Sampson, JH, Brady, ML, Petry, NA, Croteau, D, Friedman, AH, Friedman, HS et al.. 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

Department of Surgery, Duke University, Durham, North Carolina, United States
Neurosurgery (Impact Factor: 3.62). 03/2007; 60(2 Suppl 1):ONS89-98; discussion ONS98-9. DOI: 10.1227/01.NEU.0000249256.09289.5F
Source: PubMed


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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    • "CED has shown encouraging results in experimental animal models [56]. However, issues such as the limited amount of time CED can be applied [57], variable distribution, as well as safety concerns, render CED as a questionable mode of delivery of nanoparticles to glioma tissues [58, 59]. "
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    ABSTRACT: Despite all recent advances in malignant glioma research, only modest progress has been achieved in improving patient prognosis and quality of life. Such a clinical scenario underscores the importance of investing in new therapeutic approaches that, when combined with conventional therapies, are able to effectively eradicate glioma infiltration and target distant tumor foci. Nanoparticle-loaded delivery systems have recently arisen as an exciting alternative to improve targeted anti-glioma drug delivery. As drug carriers, they are able to efficiently protect the therapeutic agent and allow for sustained drug release. In addition, their surface can be easily manipulated with the addition of special ligands, which are responsible for enhancing tumor-specific nanoparticle permeability. However, their inefficient intratumoral distribution and failure to target disseminated tumor burden still pose a big challenge for their implementation as a therapeutic option in the clinical setting. Stem cell-based delivery of drug-loaded nanoparticles offers an interesting option to overcome such issues. Their ability to incorporate nanoparticles and migrate throughout interstitial barriers, together with their inherent tumor-tropic properties and synergistic anti-tumor effects make these stem cell carriers a good fit for such combined therapy. In this review, we will describe the main nanoparticle delivery systems that are presently available in preclinical and clinical studies. We will discuss their mechanisms of targeting, current delivery methods, attractive features and pitfalls. We will also debate the potential applications of stem cell carriers loaded with therapeutic nanoparticles in anticancer therapy and why such an attractive combined approach has not yet reached clinical trials.
    Full-text · Article · Mar 2013 · Oncotarget
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    • "If catheters are inaccurately placed, leakage of infusate into the intraventricular spaces and subarachnoid will result in poor drug delivery and distribution [9]. Currently, catheters generate a certain amount of backflow where the fluid flow in a tissue-free region created by fluid pressure along the outer surface of the catheter [9] [10] [11]. In addition, any large (millimeter sized) bubbles may redirect the flow away from the catheter tip in unpredictable ways. "
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    ABSTRACT: The blood brain barrier (BBB) poses a significant challenge for drug delivery of macromolecules into the brain. Convection-enhanced delivery (CED) circumvents the BBB through direct intracerebral infusion using a hydrostatic pressure gradient to transfer therapeutic compounds. The efficacy of CED is dependent on the distribution of the therapeutic agent to the targeted region. Here we present a review of convection enhanced delivery of macromolecules, emphasizing the role of tracers in enabling effective delivery anddiscuss current challenges in the field.
    Full-text · Article · Feb 2012 · Current Drug Discovery Technologies
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    • "Recent clinical trials have shown the safety of CED in the treatment of Glioblastoma Multiforme (GBM) [5]–[7]. In addition, these trials have illustrated some of the technical challenges of CED and the need to monitor the process of convection to prevent toxicity on one hand and frank ineffectiveness due to limited convection on the other [8]. Adenoviral vectors or conditionally replicating adenoviruses (CRAds) have been used preclinically and clinically in a variety of intracranial diseases [9], [10]. "
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    ABSTRACT: Convection-enhanced delivery (CED) of adenoviruses offers the potential of widespread virus distribution in the brain. In CED, the volume of distribution (Vd) should be related to the volume of infusion (Vi) and not to dose, but when using adenoviruses contrasting results have been reported. As the characteristics of the infused tissue can affect convective delivery, this study was performed to determine the effects of the gray and white matter on CED of adenoviruses and similar sized super paramagnetic iron oxide nanoparticles (SPIO). We convected AdGFP, an adenovirus vector expressing Green Fluorescent Protein, a virus sized SPIO or trypan blue in the gray and white matter of the striatum and external capsule of Wistar rats and towards orthotopic infiltrative brain tumors. The resulting Vds were compared to Vi and transgene expression to SPIO distribution. Results show that in the striatum Vd is not determined by the Vi but by the infused virus dose, suggesting diffusion, active transport or receptor saturation rather than convection. Distribution of virus and SPIO in the white matter is partly volume dependent, which is probably caused by preferential fluid pathways from the external capsule to the surrounding gray matter, as demonstrated by co-infusing trypan blue. Distant tumors were reached using the white matter tracts but tumor penetration was limited. CED of adenoviruses in the rat brain and towards infiltrative tumors is feasible when regional anatomical differences are taken into account while SPIO infusion could be considered to validate proper catheter positioning and predict adenoviral distribution.
    Full-text · Article · Oct 2011 · PLoS ONE
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