Convection Enhanced Delivery

Mathematical modeling, physiological studies, and increasing numbers of animal and clinical studies have helped to establish CED as one of the most promising of future strategies for the treatment of CNS disorders. The perpetual efforts to improve on local delivery techniques have helped move this method to the forefront, as it has distinct advantages over other local treatment modalities. CED has been described in the scientific literature by different names, including convection-enhanced intracerebral infusion, high-flow microinfusion, high-flow interstitial infusion, direct intraparenchymal con-trolled-rate infusion, intracerebral clysis, and direct convective delivery (Fig. 3) (95). The term CED has emerged as the current accepted nomenclature.

Principles

Within the extracellular environment of the CNS, fluid can move either through diffusion along concentration gradients or by bulk flow along pressure gradients. Whereas diffusion has a limited capacity to deliver high-molecular-weight solutes, bulk flow is largely independent of size and molecular weight (75). Bulk flow can, therefore, achieve homogenous solution concentrations that are less dependent on molecular size. In the CNS, volumes of distribution achievable with bulk flow strategies such as CED are orders of magnitude greater than those achievable with diffusion strategies including direct injection, polymers, or systemic delivery.

CED involves infusion of a solution into the brain interstitium through a microcannula, thereby establishing a positive pressure gradient for flow (83). The delivered infusate moves radially outward from the cannula to penetrate the surrounding parenchyma (75). The interstitial velocities achieved exceed those present endogenously, and drug is allowed to follow fiber tracts present in white and gray matter (80). An additional feature of CED is precise placement of the cannula through stereotactic technology, allowing delivery to specific and eloquent areas of the brain (97). Lesions of rat brainstem and spinal cord and of primate globus pallida have been successfully targeted, suggesting that CED can address varying CNS disorders in a site-specific manner (85-87,97)

The volume of distribution achievable by the infusion is determined by several variables including the rate of infusion, tissue architecture, the size of the cannula, the volume of infusion, and the rate of efflux. A possible dependence on dose has also been suggested (84). Rate of infusion is shown to be an essential determinant in the success of CED (74). Rates of infusion for CED are in the range of several microliters per minute and are optimal for establishing the high-flow microinfusion pressures required for effective drug delivery (78). If, however, these rates are exceeded, there can be leak-back through the cannula tract and subsequent loss of infusion pressure (77). To avoid an artificially low resistance pathway created by the cannula placement, a small cannula is preferred to a large one (74).

The architecture of the tissue being infused also helps determine the volume of distribution achieved in CED (75). Placement of the cannula into white or gray matter exploits the inherent fluid dynamic differences between these two microenvironments. The high-flow microinfusion utilized by CED is dependent on channels that develop in the brain's parenchyma and allow passage of solutions and molecules (71). Convective gradients normally exist within white matter as a result of anisotropic pathways along the parallel myelinated fibers (83,84). The parallel arrangement of these oriented fiber tracks creates a state with low resistance to interstitial infusion (81,83). CED infusion into white matter tracks therefore attains a greater volume of distribution along these low-resistance pathways (71,78). The gray matter, in contrast, is more uniform, and a more spherical volume of distribution can be obtained (2). This is significant when considering both the type of lesion treated and the placement of the can-nula into the brain. Appropriate targeting can obtain desired volumes of distribution and allow for the specific targeting of local lesions.

The volume of infusion determines the volume of distribution through a linear relationship (75,77,87). Through this linear relationship, equilibrium is eventually reached at the edge of the drug delivery sphere radiating from the cannula after a certain volume has been infused. At the periphery of the sphere, the rate of infusion is equal to the rate of efflux. At the periphery, diffusion works to carry drug further into the parenchyma, and the property of exponential decline in drug concentration away from the equilibrium point is applicable (2,81). Excessive tissue binding, leak-back through the cannula tract, large infusion rates, and differing flow patterns between white and gray matter can affect the linear ratio between infusion volume and volume of distribution.

When applying CED in practice, the properties of the infusate, including the efflux and clearance of these same molecules, must be taken into consideration, as they determine the volume of distribution. Clearance of the infusate is ultimately by catabolism, efflux through the BBB to the systemic vasculature, and dilution in the CSF (75,95). Efflux may also be influenced by P-glycoprotein, an ATP-dependent efflux pump with broad substrate specificity (66,89,98,94). The process of efflux associated with CED is counterintuitive. Increased vascular permeability actually acts to increase drug efflux and lowers the subsequent volume of distribution with CED (2). It becomes hypothetically desirable, therefore, to use drugs that are more hydrophilic in order to reduce crossing of the

BBB (69). Longer half-lives, larger local concentrations, and larger volume of distribution achieved with CED help to promote the efflux of infusate following infusion.

Several methods have been used to measure the volume of distribution with CED including autoradiography with radioactive isotopes (74,75,77,81) and histological sections after dye injection. The various dyes used to visualize the extent of spread of the infusate include fluorescein isothiocyanante (87,95) and Evans Blue (78). The effects of treatment can be easily measured with these techniques and coupled with magnetic resonance imaging technology to monitor the progression of various CNS lesions (84,95).

Neurotoxic events are the limiting factors in treatment and dictate the dose and rate of infusion (2,81). The toxicity can be divided into two components: mass effect related to increased volume of infusion and neurotoxicity from direct effects of drug on neurons and glial cells (81). The mild increase in ICP during infusion (77,80,84) is thought to be minimal (95) and has not been shown to alter local tissue structure significantly. Although remodeling of the parenchyma with dilation of channels in the interstitium can occur, it has not been associated with neuronal dysfunction (78,81). CED has also been documented to cause a mild gliosis that results either from the infusate or the infusion process. This inflammation is associated with increased glialfibrillary acidic protein immunoreactivity in the CNS local environment surrounding the cannula (78). This is a sensitive marker for astrocytic responses to neuronal trauma (75) and possibly represents a reversible phenomenon that results from changes in the interstitium (78) without significant changes to neuronal functioning. Each particular infusate will have its own toxicity profile associated with CED. These complications should be addressed when one is considering clinical trials and further research efforts. Indeed, the pH, the osmolarity, and the ionic composition of the infusate solution should be considered as well (2). The various cells of the CNS have different tolerances to different drugs, and further work needs to clarify these potential side effects of treatment with CED.

A final limitation to CED revolves around its inherent dependence on the directional bulk flow in the treatment of gliomas. If a tumor is removed, edema that had been present quickly resolves. The associated convection of fluid is now directed into the resection cavity and effectively reverses the direction of the pressure gradient (3). CED may potentially be limited to a role as a pre-treatment method or as an alternative treatment for recurring lesions (3).

Clinical Applications

A more uniform and predictable distribution of drug, a larger volume of distribution, and the potential for treating eloquent areas of the brainstem and spinal cord have helped support CED as a leading treatment modality for CNS disorders. To capitalize on these advantages, researchers have sought to couple this method with the latest treatment modalities made available in oncology, virology, and immunology. Researchers have targeted gliomas and discussed treating other CNS disorders such as Parkinson's disease and Huntington's disease with CED (97). Progress has primarily come in the realm of establishing

CED as a safe and efficacious method with animal models that has been effectively translated into human clinical trials (96.97).

Studies thus far have used models to apply CED to a variety of therapeutic agents to treat gliomas and other biochemical imbalances in the CNS. The various agents utilized include those involving chemotherapy (75,77,78,90,91), immunotherapy (92), and genetic targeting (71). The ideal therapeutic agent for CED takes advantage of its potential to deliver therapy to a larger volume of distribution more quickly with greater control of local concentrations (69). Drugs chosen for treatment with CED, however, are held to the same standards used for systemic treatment, namely, specificity for the lesion, lack of local tox-icity, pharmacodynamic stability, and some lipophilicity to promote entry into the cell.

Capitalizing on the wealth of knowledge surrounding the genetic and protein signal transduction cascades involved in tumorigenesis, researchers are now using CED to target specific enzymes (82) involved in aberrant DNA replication. One such family of nuclear enzymes is the topoisomerase group that the cell uses to coordinate unwinding of the DNA strands to replication and DNA repair. This enzyme is a prime candidate for CED treatment, given its essential role in regulation of DNA turnover (69). Drugs such as the family of cam-pothecins, which specifically target topoisomerase I, have been shown to be effective in the clinical treatment of gliomas. CED was shown to improve long-term survival, local concentration, and volume of distribution in animal glioma models (69). Clinical trials with chemotherapeutic agents such as topotecan and paclitaxel are currently underway in glioma patients (76). If successful, a new horizon for chemotherapeutic approaches to human gliomas may be opened for future research efforts.

Further studies have sought to establish the efficacy of using CED with novel treatment approaches such as antisense oligonucleotides (71), cytokines (72,92), and immunotoxins. The strategy that is furthest developed in clinical trials involves immunotoxins, which are molecules composed of a ligand such as transferrin or Il-4 that will bind with high specificity to rapidly dividing glioma cells, coupled with a toxin that will inhibit cell proliferation or induce apopto-sis, such as diphtheria toxin or Pseudomonas toxin. The diphtheria-transferrin toxin was used with CED to treat patients with recurrent gliomas since systemic delivery would not be feasible with such a complex macromolecule. By bypassing the systemic circulation, the large molecular weight (140-kDa) protein product could be delivered unaltered at high concentrations to tumors in the CNS. The advantage of using the transferrin receptor as a target is that it is up-regulated on rapidly dividing cells, including gliomas, conferring a high level of glioma specificity while avoiding local toxicity to surrounding neurons. Once inside the cells, diphtheria toxin can function to inhibit cell signaling and induce apoptosis within the tumor. In a phase I trial, tumor regression occurred in 60% of patients (9/15) treated, with complete remission in two patients. More importantly, delivery of this immunotoxin was well tolerated, and toxicity was minimal at lower doses (70). Seizures and focal brain injury were the primary complications in this study and occurred only at higher doses. This study offers the first promising result of using CED in conjunction with immunotherapy to treat human gliomas.

Success with the transferrin-diphtheria immunotoxin led to the development of other toxin conjugates for high-grade gliomas, including a formulation coupling IL-4 with Pseudomonas toxin. As with transferrin, IL-4 receptors are overexpressed in malignant glioma cells but not on other cells in the CNS, allowing the IL-4-pseudomonas organism conjugate to achieve a high degree of specificity. The Pseudomonas toxin is toxic to malignant glioma cells and induces apoptosis within tumors by ADP ribosylation of elongation factor 2, which is used in translation to form cellular proteins. In the initial clinical study, 6/9 patients had a responding tumor that underwent necrosis, while the neurotox-icity was minimal. Increased ICP was associated with pretreatment edema but was also associated with necrotic tumor-induced edema. Both factors are believed to have contributed to some level of toxicity seen in the few patients who experienced altered neurological function. The need for further studies on CED-induced toxicity is evident; however, the results of coupling CED with novel antitumor compounds show promise for a significant contribution to glioma therapy in the future (72).

Although most CED investigations have involved the treatment of gliomas, this strategy may prove to be more applicable to other CNS disease states, particularly those with more limited anatomic targets. Research on treating diseases such as Parkinson's and Huntington's with CED offers new hope for applying animal studies to human disease states (97). Additional work with CED to address spinal cord injury offers yet another avenue for exploring the applications of this treatment modality (85-87). The ultimate test for CED is to demonstrate its efficacy in clinical trials and to provide information for the development of future therapeutic modalities. Future studies will also be needed to investigate infusion parameters to optimize volumes of distribution. The development of appropriate contrast agents and imaging methods will lead to safer and more effective clinical uses of CED and more individualized therapy.

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