Real-time imaging of convection-enhanced delivery of viruses and virus-sized particles

View More View Less
  • 1 Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke;
  • 3 Laboratory of Biochemical Genetics, National Heart, Lung and Blood Institute; and
  • 4 Division of Bioengineering and Physical Science, Office of Research Services, National Institutes of Health, Bethesda, Maryland;
  • 2 Department of Neurosurgery, University of Maryland Medical Center, Baltimore, Maryland; and
  • 5 Department of Neurosurgery, George Washington University, Washington, DC
Restricted access

Purchase Now

USD  $45.00

JNS + Pediatrics - 1 year subscription bundle (Individuals Only)

USD  $505.00

JNS + Pediatrics + Spine - 1 year subscription bundle (Individuals Only)

USD  $600.00
Print or Print + Online

Object

Despite recent evidence showing that convection-enhanced delivery (CED) of viruses and virus-sized particles to the central nervous system (CNS) is possible, little is known about the factors influencing distribution of these vectors with convection. To better define the delivery of viruses and virus-sized particles in the CNS, and to determine optimal parameters for infusion, the authors coinfused adeno-associated virus ([AAV], 24-nm diameter) and/or feru-moxtran-10 (24 nm) by using CED during real-time magnetic resonance (MR) imaging.

Methods

Sixteen rats underwent intrastriatal convective coinfusion with 4 μl of 35S-AAV capsids (0.5–1.0 × 1014 viral particles/ml) and increasing concentrations (0.1, 0.5, 1, and 5 mg/ml) of a similar sized iron oxide MR imaging agent (ferumoxtran-10). Five nonhuman primates underwent either convective coinfusion of 35S-AAV capsids and 1 mg/ml ferumoxtran-10 (striatum, one animal) or infusion of 1 mg/ml ferumoxtran-10 alone (striatum in two animals; frontal white matter in two). Clinical effects, MR imaging studies, quantitative autoradiography, and histological data were analyzed.

Results

Real-time, T2-weighted MR imaging of ferumoxtran-10 during infusion revealed a clearly defined hypo-intense region of perfusion. Quantitative autoradiography confirmed that MR imaging of ferumoxtran-10 at a concentration of 1 mg/ml accurately tracked viral capsid distribution in the rat and primate brain (the mean difference in volume of distribution [Vd] was 7 and 15% in rats and primates, respectively). The Vd increased linearly with increasing volume of infusion (Vi) (R2 = 0.98). The mean Vd/Vi ratio was 4.1 ± 0.2 (mean ± standard error of the mean) in gray and 2.3 ± 0.1 in white matter (p < 0.01). The distribution of infusate was homogeneous. Postinfusion MR imaging revealed leakback along the cannula track at infusion rates greater than 1.5 μl/minute in primate gray and white matter. No animal had clinical or histological evidence of toxicity.

Conclusions

The CED method can be used to deliver AAV capsids and similar sized particles to the CNS safely and effectively over clinically relevant volumes. Moreover, real-time MR imaging of ferumoxtran-10 during infusion reveals that AAV capsids and similar sized particles have different convective delivery properties than smaller proteins and other compounds.

Abbreviations used in this paper:AAV = adeno-associated virus; CED = convection-enhanced delivery; CNS = central nervous system; MR = magnetic resonance; SEM = standard error of the mean; Vd = volume of distribution; Vi = volume of infusion.

JNS + Pediatrics - 1 year subscription bundle (Individuals Only)

USD  $505.00

JNS + Pediatrics + Spine - 1 year subscription bundle (Individuals Only)

USD  $600.00

Contributor Notes

Address reprint requests to: Russell R. Lonser, M.D., Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Building 10, Room 5D37, Bethesda, Maryland 20892-1414. email: lonserr@ninds.nih.gov.
  • 1

    Barry SI, & Aldis GK: Flow-induced deformation from pressurized cavities in absorbing porous tissues. Bull Math Biol 54:977997, 1992

  • 2

    Basser PJ: Interstitial pressure, volume, and flow during infusion into brain tissue. Microvasc Res 44:143165, 1992

  • 3

    Bobo RH, , Laske DW, , Akbasak A, , Morrison PF, , Dedrick RL, & Oldfield EH: Convection-enhanced delivery of macromolecules in the brain. Proc Natl Acad Sci U S A 91:20762080, 1994

    • Search Google Scholar
    • Export Citation
  • 4

    Brem H, , Piantadosi S, , Burger PC, , Walker M, , Selker R, & Vick NA, : Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. The Polymer-Brain Tumor Treatment Group. Lancet 345:10081012, 1995

    • Search Google Scholar
    • Export Citation
  • 5

    Broaddus WC, , Prabhu SS, , Gillies GT, , Neal J, , Conrad WS, & Chen ZJ, : Distribution and stability of antisense phosphorothioate oligonucleotides in rodent brain following direct intraparenchymal controlled-rate infusion. J Neurosurg 88:734742, 1998

    • Search Google Scholar
    • Export Citation
  • 6

    Chen MY, , Hoffer A, , Morrison PF, , Hamilton JF, , Hughes J, & Schlageter KS, : Surface properties, more than size, limiting convective distribution of virus-sized particles and viruses in the central nervous system. J Neurosurg 103:311319, 2005

    • Search Google Scholar
    • Export Citation
  • 7

    Chen MY, , Lonser RR, , Morrison PF, , Governale LS, & Oldfield EH: Variables affecting convection-enhanced delivery to the striatum: a systematic examination of rate of infusion, cannula size, infusate concentration, and tissue-cannula sealing time. J Neurosurg 90:315320, 1999

    • Search Google Scholar
    • Export Citation
  • 8

    Cheng S, & Bilston LE: Unconfined compression of white matter. J Biomech 40:117124, 2005

  • 9

    Croteau D, , Walbridge S, , Morrison PF, , Butman JA, , Vortmeyer AO, & Johnson D, : Real-time in vivo imaging of the convective distribution of a low-molecular-weight tracer. J Neurosurg 102:9097, 2005

    • Search Google Scholar
    • Export Citation
  • 10

    Cunningham J, , Oiwa Y, , Nagy D, , Podsakoff G, , Colosi P, & Bankiewicz KS: Distribution of AAV-TK following intracranial convection-enhanced delivery into rats. Cell Transplant 9:585594, 2000

    • Search Google Scholar
    • Export Citation
  • 11

    Fenstermacher J, , Gross P, , Sposito N, , Acuff V, , Pettersen S, & Gruber K: Structural and functional variations in capillary systems within the brain. Ann N Y Acad Sci 529:2130, 1988

    • Search Google Scholar
    • Export Citation
  • 12

    Fenstermacher JD, , Patlak CS, & Blasberg RG: Transport of material between brain extracellular fluid, brain cells and blood. Fed Proc 33:20702074, 1974

    • Search Google Scholar
    • Export Citation
  • 13

    Hadaczek P, , Kohutnicka M, , Krauze MT, , Bringas J, , Pivirotto P, & Cunningham J, : Convection-enhanced delivery of adeno-associated virus type 2 (AAV2) into the striatum and transport of AAV2 within monkey brain. Hum Gene Ther 17:291302, 2006

    • Search Google Scholar
    • Export Citation
  • 14

    Harisinghani MG, , Barentsz J, , Hahn PF, , Deserno WM, , Tabatabaei S, & van de Kaa CH, : Noninvasive detection of clinically occult lymph-node metastases in prostate cancer. N Engl J Med 348:24912499, 2003

    • Search Google Scholar
    • Export Citation
  • 15

    Hua Y, , Nakamura T, , Keep RF, , Wu J, , Schallert T, & Hoff JT, : Long-term effects of experimental intracerebral hemorrhage: the role of iron. J Neurosurg 104:305312, 2006

    • Search Google Scholar
    • Export Citation
  • 16

    Janson C, , McPhee S, , Bilaniuk L, , Haselgrove J, , Testaiuti M, & Freese A, : Clinical protocol. Gene therapy of Canavan disease: AAV-2 vector for neurosurgical delivery of aspartoacylase gene (ASPA) to the human brain. Hum Gene Ther 13:13911412, 2002

    • Search Google Scholar
    • Export Citation
  • 17

    Kordower JH, , Emborg ME, , Bloch J, , Ma SY, , Chu Y, & Leventhal L, : Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson's disease. Science 290:767773, 2000

    • Search Google Scholar
    • Export Citation
  • 18

    Krauze MT, , McKnight TR, , Yamashita Y, , Bringas J, , Noble CO, & Saito R, : Real-time visualization and characterization of liposomal delivery into the monkey brain by magnetic resonance imaging. Brain Res Brain Res Protoc 16:2026, 2005

    • Search Google Scholar
    • Export Citation
  • 19

    Kroin JS: Intrathecal drug administration. Present use and future trends. Clin Pharmacokinet 22:319326, 1992

  • 20

    Kroll RA, , Pagel MA, , Muldoon LL, , Roman-Goldstein S, & Neuwelt EA: Increasing volume of distribution to the brain with interstitial infusion: dose, rather than convection, might be the most important factor. Neurosurgery 38:746754, 1996

    • Search Google Scholar
    • Export Citation
  • 21

    Lang FF, , Bruner JM, , Fuller GN, , Aldape K, , Prados MD, & Chang S, : Phase I trial of adenovirus-mediated p53 gene therapy for recurrent glioma: biological and clinical results. J Clin Oncol 21:25082518, 2003

    • Search Google Scholar
    • Export Citation
  • 22

    Lieberman DM, , Laske DW, , Morrison PF, , Bankiewicz KS, & Old-field EH: Convection-enhanced distribution of large molecules in gray matter during interstitial drug infusion. J Neurosurg 82:10211029, 1995

    • Search Google Scholar
    • Export Citation
  • 23

    Lonser RR, , Walbridge S, , Garmestani K, , Butman JA, , Walters HA, & Vortmeyer AO, : Successful and safe perfusion of the primate brainstem: in vivo magnetic resonance imaging of macromolecular distribution during infusion. J Neurosurg 97:905913, 2002

    • Search Google Scholar
    • Export Citation
  • 24

    Lonser RR, , Weil RJ, , Morrison PF, , Governale LS, & Oldfield EH: Direct convective delivery of macromolecules to peripheral nerves. J Neurosurg 89:610615, 1998

    • Search Google Scholar
    • Export Citation
  • 25

    Lum JT, , Nguyen T, & Felpel LP: Drug distribution in solid tissue of the brain following chronic local perfusion utilizing implanted osmotic minipumps. J Pharmacol Methods 12:141147, 1984

    • Search Google Scholar
    • Export Citation
  • 26

    Mamot C, , Nguyen JB, , Pourdehnad M, , Hadaczek P, , Saito R, & Bringas JR, : Extensive distribution of liposomes in rodent brains and brain tumors following convection-enhanced delivery. J Neurooncol 68:19, 2004

    • Search Google Scholar
    • Export Citation
  • 27

    Mandel RJ, , Manfredsson FP, , Foust KD, , Rising A, , Reimsnider S, & Nash K, : Recombinant adeno-associated viral vectors as therapeutic agents to treat neurological disorders. Mol Ther 13:463483, 2006

    • Search Google Scholar
    • Export Citation
  • 28

    Mastakov MY, , Baer K, , Xu R, , Fitzsimons H, & During MJ: Combined injection of rAAV with mannitol enhances gene expression in the rat brain. Mol Ther 3:225232, 2001

    • Search Google Scholar
    • Export Citation
  • 29

    Morrison PF, , Chen MY, , Chadwick RS, , Lonser RR, & Oldfield EH: Focal delivery during direct infusion to brain: role of flow rate, catheter diameter, and tissue mechanics. Am J Physiol 277:R1218R1229, 1999

    • Search Google Scholar
    • Export Citation
  • 30

    Morrison PF, , Laske DW, , Bobo H, , Oldfield EH, & Dedrick RL: High-flow microinfusion: tissue penetration and pharmacodynamics. Am J Physiol 266:R292R305, 1994

    • Search Google Scholar
    • Export Citation
  • 31

    Muldoon LL, , Sandor M, , Pinkston KE, & Neuwelt EA: Imaging, distribution, and toxicity of superparamagnetic iron oxide magnetic resonance nanoparticles in the rat brain and intracerebral tumor. Neurosurgery 57:785796, 2005

    • Search Google Scholar
    • Export Citation
  • 32

    Murad GJ, , Walbridge S, , Morrison PF, , Szerlip N, , Butman JA, & Oldfield EH, : Image-guided convection-enhanced delivery of gemcitabine to the brainstem. J Neurosurg 106:351356, 2007

    • Search Google Scholar
    • Export Citation
  • 33

    Nakamura T, , Keep RF, , Hua Y, , Park JW, , Itano T, & Nagao S, : Intracerebral hemorrhage induces edema and oxidative stress and alters N-methyl-D-aspartate receptor subunits expression. Acta Neurochir Suppl 95:421424, 2005

    • Search Google Scholar
    • Export Citation
  • 34

    Nguyen JB, , Sanchez-Pernaute R, , Cunningham J, & Bankiewicz KS: Convection-enhanced delivery of AAV-2 combined with heparin increases TK gene transfer in the rat brain. Neuroreport 12:19611964, 2001

    • Search Google Scholar
    • Export Citation
  • 35

    Nguyen TT, , Pannu YS, , Sung C, , Dedrick RL, , Walbridge S, & Brechbiel MW, : Convective distribution of macromolecules in the primate brain demonstrated using computerized tomography and magnetic resonance imaging. J Neurosurg 98:584590, 2003

    • Search Google Scholar
    • Export Citation
  • 36

    Parney IF, , Kunwar S, , McDermott M, , Berger M, , Prados M, & Cha S, : Neuroradiographic changes following convection-enhanced delivery of the recombinant cytotoxin interleukin 13-pE38QQR for recurrent malignant glioma. J Neurosurg 102:267275, 2005

    • Search Google Scholar
    • Export Citation
  • 37

    Popperl G, , Goldbrunner R, , Gildehaus FJ, , Kreth FW, , Tanner P, & Holtmannspotter M, : O-(2-[18F]fluoroethyl)-L-tyrosine PET for monitoring the effects of convection-enhanced delivery of paclitaxel in patients with recurrent glioblastoma. Eur J Nucl Med Mol Imaging 32:10181025, 2005

    • Search Google Scholar
    • Export Citation
  • 38

    Sarntinoranont M, , Banerjee RK, , Lonser RR, & Morrison PF: A computational model of direct interstitial infusion of macromolecules into the spinal cord. Ann Biomed Eng 31:448461, 2003

    • Search Google Scholar
    • Export Citation
  • 39

    Urabe M, , Ding C, & Kotin RM: Insect cells as a factory to produce adeno-associated virus type 2 vectors. Hum Gene Ther 13:19351943, 2002

    • Search Google Scholar
    • Export Citation
  • 40

    Wang YX, , Hussain SM, & Krestin GP: Superparamagnetic iron oxide contrast agents: physicochemical characteristics and applications in MR imaging. Eur Radiol 11:23192331, 2001

    • Search Google Scholar
    • Export Citation

Metrics

All Time Past Year Past 30 Days
Abstract Views 321 195 16
Full Text Views 187 19 1
PDF Downloads 107 7 1
EPUB Downloads 0 0 0