Intracerebral infusate distribution by convection-enhanced delivery in humans with malignant gliomas: Descriptive effects of target anatomy and catheter positioning

Department of Surgery, Duke University, Durham, North Carolina, United States
Neurosurgery (Impact Factor: 3.03). 03/2007; 60(2 Suppl 1):ONS89-98; discussion ONS98-9. DOI: 10.1227/01.NEU.0000249256.09289.5F
Source: PubMed

ABSTRACT Convection-enhanced delivery (CED) holds tremendous potential for drug delivery to the brain. However, little is known about the volume of distribution achieved within human brain tissue or how target anatomy and catheter positioning influence drug distribution. The primary objective of this study was to quantitatively describe the distribution of a high molecular weight agent by CED relative to target anatomy and catheter position in patients with malignant gliomas.
Seven adult patients with recurrent malignant gliomas underwent intracerebral infusion of the tumor-targeted cytotoxin, cintredekin besudotox, concurrently with 123I-labeled human serum albumin. High-resolution single-photon emission computed tomographic images were obtained at 24 and 48 hours and were coregistered with magnetic resonance imaging scans. The distribution of 123I-labeled human serum albumin relative to target anatomy and catheter position was analyzed.
Intracerebral CED infusions were well-tolerated and some resulted in a broad distribution of 123I-labeled human serum albumin, but target anatomy and catheter positioning had a significant influence on infusate distribution even within non-contrast-enhancing areas of brain. Intratumoral infusions were anisotropic and resulted in limited coverage of the enhancing tumor area and adjacent peritumoral regions.
CED has the potential to deliver high molecular weight agents into tumor-infiltrated brain parenchyma with volumes of distribution that are clinically relevant. Target tissue anatomy and catheter position are critical parameters in optimizing drug delivery.

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    • "With the increasing use of CED in clinical neurosurgery (Kunwar et al., 2007; Lonser et al., 2007), investigators have sought to visualize the delivery of therapeutics intra-operatively. CED visualization with the aid of novel contrast materials co-infused with therapeutic agents has recently been investigated in rodents (Saito et al., 2004), non-human primates (Lonser et al., 2002; Murad et al., 2007; Saito et al., 2005) and humans (Lonser et al., 2007; Sampson et al., 2007). Real-time convective delivery (RCD) utilizes MRI to visualize the CED process with the aid of Gadolinium-loaded liposomes (GDL) to co-distribute with the therapeutic being delivered. "
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    ABSTRACT: We are developing a method for real-time magnetic resonance imaging (MRI) visualization of convection-enhanced delivery (CED) of adeno-associated viral vectors (AAV) to the primate brain. By including gadolinium-loaded liposomes (GDL) with AAV, we can track the convective movement of viral particles by continuous monitoring of distribution of surrogate GDL. In order to validate this approach, we infused two AAV (AAV1-GFP and AAV2-hAADC) into three different regions of non-human primate brain (corona radiata, putamen, and thalamus). The procedure was tolerated well by all three animals in the study. The distribution of GFP determined by immunohistochemistry in both brain regions correlated closely with distribution of GDL determined by MRI. Co-distribution was weaker with AAV2-hAADC, although in vivo PET scanning with FMT for AADC activity correlated well with immunohistochemistry of AADC. Although this is a relatively small study, it appears that AAV1 correlates better with MRI-monitored delivery than does AAV2. It seems likely that the difference in distribution may be due to differences in tissue specificity of the two serotypes.
    NeuroImage 12/2008; 47 Suppl 2(Suppl. 2):T27-35. DOI:10.1016/j.neuroimage.2008.11.012 · 6.36 Impact Factor
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    • "Concentration distribution of therapeutic agents after infusion is significantly related to the CED protocol (e.g., selection of infusion site, infusate concentration and infusion rate). Concentration distribution also plays an important role in the efficacy of treatment [5] [6] [7]. Real-time monitoring of agents transported within nervous tissues will not only provide information on the drug-affected region but also improve the understanding of drug pharmacokinetics and aid clinical protocol design. "
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    ABSTRACT: Convection-enhanced delivery (CED), that is, direct tissue infusion, has emerged as a promising local drug delivery method for treating diseases of the nervous system. Determination of the spatial distribution of therapeutic agents after infusion is important in evaluating the efficacy of treatment, optimizing infusion protocols and improving the understanding of drug pharmacokinetics. In this study, we provide a methodology to determine the concentration distribution of Gd-labeled tracers during infusion using contrast-enhanced magnetic resonance imaging (MRI). To the best of our knowledge, MR studies that quantify concentration profiles for CED have not been previously reported. The methodology utilizes intrinsic material properties (T(1) and R(1)) and reduces the effect of instrumental factors (e.g., inhomogeneity of MR detection field). As a methodology investigation, this study used an agarose hydrogel phantom as a tissue substitute for infusion. An 11.1-T magnet system was used to image infusion of Gd-DTPA-labeled albumin (Gd-albumin) into the hydrogel. By using data from preliminary scans, Gd-albumin distribution was determined from the signal intensity of the MR images. As a validation test, MR-derived concentration profiles were found comparable to both results measured directly using quantitative optical imaging and results from a computational transport model in porous media. In future studies, the developed methodology will be used to quantitatively monitor the distribution of Gd tracer following infusion directly into tissues.
    Magnetic Resonance Imaging 07/2008; 26(10):1433-41. DOI:10.1016/j.mri.2008.04.011 · 2.02 Impact Factor
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    ABSTRACT: Ce travail de thèse a pour objectif le traitement local des gliomes malins via l'administration de nanocapsules lipidiques (LNC) par convection enhanced delivery (CED). Deux types de complexes métalliques lipophiles aux propriétés thérapeutiques ont été encapsulés au sein des LNC. Le premier est un complexe radioactif de Rhénium-188 et le second, un agent anticancéreux dérivé du tamoxifène et du ferrocène, le ferrociphénol (Fc-diOH). Les LNC de 188Re permettent une rétention de l'émetteur β- au niveau local et une éradication complète de la tumeur est possible pour une dose de 8Gy puisque 33% des animaux sont de longs survivants. Cette dose optimisée s'est révélée être une dose efficace, intermédiaire entre des doses toxiques (10-12 Gy) ou inefficaces (3-4 Gy). Les LNC-Fc-diOH présentent des taux d'encapsulation élevés, et sont quantitativement internalisées dans les cellules 9L. De plus, l'activité du ferrociphénol est conservée après encapsulation et se révèle très efficace sur des cellules de gliome 9L (IC50=0.6μM). En revanche, l'activité est très réduite sur les astrocytes, cellules au potentiel de division quasiment nul. L'action intratumorale des LNC-Fc-diOH dans un modèle de gliome sous-cutané entraîne une réduction significative des masses et volumes tumoraux. De plus, l'association entre le ferrociphénol et les photons X est une association synergique conférant à Fc-diOH des propriétés de molécule radio-sensibilisante. La médiane de survie du groupe traité par une CED de LNC-Fc-diOH suivie d'une radiothérapie externe de 18Gy (3x6Gy) augmente de 48% par rapport au groupe contrôle avec la présence de 17% de longs survivants.