Because convection-enhanced delivery relies on bulk flow of fluid in the interstitial spaces, MR imaging techniques that detect extracellular fluid and fluid movement may be useful for tracking convective drug distribution. To determine the tracking accuracy of T2-weighted and diffusion-weighted MR imaging sequences, the authors followed convective distribution of radiolabeled compounds using these imaging sequences in nonhuman primates.
Three nonhuman primates underwent thalamic convective infusions (5 infusions) with 14C-sucrose (MW 342 D) or 14C-dextran (MW 70,000 D) during serial MR imaging (T2- and diffusion-weighted imaging). Imaging, histological, and autoradiographic findings were analyzed.
Real-time T2- and diffusion-weighted imaging clearly demonstrated the region of infusion, and serial images revealed progressive filling of the bilateral thalami during infusion. Imaging analysis for T2- and diffusion-weighted sequences revealed that the tissue volume of distribution (Vd) increased linearly with volume of infusion (Vi; R2 = 0.94, R2 = 0.91). Magnetic resonance imaging analysis demonstrated that the mean ± SD Vd/Vi ratios for T2-weighted (3.6 ± 0.5) and diffusion-weighted (3.3 ± 0.4) imaging were similar (p = 0.5). While 14C-sucrose and 14C-dextran were homogeneously distributed over the infused region, autoradiographic analysis revealed that T2-weighted and diffusion-weighted imaging significantly underestimated the Vd of both 14C-sucrose (mean differences 51.3% and 52.3%, respectively; p = 0.02) and 14C-dextran (mean differences 49.3% and 59.6%; respectively, p = 0.001).
Real-time T2- and diffusion-weighted MR imaging significantly underestimate tissue Vd during convection-enhanced delivery over a wide range of molecular sizes. Application of these imaging modalities may lead to inaccurate estimation of convective drug distribution.
Abbreviations used in this paper: AADC = aromatic l-amino acid decarboxylase; AAV2 = adeno-associated virus serotype 2; CED = convection-enhanced delivery; IL13-PE = interleukin-13 Pseudomonas exotoxin; QAR = quantitative autoradiography; Vd = volume of distribution; Vi = volume of infusion.
Address correspondence to: Russell R. Lonser, M.D., Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Building 10, Room 3D20, Bethesda, Maryland 20892-1414. email: email@example.com.
Please include this information when citing this paper: published online June 10, 2011; DOI: 10.3171/2011.5.JNS11246.
AsthagiriARWalbridgeSHeissJDLonserRR: Effect of concentration on the accuracy of convective imaging distribution of a gadolinium-based surrogate tracer. Laboratory investigation. J Neurosurg[epub ahead of print May 27 2011. DOI: 10.3171/2011.3.JNS101381]
LonserRRWalbridgeSGarmestaniKButmanJAWaltersHAVortmeyerAO: Successful and safe perfusion of the primate brainstem: in vivo magnetic resonance imaging of macromolecular distribution during infusion. J Neurosurg97:905–9132002
MardorYRothYLidarZJonasTPfefferRMaierSE: Monitoring response to convection-enhanced taxol delivery in brain tumor patients using diffusion-weighted magnetic resonance imaging. Cancer Res61:4971–49732001
NguyenTTPannuYSSungCDedrickRLWalbridgeSBrechbielMW: Convective distribution of macromolecules in the primate brain demonstrated using computerized tomography and magnetic resonance imaging. J Neurosurg98:584–5902003
SaitoRBringasJRMcKnightTRWendlandMFMamotCDrummondDC: Distribution of liposomes into brain and rat brain tumor models by convection-enhanced delivery monitored with magnetic resonance imaging. Cancer Res64:2572–25792004
SampsonJHRaghavanRProvenzaleJMCroteauDReardonDAColemanRE: Induction of hyperintense signal on T2-weighted MR images correlates with infusion distribution from intracerebral convection-enhanced delivery of a tumor-targeted cytotoxin. AJR Am J Roentgenol188:703–7092007
VallesFFiandacaMSEberlingJLStarrPALarsonPSChristineCW: Qualitative imaging of adeno-associated virus serotype 2-human aromatic L-amino acid decarboxylase gene therapy in a phase I study for the treatment of Parkinson disease. Neurosurgery67:1377–13852010