Journal of Inherited Metabolic Disease

, Volume 36, Issue 3, pp 467–477 | Cite as

Comparative binding, endocytosis, and biodistribution of antibodies and antibody-coated carriers for targeted delivery of lysosomal enzymes to ICAM-1 versus transferrin receptor

  • Jason Papademetriou
  • Carmen Garnacho
  • Daniel Serrano
  • Tridib Bhowmick
  • Edward H. Schuchman
  • Silvia Muro
Original Article


Targeting lysosomal enzymes to receptors involved in transport into and across cells holds promise to enhance peripheral and brain delivery of enzyme replacement therapies (ERTs) for lysosomal storage disorders. Receptors being explored include those associated with clathrin-mediated pathways, yet other pathways seem also viable. Well characterized examples are that of transferrin receptor (TfR) and intercellular adhesion molecule 1 (ICAM-1), involved in iron transport and leukocyte extravasation, respectively. TfR and ICAM-1 support ERT delivery via clathrin- vs. cell adhesion molecule-mediated mechanisms, displaying different valency and size restrictions. To comparatively assess this, we used antibodies vs. larger multivalent antibody-coated carriers and evaluated TfR vs. ICAM-1 binding and endocytosis in endothelial cells, as well as in vivo biodistribution and delivery of a model lysosomal enzyme required in peripheral organs and brain: acid sphingomyelinase (ASM), deficient in types A-B Niemann Pick disease. We found similar binding of antibodies to both receptors under control conditions, with enhanced binding to activated endothelium for ICAM-1, yet only anti-TfR induced endocytosis efficiently. Contrarily, antibody-coated carriers showed enhanced binding, engulfment, and endocytosis for ICAM-1. In mice, anti-TfR enhanced brain targeting over anti-ICAM, with an opposite outcome in the lungs, while carriers enhanced ICAM-1 targeting over TfR in both organs. Both targeted carriers enhanced ASM delivery to the brain and lungs vs. free ASM, with greater enhancement for anti-ICAM carriers. Therefore, targeting TfR or ICAM-1 improves lysosomal enzyme delivery. Yet, TfR targeting may be more efficient for smaller conjugates or fusion proteins, while ICAM-1 targeting seems superior for multivalent carrier formulations.


Enzyme Replacement Therapy Lysosomal Enzyme Peripheral Organ Niemann Pick Disease Multivalent Carrier 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This study was funded by grants from the American Heart Association (09BGIA2450014) and National Institutes of Health (R01 HL098416) to SM.

Conflict of interest


Supplementary material

10545_2012_9534_Fig7_ESM.jpg (43 kb)
Supplementary Fig. 1

Fluorescence microscopy of antibody binding to ICAM-1 vs. TfR on endothelial cells. Control or TNFα-activated HUVECs were incubated with anti-ICAM or anti-TfR for 15 min at 37 °C. Cells were washed to remove unbound antibody, fixed, and stained with FITC-conjugated goat anti-mouse IgG. Phase-contrast images were used to delimit cell borders (dashed lines). Scale bar = 10 μm. (JPEG 43 kb)

10545_2012_9534_MOESM1_ESM.tif (16.2 mb)
High resolution image (TIFF 16563 kb)
10545_2012_9534_Fig8_ESM.jpg (37 kb)
Supplementary Fig. 2

Fluorescence microscopy of carrier binding to ICAM-1 vs. TfR on endothelial cells. Binding of ∼250 nm FITC-labeled anti-ICAM vs. anti-TfR carriers to control or TNFα-activated HUVECs after 1 h incubation. Cells were subsequently washed to remove unbound carriers. Phase-contrast images were used to delimit cell borders (dashed lines). Scale bar = 10 μm. (JPEG 36 kb)

10545_2012_9534_MOESM2_ESM.tif (16.2 mb)
High resolution image (TIFF 16569 kb)
10545_2012_9534_Fig9_ESM.jpg (24 kb)
Supplementary Fig. 3

Fluorescence microscopy of endocytosis of antibodies targeted to endothelial ICAM-1 vs. TfR. Uptake of anti-ICAM vs. anti-TfR by TNFα-activated HUVECs, assessed after 1 h incubation at 37 °C. Unbound antibodies were washed off and surface-bound antibodies were stained with a Texas-Red secondary IgG. Cells were then permeabilized and antibodies located both at the surface + internalized were stained with FITC-labeled secondary IgG. Internalized antibodies appear as FITC single-labeled in green, while surface-bound antibodies display FITC + Texas-Red double-labeled yellow color. Phase-contrast images were used to delimit cell borders (dashed lines). Scale bar = 10 μm. (JPEG 23 kb)

10545_2012_9534_MOESM3_ESM.tif (7.6 mb)
High resolution image (TIFF 7750 kb)
10545_2012_9534_Fig10_ESM.jpg (53 kb)
Supplementary Fig. 4

Fluorescence microscopy of endocytosis of carriers targeted to endothelial ICAM-1 vs. TfR. Uptake of ∼250 nm FITC-labeled anti-ICAM vs. anti-TfR carriers, assessed after 1 h incubation at 37 °C with control or TNFα-activated HUVECs. Unbound carriers were removed and surface-bound carriers were stained with a Texas-Red secondary IgG. Internalized carriers appear as FITC single-labeled in green, while surface-bound carriers display FITC + Texas-Red double-labeled yellow color. Phase-contrast images were used to delimit cell borders (dashed lines). Scale bar = 10 μm. (JPEG 53 kb)

10545_2012_9534_MOESM4_ESM.tif (16.2 mb)
High resolution image (TIFF 16565 kb)


  1. Altieri DC, Duperray A, Plescia J, Thornton GB, Languino LR (1995) Structural recognition of a novel fibrinogen gamma chain sequence (117–133) by intercellular adhesion molecule-1 mediates leukocyte-endothelium interaction. J Biol Chem 270(2):696–699PubMedCrossRefGoogle Scholar
  2. Balyasnikova IV, Metzger R, Visintine DJ et al (2005) Selective rat lung endothelial targeting with a new set of monoclonal antibodies to angiotensin I-converting enzyme. Pulm Pharmacol Ther 18(4):251–267PubMedCrossRefGoogle Scholar
  3. Banks WA (2009) Blood–brain barrier as a regulatory interface. Forum Nutr 63:102–110PubMedCrossRefGoogle Scholar
  4. Barreiro O, Zamai M, Yáñez-Mó M et al (2008) Endothelial adhesion receptors are recruited to adherent leukocytes by inclusion in preformed tetraspanin nanoplatforms. J Cell Biol 183(3):527–542PubMedCrossRefGoogle Scholar
  5. Begley DJ, Pontikis CC, Scarpa M (2008) Lysosomal storage diseases and the blood–brain barrier. Curr Pharm Des 14(16):1566–1580PubMedCrossRefGoogle Scholar
  6. Boado RJ, Zhang Y, Xia CF, Wang Y, Pardridge WM (2008) Genetic engineering of a lysosomal enzyme fusion protein for targeted delivery across the human blood brain barrier. Biotechnol Bioeng 99(2):475–484PubMedCrossRefGoogle Scholar
  7. Boado RJ, Zhang Y, Wang Y, Pardridge WM (2009) Engineering and expression of a chimeric transferrin receptor monoclonal antibody for blood–brain barrier delivery in the mouse. Biotechnol Bioeng 102(4):1251–1258PubMedCrossRefGoogle Scholar
  8. Boado RJ, Hui EK, Lu JZ, Zhou Q, Pardridge WM (2011) Reversal of lysosomal storage in brain of adult MPS-I mice with intravenous Trojan horse-iduronidase fusion protein. Mol Pharm 8(4):1342–1350PubMedCrossRefGoogle Scholar
  9. Brady RO (2003) Enzyme replacement therapy: conception, chaos and culmination. Philos Trans R Soc Lond B Biol Sci 358(1433):915–919PubMedCrossRefGoogle Scholar
  10. Calderon AJ, Bhowmick T, Leferovich J et al (2011) Optimizing endothelial targeting by modulating the antibody density and particle concentration of anti-ICAM coated carriers. J Control Release 150(1):37–44PubMedCrossRefGoogle Scholar
  11. Cardone M, Porto C, Tarallo A et al (2008) Abnormal mannose-6-phosphate receptor trafficking impairs recombinant alpha-glucosidase uptake in Pompe disease fibroblasts. Pathogenetics 1(1):6PubMedCrossRefGoogle Scholar
  12. Carman CV, Springer TA (2004) A transmigratory cup in leukocyte diapedesis both through individual vascular endothelial cells and between them. J Cell Biol 167(2):377–388PubMedCrossRefGoogle Scholar
  13. Carman CV, Sage PT, Sciuto TE et al (2007) Transcellular diapedesis is initiated by invasive podosomes. Immunity 26(6):784–797PubMedCrossRefGoogle Scholar
  14. Carpén O, Pallai P, Staunton DE, Springer TA (1992) Association of intercellular adhesion molecule-1 (ICAM-1) with actin-containing cytoskeleton and alpha-actinin. J Cell Biol 118(5):1223–1234PubMedCrossRefGoogle Scholar
  15. Chen CH, Dellamaggiore KR, Ouellette CP et al (2008) Aptamer-based endocytosis of a lysosomal enzyme. Proc Natl Acad Sci U S A 105(41):15908–15913PubMedCrossRefGoogle Scholar
  16. Conrad ME, Umbreit JN (2000) Iron absorption and transport—an update. Am J Hematol 64(4):287–298PubMedCrossRefGoogle Scholar
  17. Dautry-Varsat A (1986) Receptor-mediated endocytosis: the intracellular journey of transferrin and its receptor. Biochimie 68(3):375–381PubMedCrossRefGoogle Scholar
  18. DeGraba T, Azhar S, Dignat-George F et al (2000) Profile of endothelial and leukocyte activation in Fabry patients. Ann Neurol 47(2):229–233PubMedCrossRefGoogle Scholar
  19. Desnick RJ, Schuchman EH (2002) Enzyme replacement and enhancement therapies: lessons from lysosomal disorders. Nat Rev Genet 3(12):954–966PubMedCrossRefGoogle Scholar
  20. Dhami R, Schuchman EH (2004) Mannose 6-phosphate receptor-mediated uptake is defective in acid sphingomyelinase-deficient macrophages: implications for Niemann-Pick disease enzyme replacement therapy. J Biol Chem 279(2):1526–1532PubMedCrossRefGoogle Scholar
  21. Dvorak AM, Feng D (2001) The vesiculo-vacuolar organelle (VVO). A new endothelial cell permeability organelle. J Histochem Cytochem 49(4):419–432PubMedCrossRefGoogle Scholar
  22. Fishman JB, Rubin JB, Handrahan JV, Connor JR, Fine RE (1987) Receptor-mediated transcytosis of transferrin across the blood–brain barrier. J Neurosci Res 18(2):299–304PubMedCrossRefGoogle Scholar
  23. Frey A, Giannasca KT, Weltzin R et al (1996) Role of the glycocalyx in regulating access of microparticles to apical plasma membranes of intestinal epithelial cells: implications for microbial attachment and oral vaccine targeting. J Exp Med 184(3):1045–1059PubMedCrossRefGoogle Scholar
  24. Fuchs H, Lucken U et al (1998) Structural model of phospholipid-reconstituted human transferrin receptor derived by electron microscopy. Structure 6(10):1235–1243PubMedCrossRefGoogle Scholar
  25. Futerman AH, van Meer G (2004) The cell biology of lysosomal storage disorders. Nat Rev Mol Cell Biol 5(7):554–565PubMedCrossRefGoogle Scholar
  26. Garnacho C, Dhami R, Simone E et al (2008a) Delivery of acid sphingomyelinase in normal and niemann-pick disease mice using intercellular adhesion molecule-1-targeted polymer nanocarriers. J Pharmacol Exp Ther 325(2):400–408PubMedCrossRefGoogle Scholar
  27. Garnacho C, Albelda SM, Muzykantov VR, Muro S (2008b) Differential intra-endothelial delivery of polymer nanocarriers targeted to distinct PECAM-1 epitopes. J Control Release 130(3):226–233PubMedCrossRefGoogle Scholar
  28. Garnacho C, Serrano D, Muro S (2012) A fibrinogen-derived peptide provides ICAM-1-specific targeting and intra-endothelial transport of polymer nanocarriers in human cell cultures and mice. J Pharmacol Exp Ther 340(3):638–647PubMedCrossRefGoogle Scholar
  29. Ghaffarian R, Bhowmick T, Muro S (2012) Transport of nanocarriers across gastrointestinal epithelial cells by a new transcellular route induced by targeting ICAM-1. J Control Release June 12 (Epub ahead of print)Google Scholar
  30. Hatakeyama H, Akita H, Maruyama K et al (2004) Factors governing the in vivo tissue uptake of transferrin-coupled polyethylene glycol liposomes in vivo. Int J Pharm 281(1–2):25–33PubMedCrossRefGoogle Scholar
  31. He X, Miranda SR, Xiong X, Dagan A, Gatt S, Schuchman EH (1999) Characterization of human acid sphingomyelinase purified from the media of overexpressing Chinese hamster ovary cells. Biochim Biophys Acta 1432(2):251–264PubMedCrossRefGoogle Scholar
  32. Hillebrand U, Hausberg M, Stock C et al (2006) 17beta-estradiol increases volume, apical surface and elasticity of human endothelium mediated by Na+/H+ exchange. Cardiovasc Res 69(4):916–924PubMedCrossRefGoogle Scholar
  33. Hirst J, Robinson MS (1998) Clathrin and adaptors. Biochim Biophys Acta 1404(1–2):173–193PubMedCrossRefGoogle Scholar
  34. Hsu J, Serrano D, Bhowmick T, Muro S (2011) Enhanced endothelial delivery and biochemical effects of alpha-galactosidase by ICAM-1-targeted nanocarriers for Fabry disease. J Control Release 149(3):323–331PubMedCrossRefGoogle Scholar
  35. Hsu J, Northrup L, Bhowmick T, Muro S (2012) Enhanced delivery of alpha-glucosidase for Pompe disease by ICAM-1-targeted nanocarriers: comparative performance of a strategy for three distinct lysosomal storage disorders. Nanomedicine 8(5):731–739PubMedCrossRefGoogle Scholar
  36. Jefferies WA, Brandon MR, Hunt SV, Williams AF, Gatter KS, Mason DY (1984) Transferrin receptor on endothelium of brain capillaries. Nature 312(5990):162–163PubMedCrossRefGoogle Scholar
  37. Jevnikar AM, Wuthrich RP, Takei F et al (1990) Differing regulation and function of ICAM-1 and class II antigens on renal tubular cells. Kidney Int 38(3):417–425PubMedCrossRefGoogle Scholar
  38. Jin M, Snider MD (1993) Role of microtubules in transferrin receptor transport from the cell surface to endosomes and the Golgi complex. J Biol Chem 268(24):18390–18397PubMedGoogle Scholar
  39. Jun CD, Carman CV, Redick SD, Shimaoka M, Erickson HP, Springer TA (2001) Ultrastructure and function of dimeric, soluble intercellular adhesion molecule-1 (ICAM-1). J Biol Chem 276(31):29019–29027PubMedCrossRefGoogle Scholar
  40. Kissel K, Hamm S et al (1998) Immunohistochemical localization of the murine transferrin receptor (TfR) on blood–tissue barriers using a novel anti-TfR monoclonal antibody. Histochem Cell Biol 110(1):63–72PubMedCrossRefGoogle Scholar
  41. Ko YT, Bhattacharya R, Bickel U (2009) Liposome encapsulated polyethylenimine/ODN polyplexes for brain targeting. J Control Release 133(3):230–237PubMedCrossRefGoogle Scholar
  42. LeBowitz JH, Grubb JH, Maga JA, Schmiel DH, Vogler C, Sly WS (2004) Glycosylation-independent targeting enhances enzyme delivery to lysosomes and decreases storage in mucopolysaccharidosis type VII mice. Proc Natl Acad Sci U S A 101(9):3083–3088PubMedCrossRefGoogle Scholar
  43. Lossinsky AS, Mossakowski MJ, Pluta R, Wisniewski HM (1995) Intercellular adhesion molecule-1 (ICAM-1) upregulation in human brain tumors as an expression of increased blood–brain barrier permeability. Brain Pathol 5(4):339–344PubMedCrossRefGoogle Scholar
  44. Lu JZ, Boado RJ, Hui EK, Zhou QH, Pardridge WM (2011) Expression in CHO cells and pharmacokinetics and brain uptake in the Rhesus monkey of an IgG-iduronate-2-sulfatase fusion protein. Biotechnol Bioeng 108(8):1954–1964PubMedCrossRefGoogle Scholar
  45. Marlin SD, Springer TA (1987) Purified intercellular adhesion molecule-1 (ICAM-1) is a ligand for lymphocyte function-associated antigen 1 (LFA-1). Cell 51(5):813–819PubMedCrossRefGoogle Scholar
  46. Matzner U, Matthes F, Weigelt C et al (2008) Non-inhibitory antibodies impede lysosomal storage reduction during enzyme replacement therapy of a lysosomal storage disease. J Mol Med 86(4):433–442PubMedCrossRefGoogle Scholar
  47. Millán J, Hewlett L, Glyn M, Toomre D, Clark P, Ridley AJ (2006) Lymphocyte transcellular migration occurs through recruitment of endothelial ICAM-1 to caveola- and F-actin-rich domains. Nat Cell Biol 8(2):113–123PubMedCrossRefGoogle Scholar
  48. Mistry PK, Wraight EP, Cox TM (1996) Therapeutic delivery of proteins to macrophages: implications for treatment of Gaucher’s disease. Lancet 348(9041):1555–1559PubMedCrossRefGoogle Scholar
  49. Moghimi SM, Hunter AC, Murray JC (2001) Long circulating and target-specific nanoparticles: theory to practice. Pharmacol Rev 53(2):283–318PubMedGoogle Scholar
  50. Murciano JC, Muro S, Koniaris L et al (2003) ICAM-directed vascular immunotargeting of antithrombotic agents to the endothelial luminal surface. Blood 101(10):3977–3984PubMedCrossRefGoogle Scholar
  51. Muro S (2010) New biotechnological and nanomedicine strategies for treatment of lysosomal storage disorders. Wiley Interdiscip Rev Nanomed Nanobiotechnol 2(2):189–204PubMedCrossRefGoogle Scholar
  52. Muro S, Wiewrodt R, Thomas A et al (2003) A novel endocytic pathway induced by clustering endothelial ICAM-1 or PECAM-1. J Cell Sci 116(Pt 8):1599–1609PubMedCrossRefGoogle Scholar
  53. Muro S, Gajewski C, Koval M, Muzykantov VR (2005) ICAM-1 recycling in endothelial cells: a novel pathway for sustained intracellular delivery and prolonged effects of drugs. Blood 105(2):650–658PubMedCrossRefGoogle Scholar
  54. Muro S, Schuchman EH, Muzykantov VR (2006a) Lysosomal enzyme delivery by ICAM-1-targeted nanocarriers bypassing glycosylation- and clathrin-dependent endocytosis. Mol Ther 13(1):135–141PubMedCrossRefGoogle Scholar
  55. Muro S, Mateescu M, Gajewski C et al (2006b) Control of intracellular trafficking of ICAM-1-targeted nanocarriers by endothelial Na+/H+ exchanger proteins. Am J Physiol Lung Cell Mol Physiol 290(5):L809–L817PubMedCrossRefGoogle Scholar
  56. Muro S, Garnacho C, Champion JA et al (2008) Control of endothelial targeting and intracellular delivery of therapeutic enzymes by modulating the size and shape of ICAM-1-targeted carriers. Mol Ther 16(8):1450–1458PubMedCrossRefGoogle Scholar
  57. Nanami M, Ookawara T, Otaki Y et al (2005) Tumor necrosis factor-alpha-induced iron sequestration and oxidative stress in human endothelial cells. Arterioscler Thromb Vasc Biol 25(12):2495–2501PubMedCrossRefGoogle Scholar
  58. Ohashi T, Iizuka S, Ida H, Eto Y (2008) Reduced alpha-Gal A enzyme activity in Fabry fibroblast cells and Fabry mice tissues induced by serum from antibody positive patients with Fabry disease. Mol Genet Metab 94(3):313–318PubMedCrossRefGoogle Scholar
  59. Osborn MJ, McElmurry RT, Peacock B, Tolar J, Blazar BR (2008) Targeting of the CNS in MPS-IH using anonviral transferrin-alpha-L-iduronidase fusion gene product. Mol Ther 16(8):1459–1466PubMedCrossRefGoogle Scholar
  60. Pang Z, Gao H, Yu Y et al (2011) Brain delivery and cellular internalization mechanisms for transferrin conjugated biodegradable polymersomes. Int J Pharm 415(1–2):284–292PubMedCrossRefGoogle Scholar
  61. Pardridge WM (2010) Biopharmaceutical drug targeting to the brain. J Drug Target 18(3):157–167PubMedCrossRefGoogle Scholar
  62. Pardridge WM, Boado RJ (2012) Reengineering biopharmaceuticals for targeted delivery across the blood–brain barrier. Methods Enzymol 503:269–292PubMedCrossRefGoogle Scholar
  63. Prince WS, McCormick LM, Wendt DJ et al (2004) Lipoprotein receptor binding, cellular uptake, and lysosomal delivery of fusions between the receptor-associated protein (RAP) and alpha-L-iduronidase or acid alpha-glucosidase. J Biol Chem 279(33):35037–35046PubMedCrossRefGoogle Scholar
  64. Rothlein R, Dustin ML, Marlin SD, Springer TA (1986) A human intercellular adhesion molecule (ICAM-1) distinct from LFA-1. J Immunol 137(4):1270–1274PubMedGoogle Scholar
  65. Schnitzer JE (2001) Caveolae: from basic trafficking mechanisms to targeting transcytosis for tissue-specific drug and gene delivery in vivo. Adv Drug Deliv Rev 49(3):265–280PubMedCrossRefGoogle Scholar
  66. Serrano D, Bhowmick T, Chadha R, Garnacho C, Muro S (2012) Intercellular adhesion molecule 1 engagement modulates sphingomyelinase and ceramide, supporting uptake of drug carriers by the vascular endothelium. Arterioscler Thromb Vasc Biol 32(5):1178–1185PubMedCrossRefGoogle Scholar
  67. Shen JS, Meng XL, Moore DF, Quirk JM, Shayman JA, Schiffmann R, Kaneski CR (2008) Globotriaosylceramide induces oxidative stress and up-regulates cell adhesion molecule expression in Fabry disease endothelial cells. Mol Genet Metab 95(3):163–168PubMedCrossRefGoogle Scholar
  68. Shi N, Boado RJ, Pardridge WM (2001) Receptor-mediated gene targeting to tissues in vivo following intravenous administration of pegylated immunoliposomes. Pharm Res 18(8):1091–1095PubMedCrossRefGoogle Scholar
  69. Steven AC, Hainfeld JF, Wall JS, Steer CJ (1983) Mass distributions of coated vesicles isolated from liver and brain: analysis by scanning transmission electron microscopy. J Cell Biol 97(6):1714–1723PubMedCrossRefGoogle Scholar
  70. Torchilin VP (2006) Multifunctional nanocarriers. Adv Drug Deliv Rev 58(14):1532–1555PubMedCrossRefGoogle Scholar
  71. Urayama A, Grubb JH, Sly WS, Banks WA (2004) Developmentally regulated mannose 6-phosphate receptor-mediated transport of a lysosomal enzyme across the blood–brain barrier. Proc Natl Acad Sci U S A 101(34):12658–12663PubMedCrossRefGoogle Scholar
  72. Vaags AK, Campbell TN, Choy FY (2005) HIV TAT variants differentially influence the production of glucocerebrosidase in Sf9 cells. Genet Mol Res 4(3):491–495PubMedGoogle Scholar
  73. van Rooy I, Mastrobattista E, Storm G, Hennink WE, Schiffelers RM (2011) Comparison of five different targeting ligands to enhance accumulation of liposomes into the brain. J Control Release 150(1):30–36PubMedCrossRefGoogle Scholar
  74. Visser CC, Voorwinden LH, Crommelin DJ, Danhof M, de Boer AG (2004) Characterization and modulation of the transferrin receptor on brain capillary endothelial cells. Pharm Res 21(5):761–769PubMedCrossRefGoogle Scholar
  75. Xia H, Anderson B, Mao Q, Davidson BL (2000) Recombinant human adenovirus: targeting to the human transferrin receptor improves gene transfer to brain microcapillary endothelium. J Virol 74(23):11359–11366PubMedCrossRefGoogle Scholar
  76. Xia H, Mao Q, Davidson BL (2001) The HIV Tat protein transduction domain improves the biodistribution of beta-glucuronidase expressed from recombinant viral vectors. Nat Biotechnol 19(7):640–644PubMedCrossRefGoogle Scholar
  77. Zhang XY, Dinh A, Cronin J, Li SC, Reiser J (2008) Cellular uptake and lysosomal delivery of galactocerebrosidase tagged with the HIV Tat protein transduction domain. J Neurochem 104(4):1055–1064PubMedCrossRefGoogle Scholar
  78. Zhou QH, Boado RJ, Lu JZ, Hui EK, Pardridge WM (2012) Brain-penetrating IgG-iduronate 2-sulfatase fusion protein for the mouse. Drug Metab Dispos 40(2):329–335PubMedCrossRefGoogle Scholar

Copyright information

© SSIEM and Springer 2012

Authors and Affiliations

  • Jason Papademetriou
    • 1
  • Carmen Garnacho
    • 2
  • Daniel Serrano
    • 3
  • Tridib Bhowmick
    • 4
  • Edward H. Schuchman
    • 5
  • Silvia Muro
    • 1
    • 4
  1. 1.Fischell Department of Bioengineering, School of EngineeringUniversity of Maryland College ParkCollege ParkUSA
  2. 2.Department of Normal and Pathological Cytology and Histology, School of MedicineUniversity of SevilleSevilleSpain
  3. 3.Department of Cell Biology & Molecular Genetics and Biological Sciences Graduate ProgramUniversity of MarylandCollege ParkUSA
  4. 4.Institute for Bioscience and Biotechnology ResearchUniversity of MarylandCollege ParkUSA
  5. 5.Department of Human GeneticsMount Sinai School of MedicineNew YorkUSA

Personalised recommendations