothelial growth factor-C inhibits tumor lymphangiogenesis and growth of gastric cancer in vivo in mice. Tumour Biol 34:1493–501
     [Google Scholar]
  72. 72. 
    Shi Y, Tong M, Wu Y et al. 2013. VEGF-C ShRNA inhibits pancreatic cancer growth and lymphangiogenesis in an orthotopic fluorescent nude mouse model. Anticancer Res 33:409–17
     [Google Scholar]
  73. 73. 
    Shibata MA, Morimoto J, Shibata E, Otsuki Y 2008. Combination therapy with short interfering RNA vectors against VEGF-C and VEGF-A suppresses lymph node and lung metastasis in a mouse immunocompetent mammary cancer model. Cancer Gene Ther 15:776–86
     [Google Scholar]
  74. 74. 
    Shibata MA, Ambati J, Shibata E et al. 2012. Mammary cancer gene therapy targeting lymphangiogenesis: VEGF-C siRNA and soluble VEGF receptor-2, a splicing variant. Med. Mol. Morphol. 45:179–84
     [Google Scholar]
  75. 75. 
    Saif MW, Knost JA, Chiorean EG et al. 2016. Phase 1 study of the anti-vascular endothelial growth factor receptor 3 monoclonal antibody LY3022856/IMC-3C5 in patients with advanced and refractory solid tumors and advanced colorectal cancer. Cancer Chemother. Pharmacol. 78:815–24
     [Google Scholar]
  76. 76. 
    Tester A, Phelan D, McColl B et al. 2010. VGX-100, a novel therapeutic monoclonal antibody targeting VEGF-C that inhibits tumor growth. Cancer Res 70:2442 (Abstr.)
     [Google Scholar]
  77. 77. 
    Falchook GS, Goldman JW, Desai J et al. 2014. A first-in-human phase I study of VGX-100, a selective anti-VEGF-C antibody, alone and in combination with bevacizumab in patients with advanced solid tumors. J. Clin. Oncol. 32:2524 (Abstr.)
     [Google Scholar]
  78. 78. 
    Stacker SA, Caesar C, Baldwin ME et al. 2001. VEGF-D promotes the metastatic spread of tumor cells via the lymphatics. Nat. Med. 7:186–91
     [Google Scholar]
  79. 79. 
    Harris NC, Paavonen K, Davydova N et al. 2011. Proteolytic processing of vascular endothelial growth factor-D is essential for its capacity to promote the growth and spread of cancer. FASEB J 25:2615–25
     [Google Scholar]
  80. 80. 
    Honkanen HK, Izzi V, Petaisto T et al. 2016. Elevated VEGF-D modulates tumor inflammation and reduces the growth of carcinogen-induced skin tumors. Neoplasia 18:436–46
     [Google Scholar]
  81. 81. 
    Qin S, Li A, Yi M et al. 2019. Recent advances on anti-angiogenesis receptor tyrosine kinase inhibitors in cancer therapy. J. Hematol. Oncol. 12:27
     [Google Scholar]
  82. 82. 
    Michaelsen SR, Staberg M, Pedersen H et al. 2018. VEGF-C sustains VEGFR2 activation under bevacizumab therapy and promotes glioblastoma maintenance. Neuro Oncol 20:1462–74
     [Google Scholar]
  83. 83. 
    Osborn AJ, Dickie P, Neilson DE et al. 2015. Activating PIK3CA alleles and lymphangiogenic phenotype of lymphatic endothelial cells isolated from lymphatic malformations. Hum. Mol. Genet. 24:926–38
     [Google Scholar]
  84. 84. 
    Zenner K, Cheng CV, Jensen DM et al. 2019. Genotype correlates with clinical severity in PIK3CA-associated lymphatic malformations. JCI Insight 4:e129884
     [Google Scholar]
  85. 85. 
    Luks VL, Kamitaki N, Vivero MP et al. 2015. Lymphatic and other vascular malformative/overgrowth disorders are caused by somatic mutations in PIK3CA. J. Pediatr. 166:1048–54.e1–5
     [Google Scholar]
  86. 86. 
    Martinez-Corral I, Zhang Y, Petkova M et al. 2020. Blockade of VEGF-C signaling inhibits lymphatic malformations driven by oncogenic PIK3CA mutation. Nat. Commun. 11:2869
     [Google Scholar]
  87. 87. 
    Hammer J, Seront E, Duez S et al. 2018. Sirolimus is efficacious in treatment for extensive and/or complex slow-flow vascular malformations: a monocentric prospective phase II study. Orphanet. J. Rare Dis. 13:191
     [Google Scholar]
  88. 88. 
    Wiegand S, Wichmann G, Dietz A 2018. Treatment of lymphatic malformations with the mTOR inhibitor sirolimus: a systematic review. Lymphat. Res. Biol. 16:330–39
     [Google Scholar]
  89. 89. 
    Nykanen AI, Sandelin H, Krebs R et al. 2010. Targeting lymphatic vessel activation and CCL21 production by vascular endothelial growth factor receptor-3 inhibition has novel immunomodulatory and antiarteriosclerotic effects in cardiac allografts. Circulation 121:1413–22
     [Google Scholar]
  90. 90. 
    Dashkevich A, Raissadati A, Syrjala SO et al. 2016. Ischemia-reperfusion injury enhances lymphatic endothelial VEGFR3 and rejection in cardiac allografts. Am. J. Transplant. 16:1160–72
     [Google Scholar]
  91. 91. 
    Edwards LA, Nowocin AK, Jafari NV et al. 2018. Chronic rejection of cardiac allografts is associated with increased lymphatic flow and cellular trafficking. Circulation 137:488–503
     [Google Scholar]
  92. 92. 
    Hara Y, Torii R, Ueda S et al. 2018. Inhibition of tumor formation and metastasis by a monoclonal antibody against lymphatic vessel endothelial hyaluronan receptor 1. Cancer Sci 109:3171–82
     [Google Scholar]
  93. 93. 
    Karpinich NO, Kechele DO, Espenschied ST et al. 2013. Adrenomedullin gene dosage correlates with tumor and lymph node lymphangiogenesis. FASEB J 27:590–600
     [Google Scholar]
  94. 94. 
    Berenguer-Daize C, Boudouresque F, Bastide C et al. 2013. Adrenomedullin blockade suppresses growth of human hormone-independent prostate tumor xenograft in mice. Clin. Cancer Res. 19:6138–50
     [Google Scholar]
  95. 95. 
    Baluk P, Yao LC, Flores JC et al. 2017. Rapamycin reversal of VEGF-C-driven lymphatic anomalies in the respiratory tract. JCI Insight 2:e90103
     [Google Scholar]
  96. 96. 
    Yáñez JA, Wang SW, Knemeyer IW et al. 2011. Intestinal lymphatic transport for drug delivery. Adv. Drug Deliv. Rev. 63:923–42
     [Google Scholar]
  97. 97. 
    Reddy ST, Rehor A, Schmoekel HG et al. 2006. In vivo targeting of dendritic cells in lymph nodes with poly(propylene sulfide) nanoparticles. J. Control Release 112:26–34
     [Google Scholar]
  98. 98. 
    Sarin H. 2010. Physiologic upper limits of pore size of different blood capillary types and another perspective on the dual pore theory of microvascular permeability. J. Angiogenesis Res. 2:14
     [Google Scholar]
  99. 99. 
    Thomas SN, Schudel A. 2015. Overcoming transport barriers for interstitial-, lymphatic-, and lymph node-targeted drug delivery. Curr. Opin. Chem. Eng. 7:65–74
     [Google Scholar]
  100. 100. 
    Porter CJ. 1997. Drug delivery to the lymphatic system. Crit. Rev. Ther. Drug Carrier Syst. 14:333–93
     [Google Scholar]
  101. 101. 
    Rohner NA, Thomas SN. 2017. Flexible macromolecule versus rigid particle retention in the injected skin and accumulation in draining lymph nodes are differentially influenced by hydrodynamic size. ACS Biomater. Sci. Eng. 3:153–59
     [Google Scholar]
  102. 102. 
    Schudel A, Francis DM, Thomas SN 2019. Material design for lymph node drug delivery. Nat. Rev. Mater. 4:415–28
     [Google Scholar]
  103. 103. 
    Ryan GM, Kaminskas LM, Bulitta JB et al. 2013. PEGylated polylysine dendrimers increase lymphatic exposure to doxorubicin when compared to PEGylated liposomal and solution formulations of doxorubicin. J. Control Release 172:128–36
     [Google Scholar]
  104. 104. 
    Guo Q, Liu Y, Xu K et al. 2013. Mouse lymphatic endothelial cell targeted probes: anti-LYVE-1 antibody-based magnetic nanoparticles. Int. J. Nanomed. 8:2273–84
     [Google Scholar]
  105. 105. 
    Jiang G, Park K, Kim J et al. 2008. Hyaluronic acid-polyethyleneimine conjugate for target specific intracellular delivery of siRNA. Biopolymers 89:635–42
     [Google Scholar]
  106. 106. 
    Hirosue S, Vokali E, Raghavan VR et al. 2014. Steady-state antigen scavenging, cross-presentation, and CD8+ T cell priming: a new role for lymphatic endothelial cells. J. Immunol. 192:5002–11
     [Google Scholar]
  107. 107. 
    Wang C, Liu P, Zhuang Y et al. 2014. Lymphatic-targeted cationic liposomes: a robust vaccine adjuvant for promoting long-term immunological memory. Vaccine 32:5475–83
     [Google Scholar]
  108. 108. 
    Liu H, Moynihan KD, Zheng Y et al. 2014. Structure-based programming of lymph-node targeting in molecular vaccines. Nature 507:519–22
     [Google Scholar]
  109. 109. 
    Charman WNA, Stella VJ. 1986. Estimating the maximal potential for intestinal lymphatic transport of lipophilic drug molecules. Int. J. Pharm. 34:175–78
     [Google Scholar]
  110. 110. 
    Chlebowski RT. 1979. Adriamycin (doxorubicin) cardiotoxicity: a review. West. J. Med. 131:364–68
     [Google Scholar]
  111. 111. 
    Rupniak HT, Whelan RD, Hill BT 1983. Concentration and time-dependent inter-relationships for antitumour drug cytotoxicities against tumour cells in vitro. Int. J. Cancer 32:7–12
     [Google Scholar]
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Lymphatic Vasculature: An Emerging Therapeutic Target and Drug Delivery Route
Annual Review of Medicine 72, 167 (2021); https://doi.org/10.1146/annurev-med-051419-114417
/content/journals/10.1146/annurev-med-051419-114417
/content/journals/10.1146/annurev-med-051419-114417
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