Safety and efficacy of convection-enhanced delivery of gemcitabine or carboplatin in a malignant glioma model in rats

Degen, Jeffrey W.; Walbridge, Stuart; Vortmeyer, Alexander O.; Oldfield, Edward H.; Lonser, Russell R.

doi:10.3171/jns.2003.99.5.0893

Cited by 124 publications

(71 citation statements)

References 22 publications

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“…The volume in which a particle (i.e., drug, virus or growth factor) distributes with CED in the brain is primarily the function of infusion rate and specific tissue characteristics. These brain tissue characteristics and CED have been modeled in animals, 27,28 and have recently been evaluated in human brain tumor trials.…”

Section: Introductionmentioning

confidence: 99%

“…The larger the catheter diameter, the more easily reflux can be induced. We, 40 along with others, 27,41,42 have documented that CED infusion flow rates less than 0.5 L/min may be necessary to prevent reflux in catheters up to 0.6 mm (outer diameter [OD]). However, in a recent phase III trial of transferrin-CRM107 (Xenova Biomedix Ltd, Guilford, Surrey, UK) in glioblastoma, investigators used a ventriculo-peritoneal shunt catheter (2.5 mm OD) at a flow rate of 3.3 L/min (unpublished data).…”

Section: Introductionmentioning

confidence: 99%

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Image-Guided Convection-Enhanced Delivery Platform in the Treatment of Neurological Diseases

et al. 2008

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Summary: Convection-enhanced delivery (CED) of substances within the human brain is becoming a more frequent experimental treatment option in the management of brain tumors, and more recently in phase 1 trials for gene therapy in Parkinson's disease (PD). Benefits of this intracranial drugtransfer technology include a more efficient delivery of large volumes of therapeutic agent to the target region when compared with more standard delivery approaches (i.e., biopolymers, local infusion). In this article, we describe specific technical modifications we have made to the CED process to make it more effective. For example, we developed a reflux-resistant infusion cannula that allows increased infusion rates to be used. We also describe our efforts to visualize the CED process in vivo, using liposomal nanotechnology and real-time intraoperative MRI. In addition to carrying the MRI contrast agent, nanoliposomes also provide a standardized delivery vehicle for the convection of drugs to a specific brain-tissue volume. This technology provides an added level of assurance via visual confirmation of CED, allowing intraoperative alterations to the infusion if there is reflux or aberrant delivery. We propose that these specific modifications to the CED technology will improve efficacy by documenting and standardizing the treatment-volume delivery. Furthermore, we believe that this image-guided CED platform can be used in other translational neuroscience efforts, with eventual clinical application beyond neuro-oncology and PD.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Image-Guided Convection-Enhanced Delivery Platform in the Treatment of Neurological Diseases

et al. 2008

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“…CED can be used to deliver a variety of agents, including purified proteins, small molecule drugs, and viruses (Gill 2003, Degen 2003, Szerlip 2007). The range of diseases that can be treated with CED includes cancers of the CNS (Yamashita 2007) as well as neurodegenerative diseases such as Parkinson's disease (Gill 2003).…”

Section: Discussionmentioning

confidence: 99%

Systemic and Local Drug Delivery for Treating Diseases of the Central Nervous System in Rodent Models

Serwer

Hashizume

Ozawa

et al. 2010

JoVE

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Thorough preclinical testing of central nervous system (CNS) therapeutics includes a consideration of routes of administration and agent biodistribution in assessing therapeutic efficacy. Between the two major classifications of administration, local vs. systemic, systemic delivery approaches are often preferred due to ease of administration. However, systemic delivery may result in suboptimal drug concentration being achieved in the CNS, and lead to erroneous conclusions regarding agent efficacy. Local drug delivery methods are more invasive, but may be necessary to achieve therapeutic CNS drug levels. Here, we demonstrate proper technique for three routes of systemic drug delivery: intravenous injection, intraperitoneal injection, and oral gavage. In addition, we show a method for local delivery to the brain: convection-enhanced delivery (CED). The use of fluorescently-labeled compounds is included for in vivo imaging and verification of proper drug administration. The methods are presented using murine models, but can easily be adapted for use in rats. Video LinkThe video component of this article can be found at http://www.jove.com/video/1992/ Protocol Systemic Delivery MethodsAlthough systemic delivery of drugs is not the most efficient approach for achieving high drug concentrations in the CNS, systemic deliveries are convenient and well accepted by patients. Here, we will demonstrate proper procedures for three routinely used systemic administration approaches: intravenous injection, intraperitoneal injection, and oral gavage.

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“…The beneficial implications concerning survival elongation have already been reported. 8,12) However, the solute concentration for adequate antitumor activity, the infusion volume sufficient to prevent tumor spread, and the fluid dynamics in the intracerebral environment affected by the tumor are still unclear. 6,14) The present study investigated the drug distribution and efficacy of carboplatin administered by intracerebral microinfusion, and the temporal profile of vascular permeability in malignant glioma-bearing rats treated with two different concentrations of carboplatin using osmotic mini-pumps.…”

Section: Intracerebral Microinfusion Of Carboplatinmentioning

confidence: 99%

Novel Antitumor Effect of Carboplatin Delivered by Intracerebral Microinfusion in a Rat Malignant Glioma Model

Tange

Miyazaki

Iwata

et al. 2009

Neurol. Med. Chir.(Tokyo)

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Carboplatin loaded osmotic mini-pumps were implanted in 24 9L malignant glioma-bearing rats to investigate the implications of direct intracerebral microinfusion. Carboplatin using 0.1 mg/ml (low dose group) or 1.0 mg/ml (high dose group) with eight rats in each group, or 5% D-glucose (control group) in eight rats were infused at 1 ml/hr for 7 days. The tumor volume was serially measured by magnetic resonance (MR) imaging with gadolinium as the enhanced area, and the survival periods and histological findings were also examined. Separately, to examine the effects of intracerebral carboplatin infusion on vascular permeability, tumor-bearing rats received intravenous administration of 2% Evans blue at 21 days after infusion. The high dose group showed transient increase of enhanced volume at 21 days associated with mass effect, and significantly decreased tumor volume at 28 and 35 days compared with the control and low dose groups. The high dose group showed significant longer survival time than the control and low dose groups. Histological examination of the high dose group at 21 days showed the central tumor necrotic area around the infusion site and Evans blue leakage into the surrounding enhanced rim and the necrotic core. Therefore, leakage of plasma fluid into the necrotic area was considered to be the cause of apparent transient swelling. The present study demonstrated quantitatively using MR imaging that intracerebral carboplatin microinfusion significantly inhibited the rapid growth of experimental rat glioma but that the high dose required carries the risk of transient swelling of the target tumor.

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Safety and efficacy of convection-enhanced delivery of gemcitabine or carboplatin in a malignant glioma model in rats

Cited by 124 publications

References 22 publications

Image-Guided Convection-Enhanced Delivery Platform in the Treatment of Neurological Diseases

Image-Guided Convection-Enhanced Delivery Platform in the Treatment of Neurological Diseases

Systemic and Local Drug Delivery for Treating Diseases of the Central Nervous System in Rodent Models

Novel Antitumor Effect of Carboplatin Delivered by Intracerebral Microinfusion in a Rat Malignant Glioma Model

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