Delivery of Radiolabeled Antitenascin Monoclonal Antibodies
Delivery of Radiolabeled Antitenascin Monoclonal Antibodies
Objectives. Convection-enhanced delivery (CED) is a novel technique used to deliver agents to the brain parenchyma for treatment of neoplastic, infectious, and degenerative conditions. The purpose of this study was to determine if CED would provide a larger volume of distribution (Vd) of a radiolabeled monoclonal antibody (mAb) than a bolus injection.
Methods. Patients harboring a recurrent glioblastoma multiforme that reacted with the antitenascin mAb 81C6 during immunohistochemical analysis were randomized to receive an intratumoral injection of the human-murine chimeric mAb Ch81C6, which had been labeled with the I tracer. The mAb was administered by either a bolus injection or CED via a stereotactically placed catheter; between 48 and 72 hours later the mAb was again administered using the other technique. Injections of escalating doses of a I-labeled therapeutic mAb were then delivered using the technique shown to produce the largest Vd by single-photon emission computerized tomography.
Conclusions. Convection-enhanced delivery has enormous potential for administering drugs to sites within the central nervous system. For the relatively small volumes injected in this study, however, CED did not provide a significant increase in the Vd when compared with the bolus injection. Nevertheless, a clear cross-over effect was seen, which was probably related to the temporal proximity of the two infusions.
Malignant gliomas remain nearly uniformly fatal despite aggressive, computer-guided tumor resection, high doses of external beam radiation therapy or intracavitary brachytherapy, and multiple chemotherapy agents delivered at toxic doses. Although conventional forms of treatment sometimes result in positive responses on neuroimages, microscopic analyses of apparently normal brain tissue located some distance from the gross contrast-enhancing tumor show that the brain is diffusely infiltrated by frankly neoplastic cells at the time of diagnosis. This finding underscores the need for developing drug delivery systems capable of targeting neoplastic cells that may have migrated significant distances beyond the region of tumor visible on contrast-enhanced MR images. Although systemic drug delivery is theoretically capable of such broad coverage, available agents are severely limited by systemic dose-limiting toxicity, the tight junctions of the bloodbrain barrier, and high intratumoral pressure. Similarly, surgery and radiation therapy cannot address these regions of likely tumor recurrence without inducing incapacitating tissue damage to the functional brain.
Convection-enhanced delivery is an innovative technique of administering drugs that promises to enhance the spatial distribution of therapeutic agents throughout the brain parenchyma. The tremendous potential of this simple approach has been clearly demonstrated in preclinical and early clinical studies conducted by our group and by others. To achieve therapeutic concentrations of a drug within the interstitium of the brain, extremely high systemic doses are needed, which normally result in unacceptable toxicities. Traditional methods of local delivery of most therapeutic agents into the brain (by biodegradable polymers or direct in traventricular injection) has relied on diffusion, which is de pendent on a concentration gradient, is inversely related to the size of the agent, and is usually slow with respect to tissue clearance. Thus, diffusion results in the nonhomogeneous distribution of most agents, which is restricted to a few millimeters from the source. In contrast to diffusion, CED uses a pressure gradient established at the tip of an in fusion catheter that creates bulk flow, which "pushes" the drug in the extra cellular space). As a result, the drug is distributed more evenly, at higher concentrations, and over a larger area than in the absence of bulk flow (that is, when administered by diffusion alone).
For a given agent, the Vd depends on the structural properties of the tissue (hydraulic conductivity, vascular volume fraction, and extracellular fluid fraction) and the parameters of the infusion procedure (cannula placement, cannula design, and infusion rate). To maximize delivery and minimize reflux, the infusion procedure must be adjusted according to the tissue properties.
Although CED is being used clinically to treat human brain tumors, the pharmacokinetics of drug delivery using this system are very poorly understood, and the approach, which holds great promise, may fail unless the drug-delivery issues are well understood. In this paper we compare the Vd of a radiolabeled mAb delivered intratumorally using a traditional bolus injection with that of a radiolabeled mAb administered using CED.
Abstract and Introduction
Abstract
Objectives. Convection-enhanced delivery (CED) is a novel technique used to deliver agents to the brain parenchyma for treatment of neoplastic, infectious, and degenerative conditions. The purpose of this study was to determine if CED would provide a larger volume of distribution (Vd) of a radiolabeled monoclonal antibody (mAb) than a bolus injection.
Methods. Patients harboring a recurrent glioblastoma multiforme that reacted with the antitenascin mAb 81C6 during immunohistochemical analysis were randomized to receive an intratumoral injection of the human-murine chimeric mAb Ch81C6, which had been labeled with the I tracer. The mAb was administered by either a bolus injection or CED via a stereotactically placed catheter; between 48 and 72 hours later the mAb was again administered using the other technique. Injections of escalating doses of a I-labeled therapeutic mAb were then delivered using the technique shown to produce the largest Vd by single-photon emission computerized tomography.
Conclusions. Convection-enhanced delivery has enormous potential for administering drugs to sites within the central nervous system. For the relatively small volumes injected in this study, however, CED did not provide a significant increase in the Vd when compared with the bolus injection. Nevertheless, a clear cross-over effect was seen, which was probably related to the temporal proximity of the two infusions.
Introduction
Malignant gliomas remain nearly uniformly fatal despite aggressive, computer-guided tumor resection, high doses of external beam radiation therapy or intracavitary brachytherapy, and multiple chemotherapy agents delivered at toxic doses. Although conventional forms of treatment sometimes result in positive responses on neuroimages, microscopic analyses of apparently normal brain tissue located some distance from the gross contrast-enhancing tumor show that the brain is diffusely infiltrated by frankly neoplastic cells at the time of diagnosis. This finding underscores the need for developing drug delivery systems capable of targeting neoplastic cells that may have migrated significant distances beyond the region of tumor visible on contrast-enhanced MR images. Although systemic drug delivery is theoretically capable of such broad coverage, available agents are severely limited by systemic dose-limiting toxicity, the tight junctions of the bloodbrain barrier, and high intratumoral pressure. Similarly, surgery and radiation therapy cannot address these regions of likely tumor recurrence without inducing incapacitating tissue damage to the functional brain.
Convection-enhanced delivery is an innovative technique of administering drugs that promises to enhance the spatial distribution of therapeutic agents throughout the brain parenchyma. The tremendous potential of this simple approach has been clearly demonstrated in preclinical and early clinical studies conducted by our group and by others. To achieve therapeutic concentrations of a drug within the interstitium of the brain, extremely high systemic doses are needed, which normally result in unacceptable toxicities. Traditional methods of local delivery of most therapeutic agents into the brain (by biodegradable polymers or direct in traventricular injection) has relied on diffusion, which is de pendent on a concentration gradient, is inversely related to the size of the agent, and is usually slow with respect to tissue clearance. Thus, diffusion results in the nonhomogeneous distribution of most agents, which is restricted to a few millimeters from the source. In contrast to diffusion, CED uses a pressure gradient established at the tip of an in fusion catheter that creates bulk flow, which "pushes" the drug in the extra cellular space). As a result, the drug is distributed more evenly, at higher concentrations, and over a larger area than in the absence of bulk flow (that is, when administered by diffusion alone).
For a given agent, the Vd depends on the structural properties of the tissue (hydraulic conductivity, vascular volume fraction, and extracellular fluid fraction) and the parameters of the infusion procedure (cannula placement, cannula design, and infusion rate). To maximize delivery and minimize reflux, the infusion procedure must be adjusted according to the tissue properties.
Although CED is being used clinically to treat human brain tumors, the pharmacokinetics of drug delivery using this system are very poorly understood, and the approach, which holds great promise, may fail unless the drug-delivery issues are well understood. In this paper we compare the Vd of a radiolabeled mAb delivered intratumorally using a traditional bolus injection with that of a radiolabeled mAb administered using CED.
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