Convection-enhanced distribution of large molecules in gray matter during interstitial drug infusion

Abstract

Many novel experimental therapeutic agents, such as neurotrophic factors, enzymes, biological modifiers, and genetic vectors, do not readily cross the blood-brain barrier. An effective strategy to deliver these compounds to the central nervous system is required for their application in vivo. Under normal physiological conditions, brain interstitial fluid moves by both bulk flow (convection) and diffusion. It has recently been shown that interstitial infusion into the white matter can be used to increase bulk flow, produce interstitial convection, and efficiently and homogeneously deliver drugs to large regions of brain without significant functional or structural damage. In theory, even more uniform distribution is likely in gray matter. In the current study, four experiments were performed to examine if convection-enhanced delivery could be used to achieve regional distribution of large molecules in gray matter. First, the volume and consistency of anatomical distribution of 20 microliters of phaseolus vulgaris-leukoagglutinin (PHA-L; molecular weight (MW) 126 kD) after continuous high-flow microinfusion into the striatum of five rats over 200 minutes were determined using immunocytochemistry and quantified with image analysis. Second, the concentration profile of 14C-albumin (MW 69 kD) infused under identical conditions was determined in four hemispheres using quantitative autoradiography. Third, the volume of distribution after convection-enhanced infusion of 250 or 500 microliters biotinylated dextran (b-dextran, MW 10 kD), delivered over 310 minutes into the caudate and putamen of a rhesus monkey from one (250 microliters) or two (500 microliters) cannulas, was determined using immunocytochemistry and quantified with image analysis. Finally, the ability to target all dopaminergic neurons of the nigrostriatal tract via perfusion of the striatum with subsequent retrograde transport was assessed in three experiments by immunohistochemical analysis of the mesencephalon following a 300-minute infusion of 27 microliters horseradish peroxidase-labeled wheat germ agglutinin (WGA-HRP) into the striatum. Convection-enhanced delivery reproducibly distributed the large-compound PHA-L throughout the rat striatum (the percent volume of the striatum perfused, Vs, was 86% +/- 5%; mean +/- standard deviation) and produced a homogeneous tissue concentration in the perfused region (concentration of 14C-albumin relative to infusate concentration 30% +/- 5%). In the monkey, the infusion widely distributed b-dextran within the striatum using one cannula (caudate and putamen Vs = 76% and 76%) or two cannulas (Vs = 90% and 71%).(ABSTRACT TRUNCATED AT 400 WORDS)

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

“…The fluid convection established by maintenance of a pressure gradient during interstitial infusion has been shown to greatly enhance the distribution of various molecules in the brain (4,5). 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.…”

“…Salirasib is currently undergoing trials in patients with pancreatic cancer and with non-small cell lung cancer. 4 In a study carried out by our group in a mouse model of head trauma (in which the blood-brain barrier is impaired), the highest concentrations of salirasib measured in brain homogenates from treated rats were of the order of 4.5 Amol/L (37). In the present study, the concentration of salirasib that was delivered directly into the tissue was 50 Amol/L, which is the concentration that was shown to effectively inhibit cell growth in vitro (Fig.…”

Maximizing Local Access to Therapeutic Deliveries in Glioblastoma. Part II: Arborizing Catheter for Convection-Enhanced Delivery in Tissue Phantoms

“…Moreover, CED per se does not lead to cerebral edema and is unaffected by capillary loss or metabolism of the macromolecule (5). With these initial studies, CED was established as a viable method for providing regional distribution of large molecules, such as proteins and some conventional chemotherapeutic agents, in the brain (6)(7)(8)(9). Compared with other therapies, CED minimizes systemic and CNS toxicity by local delivery of high concentrations of therapeutics directly to the brain tissue and has led to treatment applications in several cerebral disorders, including Parkinson' s (10,11), epilepsy (12), Alzheimer' s (13,14), and malignant gliomas (4,5,(15)(16)(17)(18)(19)(20)(21).…”

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

“…12) This technique provides more homogeneous and greatly extended regional distribution of a chemotherapeutic agent driven by the pressure gradient of the solution, and can achieve drug concentrations in the brain orders of magnitude greater than systemic levels, 3,17) in contrast with the distribution by diffusion-driven deliveries such as biodegradable polymers and carmustine wafers. 2,11,18) Intracerebral microinfusion also bypasses vulnerable organs outside the central nervous system such as the bone marrow, the mucosae of the digestive tract, and the hair follicle cells, which are all vulnerable to cytotoxic agents because…”