High-flow microinfusion: tissue penetration and pharmacodynamics

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

doi:10.1152/ajpregu.1994.266.1.r292

Cited by 205 publications

(264 citation statements)

References 18 publications

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“…To improve the penetration of monoclonal antibodies, gene vectors and other therapeutic agents in normal or tumour tissues, interstitial infusion methods have been developed Morrison et al, 1994;Order et al, 1994) The present technique is able to characterize key determinants (K, compliance, pressure gradients and reabsorption) that will influence the success of intratumoral infusions. If K is elevated, a uniform distribution of the infused drug throughout the tumour would be expected.…”

Section: Estimation Of C and Implication For Estimation Of Lpmentioning

confidence: 99%

Intratumoral infusion of fluid: estimation of hydraulic conductivity and implications for the delivery of therapeutic agents

Boucher

Brekken²,

Netti³

et al. 1998

Br J Cancer

100

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Summary We have developed a new technique to measure in vivo tumour tissue fluid transport parameters (hydraulic conductivity and compliance) that influence the systemic and intratumoral delivery of therapeutic agents. An infusion needle approximating a point source was constructed to produce a radially symmetrical fluid source in the centre of human tumours in immunodeficient mice. At constant flow, the pressure gradient generated in the tumour by the infusion of fluid (Evans blue-albumin in saline) was measured as a function of the radial position with micropipettes connected to a servo-null system. To evaluate whether the fluid infused was reabsorbed by blood vessels, infusions were also performed after circulatory arrest. In the colon adenocarcinoma LS174T with a spherically symmetrical distribution of Evans blue-albumin, the median hydraulic conductivity in vivo and after circulatory arrest at a flow rate of 0.1 ,ul min-' was, respectively, 1 .7x1 0-7 and 2.3x1 0-7 cm2 mmHg-' s. Compliance estimates were 35 gl mmHg-' in vivo, and 100 ,ul mmHg-' after circulatory arrest In the sarcoma HSTS 26T, hydraulic conductivity and compliance were not calculated because of the asymmetric distribution of the fluid infused. The technique will be helpful in identifying strategies to improve the intratumoral and systemic delivery of gene targeting vectors and other therapeutic agents.Keywords: human tumour xenografts; intratumoral fluid infusion; hydraulic conductivity; compliance; interstitial fluid pressure Systemic delivery of therapeutic agents to solid tumours is generally hindered by vascular and interstitial barriers (Sands, 1992;Jain, 1993). To circumvent these transport barriers, intratumoral infusions or injections have received increasing interest in recent years (Order et al, 1994;Viola et al, 1995;Heise et al, 1997;Nomura et al, 1997). While the vascular barrier is circumvented by this route, the interstitial matrix still poses a formidable barrier. Key determinants for the success of intratumoral delivery include the tissue hydraulic conductivity (K) and compliance (C). However, there are presently no direct in vivo data for these two parameters in solid tumours. The lack of such measurements is mainly due to experimental difficulties.In normal tissues, resistance to fluid flow is a function of the concentration of interstitial matrix constituents (glycosaminoglycans and collagen content) and the degree of hydration of the matrix (Swabb et al, 1974;Jain, 1987;Levick, 1987). K has been estimated mostly under in vitro conditions and in a few studies in vivo. In vitro, K is generally estimated by measuring the flow after applying pressure across a tissue slice of known area and thickness. In this case, hydration, slicing of the tissue and compression are potential factors that can influence the determination of K. In vivo estimates of K are also not straightforward, because the characterization of tissue dimensions can be difficult. Furthermore, fluid reabsorption by blood vessels or lymphatics may result in an ...

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Section: Estimation Of C and Implication For Estimation Of Lpmentioning

confidence: 99%

Intratumoral infusion of fluid: estimation of hydraulic conductivity and implications for the delivery of therapeutic agents

Boucher

Brekken²,

Netti³

et al. 1998

Br J Cancer

100

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“…Those studies showed the ability of fluid convection to obtain in situ drug concentrations several orders of magnitude greater than those achieved by systemic administration over large volumes of the brain at various time intervals. The concentration profile obtained with convectionenhanced drug delivery (CED) is relatively flat up to the flow front, providing control over undesired toxicity (6).…”

Section: Introductionmentioning

confidence: 99%

Salirasib (farnesyl thiosalicylic acid) for brain tumor treatment: a convection-enhanced drug delivery study in rats

Goldberg

Ocherashvilli²,

Daniels³

et al. 2008

Molecular Cancer Therapeutics

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Our aim was to assess the ability of convection-enhanced drug delivery (CED), a novel approach of direct delivery of drugs into brain tissue and brain tumors, to treat brain tumors using salirasib (farsnesyl thiosalicylic acid). CED was achieved by continuous infusion of drugs via intracranial catheters, thus enabling convective distribution of high drug concentrations over large volumes while avoiding systemic toxicity. Several phase II/III CED-based trials are currently in progress but have yet to overcome two major pitfalls of this methodology (the difficulty in attaining efficient CED and the significant nonspecific neurotoxicity caused by high drug doses in the brain). In this study, we addressed both issues by employing our previously described novel CED imaging and increased efficiency methodologies to exclusively target the activated form of the Ras oncogene in a 9L gliosarcoma rat model. The drug we used was salirasib, a highly specific Ras inhibitor shown to exert its suppressive effects on growth and migration of proliferating tumor cells in in vitro and in vivo models, including human glioblastoma, without affecting normal tissues. The results show a significant decrease in tumor growth rate in salirasibtreated rats relative to vehicle-treated rats as well as a significant correlation between CED efficacy and tumor growth rate with no observed toxicity despite drug concentrations an order of magnitude higher than previously detected in the brain. The results show that CED of salirasib is efficient and nontoxic for the treatment of glioblastoma in a rat model, thus suggesting that it may be considered for clinical application.

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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: 98%

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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High-flow microinfusion: tissue penetration and pharmacodynamics

Cited by 205 publications

References 18 publications

Intratumoral infusion of fluid: estimation of hydraulic conductivity and implications for the delivery of therapeutic agents

Intratumoral infusion of fluid: estimation of hydraulic conductivity and implications for the delivery of therapeutic agents

Salirasib (farnesyl thiosalicylic acid) for brain tumor treatment: a convection-enhanced drug delivery study in rats

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

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