Convection-enhanced delivery of macromolecules in the brain.

Bobo, R. H.; Laske, Douglas W.; Akbasak, Aytac; Morrison, Paul F.; Dedrick, Robert L.; Oldfield, Edward H.

doi:10.1073/pnas.91.6.2076

Cited by 1,292 publications

(948 citation statements)

References 32 publications

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“…Many invasive strategies have been used or proposed for circumventing the blood-brain barrier, including intraparenchymal injections of therapeutic proteins, intraparenchymal gene therapy, chemical or physical agents to open the blood-brain barrier (such as mannitol), and hematopoietic stem cell transplantation [1][2][3][4][5][6][7][8][9]. Treatment via the cerebrospinal fluid has not been successful in the past due to the inability of the proteins to traverse the ependymal layer and diffuse through brain tissue, even though this route would be clinically easier for application to patients.…”

Section: Introductionmentioning

confidence: 99%

Intrathecal enzyme replacement therapy: Successful treatment of brain disease via the cerebrospinal fluid

Dickson

McEntee

Vogler

et al. 2007

Molecular Genetics and Metabolism

161

138

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Treatment of brain disease with recombinant proteins is difficult due to the blood-brain barrier. As an alternative to direct injections into the brain, we studied whether application of high concentrations of therapeutic enzymes via intrathecal (IT) injections could successfully drive uptake across the ependyma to treat brain disease. We studied IT enzyme replacement therapy with recombinant human iduronidase (rhIDU) in canine mucopolysaccharidosis I (MPS I, Hurler syndrome), a lysosomal storage disorder with brain and meningeal involvement. Monthly or quarterly IT treatment regimens with rhIDU achieved supranormal iduronidase enzyme levels in the brain, spinal cord, and spinal meninges. All regimens normalized total brain glycosaminoglycan (GAG) storage and reduced spinal meningeal GAG storage by 58-70%. The improvement in GAG storage levels persisted three months after the final IT dose. The successful use of enzyme therapy via the CSF represents a potentially useful approach for lysosomal storage disorders.

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Section: Introductionmentioning

confidence: 99%

Intrathecal enzyme replacement therapy: Successful treatment of brain disease via the cerebrospinal fluid

Dickson

McEntee

Vogler

et al. 2007

Molecular Genetics and Metabolism

161

138

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“…As the BBB is a major obstacle to the delivery of many therapeutic and imaging agents (Abbott and Romero 1996), such a method could be used to facilitate targeted drug delivery in the brain. Other strategies that have been tested for getting drugs past the BBB include designing drugs or drug carriers that can outwit the barrier (Pardridge 2002), directly infusing agents to the brain tissue (Bobo et al 1994), implanting devices to deliver agents (Guerin et al 2004), and introducing a catheter into an arterial branch and infusing a hyperosmotic solution or other agent to produce diffuse disruption of the BBB (Doolittle et al 2000;Neuwelt et al 1979). The use of focused ultrasound offers several potential advantages over these strategies, as it can be applied non-invasively, it will not require the development of new drugs or drug carriers, and it can be applied to a targeted locationor potentially to a large area or even the whole brain via beam steering if desired.…”

Section: Introductionmentioning

confidence: 99%

Use of Ultrasound Pulses Combined with Definity for Targeted Blood-Brain Barrier Disruption: A Feasibility Study

McDannold

Vykhodtseva

Hynynen

2007

Ultrasound in Medicine & Biology

134

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We have developed a method to use low-intensity focused ultrasound pulses combined with an ultrasound contrast agent to produce temporary blood-brain barrier disruption (BBBD). This method could provide a means for the targeted delivery of drugs or imaging agents into the brain. All of our previous work used Optison ® as the ultrasound contrast agent. The purpose of this work was to test the feasibility of using the contrast agent Definity ® for BBBD. Thirty-six non-overlapping locations were sonicated through a craniotomy in experiments in the brains of nine rabbits (4 locations per rabbit; US frequency: 0.69MHz, burst: 10ms, PRF: 1Hz, duration: 20s). The peak negative pressure amplitude ranged from 0.2-1.5 MPa. Eleven additional locations were sonicated using Optison ® at a pressure amplitude of 0.5 MPa. Definity ® and Optison ® dosages were those used clinically for ultrasound imaging: 10 and 50 μl/kg, respectively. The probability for BBBD (determined using MRI contrast agent enhancement) as a function of pressure amplitude was similar to that found earlier with Optison ® . For both agents, the probability was estimated to be 50% at 0.4 MPa using probit regression. Histological examination revealed small isolated areas of extravasated erythrocytes in some locations. At 0.8 MPa and above, this extravasation was sometimes accompanied by tiny (dimensions of 100 μm or less) regions of damaged brain parenchyma. The magnitude of the BBBD was larger with Optison ® than with Definity ® at 0.5 MPa (signal enhancement: 13.3 ± 4.4% vs. 8.4 ± 4.9%, P=0.04), and more areas with extravasated erythrocytes were observed with Optison ® (5.0 ± 3.5 vs. 1.4 ± 1.9 areas with extravasation in histology section with largest effect; P=0.03). We conclude that BBBD is possible using Definity ® for the dosage of contrast agent and the acoustic parameters tested in this study. While the probability for BBBD as a function of pressure amplitude and the type of acute tissue effects were similar to what has been observed with Optison ® , under these experimental conditions, Optison ® produced a larger effect for the same acoustic pressure amplitude.

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“…The concentrations might be further increased in future studies by using BBB opening molecules such as Mannitol 25 or by convection enhanced delivery supplying large quantities of iodine directly in the brain. 26,27 The average vascular concentration (arteries and veins) remains below 8 mg/mL, but is two to four times higher than the target concentration. Major vessels are thus to be avoided in the patients treatment planning and X-ray beams are placed accordingly.…”

Section: Discussionmentioning

confidence: 99%

Absolute Perfusion Measurements and Associated Iodinated Contrast Agent Time Course in Brain Metastasis: A Study for Contrast-Enhanced Radiotherapy

Obeid

Deman

Tessier

et al. 2014

J Cereb Blood Flow Metab

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Contrast-enhanced radiotherapy is an innovative treatment that combines the selective accumulation of heavy elements in tumors with stereotactic irradiations using medium energy X-rays. The radiation dose enhancement depends on the absolute amount of iodine reached in the tumor and its time course. Quantitative, postinfusion iodine biodistribution and associated brain perfusion parameters were studied in human brain metastasis as key parameters for treatment feasibility and quality. Twelve patients received an intravenous bolus of iodinated contrast agent (CA) (40 mL, 4 mL/s), followed by a steady-state infusion (160 mL, 0.5 mL/s) to ensure stable intratumoral amounts of iodine during the treatment. Absolute iodine concentrations and quantitative perfusion maps were derived from 40 multislice dynamic computed tomography (CT) images of the brain. The postinfusion mean intratumoral iodine concentration (over 30 minutes) reached 1.94±0.12 mg/mL. Reasonable correlations were obtained between these concentrations and the permeability surface area product and the cerebral blood volume. To our knowledge, this is the first quantitative study of CA biodistribution versus time in brain metastasis. The study shows that suitable and stable amounts of iodine can be reached for contrast-enhanced radiotherapy. Moreover, the associated perfusion measurements provide useful information for the patient recruitment and management processes.

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Convection-enhanced delivery of macromolecules in the brain.

Cited by 1,292 publications

References 32 publications

Intrathecal enzyme replacement therapy: Successful treatment of brain disease via the cerebrospinal fluid

Intrathecal enzyme replacement therapy: Successful treatment of brain disease via the cerebrospinal fluid

Use of Ultrasound Pulses Combined with Definity for Targeted Blood-Brain Barrier Disruption: A Feasibility Study

Absolute Perfusion Measurements and Associated Iodinated Contrast Agent Time Course in Brain Metastasis: A Study for Contrast-Enhanced Radiotherapy

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