Abstract
Convection-enhanced drug delivery is a novel technology used to deliver drugs into brain tissue and which is currently evaluated in clinical trials. Drugs are delivered continuously via intracranial catheters and enable to achieve large volume of distributions at high drug concentrations with minimum systemic toxicity.
Accumulated clinical experience has shown that convection does not always form and the efficiency of distribution varies among patients and different drugs. The efficiency of drug distribution depends on multiple treatment and physiological parameters, such as infusate characteristics, catheter type, flow rate, volume of distribution, and tissue characterization along the catheter path and at the catheter tip. Therefore, extensive research is ongoing focusing on optimizing convection to enhance the therapeutic effect of drugs in various brain disorders.
This chapter describes various aspects of performing convection-enhanced drug delivery experiments in a rat brain model.
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References
Bobo, R.H., Laske, D.W., Akbasak, A., Morrison, P.F., Dedrick, R.L., and Oldfield, E.H. (1994) Convection-enhanced delivery of macromolecules in the brain. Proc Natl Acad Sci USA 91(6), 2076–2080.
Lieberman, D.M., Laske, D.W., Morrison, P.F., Bankiewicz, K.S., and Oldfield, E.H. (1995) Convection-enhanced distribution of large molecules in gray matter during interstitial drug infusion. J Neurosurg 82(6), 1021–1029.
Chen, M.Y., Lonser, R.R., Morrison, P.F., Governale, L.S., and Oldfield, E.H. (1999) Variables affecting CED to the striatum: a systematic examination of rate of infusion, cannula size, infusate concentration, and tissue-cannula sealing time. J Neurosurg 90, 315–320.
Chen, M.Y., Hoffer, A., Morrison, P.F., Hamilton, J.F., Hughes, J., Schlageter, K.S., Lee, J., Kelly, B.R., and Oldfield, E.H. (2005) Surface properties, more than size, limiting convective distribution of virus-sized particles and viruses in the central nervous system. J Neurosurg 103(2), 311–319.
Sampson, J.H., Brady, M.L., Petry, N.A., Croteau, D., Friedman, A.H., Friedman, H.S., Wong, T., Bigner, D.D., Pastan, I., Puri, R.K., and Pedain, C. (2007) Intracerebral infusate distribution by convection-enhanced delivery in humans with malignant gliomas: descriptive effects of target anatomy and catheter positioning. Neurosurgery 60(2 Suppl 1), ONS89–98; discussion ONS98–9.
Mardor, Y., Rahav, O., Zauberman, Y., Lidar, Z., Ocherashvilli, A., Daniels, D., Roth, Y., Maier, S.E., Orenstein, A., and Ram, Z. (2005) Convection-enhanced drug delivery: increased efficacy and magnetic resonance image monitoring. Cancer Res 65(15), 6858–6863.
Jagannathan, J., Walbridge, S., Butman, J.A., Oldfield, E.H., and Lonser, R.R. (2008) Effect of ependymal and pial surfaces on convection-enhanced delivery. J Neurosurg 109(3), 547–552.
MacKay, J.A., Deen, D.F., and Szoka, F.C. Jr. (2005) Distribution in brain of liposomes after convection enhanced delivery; modulation by particle charge, particle diameter, and presence of steric coating. Brain Res 1035(2), 139–153.
Saito, R., Krauze, M.T., Noble, C.O., Tamas, M., Drummond, D.C., Kirpotin, D.B., Berger, M.S., Park, J.W., and Bankiewicz, K.S. (2006) Tissue affinity of the infusate affects the distribution volume during convection-enhanced delivery into rodent brains: implications for local drug delivery. J Neurosci Methods 154(1–2), 225–232.
Neeves, K.B., Sawyer, A.J., Foley, C.P., Saltzman, W.M., and Olbricht, W.L. (2007) Dilation and degradation of the brain extracellular matrix enhances penetration of infused polymer nanoparticles. Brain Res 1180, 121–132.
Saito, R., Bringas, J.R., McKnight, T.R., Wendland, M.F., Mamot, C., Drummond, D.C., Kirpotin, D.B., Park, J.W., Berger, M.S., and Bankiewicz, K.S. (2004) Distribution of liposomes into brain and rat brain tumor models by convection-enhanced delivery monitored with magnetic resonance imaging. Cancer Res 64(7), 2572–2579.
Croteau, D., Walbridge, S., Morrison, P.F., Butman, J.A., Vortmeyer, A.O., Johnson, D., Oldfield, E.H., and Lonser, R.R. (2005) Real-time in vivo imaging of the convective distribution of a low-molecular-weight tracer. J Neurosurg 102(1), 90–97.
Lonser, R.R., Warren, K.E., Butman, J.A., Quezado, Z., Robison, R.A., Walbridge, S., Schiffman, R., Merrill, M., Walker, M.L., Park, D.M., Croteau, D., Brady, R.O., and Oldfield, E.H. (2007) Real-time image-guided direct convective perfusion of intrinsic brainstem lesions. Technical note. J Neurosurg 107(1), 190–197.
Kroll, R.A., Michael, A., Muldoon, L.L., Roman-Goldstein, S., and Neuwelt, E.A. (1996) Increasing volume of distribution to the brain with interstitial infusion: dose, rather than convection, might be the most important factor. Neurosurg Online 38(4), 746–754.
Perlstein, B., Ram, Z., Daniels, D., Ocherashvilli, A., Roth, Y., Margel, S., and Mardor, Y. (2008) Convection-enhanced delivery of maghemite nanoparticles: Increased efficacy and MRI monitoring. Neuro Oncol 10(2), 153–161.
Noble, C.O., Krauze, M.T., Drummond, D.C., Yamashita, Y., Saito, R., Berger, M.S., Kirpotin, D.B., Bankiewicz, K.S., and Park, J.W. (2006) Novel nanoliposomal CPT-11 infused by convection-enhanced delivery in intracranial tumors: pharmacology and efficacy. Cancer Res 66(5), 2801–2806.
Chen, Z.J., Broaddus, W.C., Viswanathan, R.R., Raghavan, R., and Gillies, G.T. (2002) Intraparenchymal drug delivery via positive-pressure infusion: experimental and modeling studies of poroelasticity in brain phantom gels. IEEE Trans Biomed Eng 49(2), 85–96.
Raghavan, R., Brady, M.L., Rodríguez-Ponce, M.I., Hartlep, A., Pedain, C., and Sampson, J.H. (2006) Convection-enhanced delivery of therapeutics for brain disease, and its optimization. Neurosurg Focus 20(4), E12.
Hadaczek, P., Yamashita, Y., Mirek, H., Tamas, L., Bohn, M.C., Noble, C., Park, J.W., and Bankiewicz, K. (2006) The “perivascular pump” driven by arterial pulsation is a powerful mechanism for the distribution of therapeutic molecules within the brain. Mol Ther 14(1), 69–78.
Mamot, C., Nguyen, J.B., Pourdehnad, M., Hadaczek, P., Saito, R., Bringas, J.R., Drummond, D.C., Hong, K., Kirpotin, D.B., McKnight, T., Berger, M.S., Park, J.W., and Bankiewicz, K.S. (2004) Extensive distribution of liposomes in rodent brains and brain tumors following convection-enhanced delivery. J Neurooncol 68(1), 1–9.
Nguyen, T.T., Pannu, Y.S., Sung, C., Dedrick, R.L., Walbridge, S., Brechbiel, M.W., Garmestani, K., Beitzel, M., Yordanov, A.T., and Oldfield, E.H. (2003) Convective distribution of macromolecules in the primate brain demonstrated using computerized tomography and magnetic resonance imaging. J Neurosurg 98(3), 584–590.
Lonser, R.R., Walbridge, S., Garmestani, K., Butman, J.A., Walters, H.A., Vortmeyer, A.O., Morrison, P.F., Brechbiel, M.W., and Oldfield, E.H. (2002) Successful and sage perfusion of the primate brainstem: in vivo MRI of macromolecular distribution during infusion. J Neurosurg 97, 905–913.
Van Zijl, P.C., Moonen, C.T., Faustino, P., Pekar, J., Kaplan, O., and Cohen, J.S. (1991) Complete separation of intracellular, and extracellular information in NMR spectra by diffusion weighting. Proc Natl Acad Sci USA 88, 3228–3232.
Pilatus, U., Shim, H., Artemov, D., Davis, D., van Zijl, P.C., and Glickson, J.D. (1997) Intracellular volume and apparent diffusion constants of perfused cancer cell cultures, as measured by NMR. Magn Reson Med 37, 825–832.
Mardor, Y., Roth, Y., Lidar, Z., Jonas, T., Pfeffer, R., Maier, S.E., Faibel, M., Nass, D., Hadani, M., Orenstein, A., Cohen, J.S., and Ram, Z. (2001) Monitoring response to convection-enhanced taxol delivery in brain tumor patients using diffusion-weighted magnetic resonance imaging. Cancer Res 61(13), 4971–4973.
Lidar, Z., Mardor, Y., Jonas, T., Pfeffer, R., Faibel, M., Nass, D., Hadani, M., and Ram, Z. (2004) Convection-enhanced delivery of paclitaxel for the treatment of recurrent malignant glioma: a phase I/II clinical study. J Neurosurg 100(3), 472–479.
Tanner, P.G., Holtmannspötter, M., Tonn, J.C., and Goldbrunner, R. (2007) Effects of drug efflux on convection-enhanced paclitaxel delivery to malignant gliomas: technical note. Neurosurgery 61(4), E880–2; discussion E882.
Acknowledgments
The work in our lab was supported by grants from The Israeli ministry of health, Israel Science Foundation, Israel Cancer Association, Goldhirsh Foundation, and Adams Brain Research Center at Tel-Aviv University.The authors would like to thank the MRI Research Group at The Advanced Technology Center, Sheba Medical Center – Dianne Daniels, David Last, Ran Shneor, Gregory Tamar and Sharona Salomon – for their help in obtaining the figures and the unpublished data that have been incorporated in this chapter.
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Mardor, Y., Ram, Z. (2010). Convection-Enhanced Drug Delivery and Monitoring in a Rat Model. In: Jain, K. (eds) Drug Delivery to the Central Nervous System. Neuromethods, vol 45. Humana Press. https://doi.org/10.1007/978-1-60761-529-3_9
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DOI: https://doi.org/10.1007/978-1-60761-529-3_9
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