Effective drug delivery remains the single greatest obstacle to the treatment of many central nervous system, or CNS, disorders. Despite the development of numerous compounds that have promising therapeutic effects in the laboratory, the clinical application and efficacy of these agents has been restricted by the limitations associated with currently available delivery techniques.
Current CNS delivery techniques rely on systemic delivery, intrathecal or intraventricular administration, and polymer implantation. However, systemic delivery is restricted by systemic toxicity, nontargeted distribution, and the inability of many substances to cross the blood-nervous system barrier. Diffusion-dependent methods, which include intrathecal or intraventricular administration and polymer implantation, similarly are limited by nontargeted distribution, nonuniform dispersion, and ineffective volumes of distribution.
To overcome these obstacles, Edward Oldfield, MD, and colleagues at the National Institutes of Health developed a method of drug delivery in the late 1980s called convection-enhanced delivery. This method employs bulk flow rather than diffusion to distribute small and large molecules within a targeted region of the CNS. Direct perfusion of the CNS interstitial spaces using convective force is achieved by a slight hydrostatic pressure generated by a syringe pump. Convective delivery allows for the safe, targeted, homogeneous delivery of agents into small and large tissue volumes (multiple orders of magnitude larger than diffusion-driven processes for large molecules) in a manner that bypasses the blood-nervous system barrier.
An emerging advantage of convection-enhanced delivery is the ability to use imaging technology that allows drug distribution to be seen during infusion. Recent animal studies have shown that gadolinium- and iodine-based imaging compounds can be used as surrogate tracers to safely and accurately track drug distribution in real-time using magnetic resonance imaging, as shown on these pages, and computed tomography imaging. These tracers show the distribution of both small- and large-molecular-weight compounds with similar convective properties during infusion. Real-time monitoring that ensures precise drug delivery to the desired location will be a critical component for investigating the use of convection-enhanced drug delivery and attaining optimal treatment results in humans.
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| Real-time T1-weighted magnetic resonance imaging in the coronal and midsagittal planes of a monkey brain at various times during the infusion of gadolinium-bound albumin (total volume of infusion 85 microliters). Upper left: The coronal image demonstrates the position of the cannula tip (arrow) just before starting the infusion of gadolinium-bound albumin. Midsagittal images reveal that the region infused with gadolinium-bound albumin (white) increased as the infusion progressed (approximately every 20 to 40 minutes; left to right and top to bottom), filling large portions of the pontine and midbrain regions of the brainstem. The volumes of infusion seen in these midsagittal images include 7.5, 15, 30, 40, 50, 65, and 85 microliters. From R.R. Lonser et al., Journal of Neurosurgery, 97:905-913, 2002 |
The unique properties of convection-enhanced delivery and the new imaging techniques have led to development of new treatment paradigms for various CNS disorders.
Malignant Tumors Because glial neoplasms are locally invasive, usually spread along white matter tracts, and have an exceptionally low metastatic potential, the properties of convection-enhanced delivery offer a promising new approach for their treatment. Convection-enhanced delivery can perfuse large regions of the CNS with high concentrations of small- or large-molecular-weight therapeutic agents. Several ongoing clinical trials have shown that convective delivery can distribute small-molecular-weight chemotherapeutic agents and large-molecular-weight toxins conjugated to tumor-specific proteins, such as transferrin conjugated to diptheria toxin, to treat high-grade glial neoplasms. While the efficacy of the various infused agents remains to be determined, early evidence from these trials suggests that convection can be used safely for drug delivery while at the same time overcoming many problems associated with other drug delivery techniques used for tumor therapy.
Parkinson’s and Other Neurodegenerative Diseases Convection-enhanced delivery is being investigated for treatment of specific aberrant CNS nuclei or regions that underlie the pathophysiology of a number of neurodegenerative diseases, including Parkinson’s disease. Recently, convection-enhanced delivery of quinolinic acid was used to create lesions in targeted areas of the globus pallidus interna and effectively treat primates that have Parkinson’s disease induced by MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). Based on this success, a clinical protocol was developed in which a surrogate imaging tracer is co-infused with a reversible chemical agent (such as muscimol, a gamma-aminobutyric acid agonist) to show the distribution of the infused agent and temporarily block neuronal activity in specific regions or all of the globus pallidus interna. This treatment paradigm permits functional testing to determine the clinical consequences before selective neuronal lesioning with quinolinic acid. The combination of these techniques should allow precise anatomical placement of lesions and determination of lesion distribution; it also will provide careful clinical assessment of the treatment effects before definitive therapeutic intervention. Using similar convective delivery techniques, surgeons eventually could tailor a lesion to maximize patient benefit, while avoiding difficulties inherently associated with conventional surgical methods.
In addition, the convection-enhanced delivery of commonly used therapeutic agents to overcome the physiological causes of Parkinson’s disease is being investigated. These agents locally enhance the production of dopamine, enhance or support striatal neurons such as glial cell line-derived neurotrophic factor, or manipulate gene products via viral delivery. It also may be possible to employ convective delivery of such agents for the treatment of Alzheimer’s disease and other neurodegenerative and metabolic disorders.
Epilepsy The ability to pharmacologically alter the activity of precise regions of the brain with a reversible neuron-specific suppressive agent may provide a new method for treatment of medically intractable epilepsy. A clinical trial is being designed to selectively and temporarily suppress neuronal activity using targeted convective infusion of muscimol to suppress neurons in the epileptic region. As an increasing number of neurons in and around the epileptic focus are suppressed, clinical effects-cessation of seizures and/or deterioration in neurological function-will be analyzed. This approach could identify the epileptic focus and subsequently may more accurately define the minimum treatment area that is required for surgical success. The data obtained from this clinical trial may also support the use of convection-enhanced delivery of either neurotransmitter-specific or lesioning agents into an epileptic focus to treat patients with medically intractable epilepsy.
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| Coronal section of monkey brain stained for biotin (black region) through the globus pallidus interna (white lettering, Gpi) in an animal infused with 5 microliters of biotinylated albumin. The infusate completely fills the Gpi with minimal extravasation in the globus pallidus externa (Gpe) or adjacent structures. Abbreviations on the side opposite the infusion indicate regions of the internal capsule (IC), putamen (Put), Gpi, Gpe, and otic tract (OT). From R.R. Lonser et al., Journal of Neurosurgery, 91:294-302, 1999. |
Pain Because convection-enhanced delivery can be used to uniformly perfuse cranial and peripheral nerves as well as their associated structures, there are a number of disorders, including pain, that may be treated by perfusion of these areas. Recent animal studies have shown that convective delivery of resinferatoxin (a vanilloid receptor 1 agonist that selectively ablates type 2 A-delta-fiber and C-fiber neurons) into peripheral nerves or their associated ganglia can eliminate pain and associated inflammation. Because A-beta-fiber, type 1 A-delta-fiber and motor neurons are not affected by resinferatoxin infusion, normal tactile sensation, perception of harmful heat, acute pain sensation and motor function are reliably preserved after infusion. These findings suggest that intraganglionic perfusion with resinferatoxin may provide a new site-specific, physiologically based treatment of painful disorders such as trigeminal neuralgia.
In conclusion, convection-enhanced delivery of various therapeutic compounds in conjunction with real-time imaging of distribution should permit a number of new treatment paradigms for CNS disorders to be developed. Greater understanding of the molecular basis of neurological disorders and further development of new compounds are expected to expand the potential role of convection-enhanced delivery in the future.
Russell R. Lonser, MD, and Edward H. Oldfield, MD, are neurosurgeons in the surgical neurology branch of the National Institute of Neurological Disorders and Stroke, the National Institutes of Health, in Bethesda, Md.
| The NS Innovations column explores neurosurgical innovations that are changing the way neurosurgeons practice. The column’s emphasis is applied science, including topics such as new instrumentation and novel applications of familiar technology, but discoveries in basic science that have the potential to impact neurosurgery and aid our patients will be considered as well. I invite you to send your ideas for this column to me at [email protected]. William T. Couldwell, MD, NS Innovations editor |
