Distribution of therapeutic agents in the central nervous system (CNS) with currently available delivery techniques is problematic. Systemic delivery is limited by the blood-brain barrier, non-targeted distribution, and systemic toxicity. Diffusion-dependent methods that delivery substances by """"""""push- pull"""""""" catheters, intrathecal injection, mini-osmotic pumps, and drug impregnated polymers, can result in non-targeted distribution and a volume of distribution (Vd) limited by molecular weight and infusate diffusivity. An approach developed to overcome the obstacles associated with current CNS drug delivery techniques is convective delivery which uses bulk flow to enhance distribution. Our studies have demonstrated that convection-enhanced delivery to the brain, spinal cord, and peripheral nerve in large and small animals can be used to distribute macromolecules in a homogenous, targeted, and safe manner with a clinically effective Vd that is proportional to the volume of infusion (Vi). Recent efforts have focused on determining the factors that optimize convection-enhanced delivery into the brains of small animals. We have found that the rate of infusion and canula size significantly affect convective distribution of molecules while, in contrast, pre- infusion sealing time and variation of concentration has no effect. To further our understanding of the variables which affect convective delivery we are examining the effect of particle size on distribution in brain, spinal cord, and peripheral nerves. We hypothesize that the extracellular space places limits on the size of the particle which can move through it. The particles used in the study are latex microspheres which model genetic vectors (liposomes, viruses) used for gene therapy and genetic vectors. High-flow interstitial infusion is being used to deliver various agents, such as immunotoxins, genetic vectors, and chemotherapeutic molecules in the investigation of treatment of various disorders of the central nervous system. Currently, no technique is available to monitor infusions of macromolecular agents. Here, we describe two new imaging contrast agents for noninvasively monitoring infusion volume of distribution and concentration: 1) iodopanoic acid (telepaque) covalently linked to bovine serum albumin (MW 98 kDa) for CT and (2) gadolinium- DTPA (Magnevist) covalently linked to human serum albumin (MW 77 Kda) for MRI. Each of these agents, at volumes ranging from 130 to 235 ul, was co-infused with 14C-labeled albumin into brains of macaque rhesus monkeys. The radiographic volume of distribution (RVd) was determined at the end of the infusion by CT or MRI by two methods and compared to the volume of infusion (Vi). Quantitative audioradiography (QAR) was performed on brain slices of animals sacrificed at the end of the infusion, and a tissue volume of distribution Tvd) was determined. A 3-D reconstruction algorithm gave RVd1/Vi of 3.73 + 0.20 for CT and 3.85 + 0.06 for MRI. Similar results were obtained using a voxel-summation method: RVd2/Vi values were 4.26 + 0.07 for CT and 4.14 + 0.40 for MRI. These values are in excellent agreement with the interstitial volume of brain gray matter. The corresponding QAR-derived Tvd/Vi values were 4.26 + 0.19 and 3.86 + 1.06, respectively. Thus, a nearly one-to-one correlation of radiographic and tissue volume of distribution was obtained. CT hounsfield units correlated linearly with tissue concentrations calculated from QAR images, indicating that CT images can also be used to monitor tissue concentration during infusion. Neurotoxicity testing of these imaging agents revealed no evidence of neuronal degeneration up to three months after infusion in rat brains. Thus, we have demonstrated the utility of these imaging agents for monitoring the distribution of treatment during infusion of macromolecular drugs. Clinical investigation is planned.
| Lonser, Russell R; Warren, Katherine E; Butman, John A et al. (2007) Real-time image-guided direct convective perfusion of intrinsic brainstem lesions. Technical note. J Neurosurg 107:190-7 |
| Morrison, Paul F; Lonser, Russell R; Oldfield, Edward H (2007) Convective delivery of glial cell line-derived neurotrophic factor in the human putamen. J Neurosurg 107:74-83 |
| Szerlip, Nicholas J; Fox, Elizabeth; Manosca, Frances et al. (2007) Pancreatoblastoma metastases to the brain. Case illustration. J Neurosurg 106:169 |
| Lonser, R R; Schiffman, R; Robison, R A et al. (2007) Image-guided, direct convective delivery of glucocerebrosidase for neuronopathic Gaucher disease. Neurology 68:254-61 |
| Murad, Gregory J A; Walbridge, Stuart; Morrison, Paul F et al. (2006) Real-time, image-guided, convection-enhanced delivery of interleukin 13 bound to pseudomonas exotoxin. Clin Cancer Res 12:3145-51 |
| Walbridge, Stuart; Murad, Gregory J A; Heiss, John D et al. (2006) Technique for enhanced accuracy and reliability in non-human primate stereotaxy. J Neurosci Methods 156:310-3 |
| Tender, Gabriel C; Walbridge, Stuart; Olah, Zoltan et al. (2005) Selective ablation of nociceptive neurons for elimination of hyperalgesia and neurogenic inflammation. J Neurosurg 102:522-5 |
| Heiss, John D; Walbridge, Stuart; Morrison, Paul et al. (2005) Local distribution and toxicity of prolonged hippocampal infusion of muscimol. J Neurosurg 103:1035-45 |
| Lonser, Russell R; Walbridge, Stuart; Murray, Gary J et al. (2005) Convection perfusion of glucocerebrosidase for neuronopathic Gaucher's disease. Ann Neurol 57:542-8 |
| Croteau, David; Walbridge, Stuart; Morrison, Paul F et al. (2005) Real-time in vivo imaging of the convective distribution of a low-molecular-weight tracer. J Neurosurg 102:90-7 |
Showing the most recent 10 out of 35 publications
