Early Strategies For Local Delivery

Direct injection of therapeutic compounds into the CNS is one of the earliest forms of local delivery for CNS lesions. This treatment modality includes intrathecal and intraventricular injections and has been successful in the control of patient pain and in the treatment of leptomeningeal metastases. Direct injection has also been used to facilitate recent advances in gene therapy with viral vectors and immunotherapy with activated lymphocytes. Improved engineering of injection catheters, implantable pumps, and refillable Ommaya reservoirs has expanded the versatility and success of this approach in clinical trials.

Methods of Direct Injection

Injection into the CNS has been studied by targeting different compartments of the CNS. Clinical trials have been conducted using intrathecal, intraventric-ular, and intracerebral injections. Each route of administration possesses different properties and limitations based on its cellular environment and fluid dynamics. Variables include drug distribution following delivery, time of injection, number of injections, site of infusion, and property of drug or therapy being delivered (22). Clinical trials have utilized reservoirs (16), implantable pumps (20), and catheters (35) as delivery devices.

Intrathecal Delivery

The thecal sac and lateral ventricles share many of the same properties of drug distribution and fluid dynamics. Intrathecal injection involves administration of drug into the subarachnoid space, primarily in the lumbar area; intra-ventricular drug injection refers to infusion into the lateral ventricles. The primary property governing drug distribution within these spaces is bulk flow of cerebrospinal fluid (CSF). CSF flow is directional, with a variable velocity within the CNS that can further affect a drug's distribution (2). Because of CSF flow, the initial concentration of drug is directly proportional to the concentration of the infusate (2). CSF is an ideal medium for drug delivery, allowing therapeutic agents to be delivered unaltered to their targeted site at desired concentrations (20,22). Drug concentration in the CSF is governed by several variables including the number and duration of injections as well as the drug's ability to cross the CSF-brain barrier and distribute further by diffusion (2,4,22).

Intraparenchymal Injection

Drug distribution following local injection into brain parenchyma largely depends on the size and molecular weight of the drug being injected (Fig. 1). Distribution from the point source occurs along a concentration gradient by diffusion, a process that is slow in solid tissue. A larger drug may require repeat injections or a sustained release in order to reach therapeutic levels. An addi-

Fig. 1. Direct parenchymal injection under stereotactic guidance has been used in clinical trials to deliver gene therapy to malignant gliomas.

tional factor to consider is the hydrophobicity of the drug being infused, since lipophilic drugs cross into the systemic vasculature and the surrounding CNS more readily, further limiting the volume of distribution. The infusate solution pH and composition should be compatible with the delivery mechanism since corrosive drugs can lead to malfunctioning of delivery devices and treatment failure (22,37). The potential limiting factor for intraparenchymal treatment is neurotoxicity (2,5,34).

Injection Technology

Different mechanical devices have been developed to facilitate intrathecal delivery including the Ommaya reservoir and different implantable pumps. Early efforts to treat intracranial lesions utilized injections through a catheter left outside the cranial vault (5). The Ommaya reservoir was developed for intraventricular therapy (4) and consists of a Silastic catheter connected to a depressible capsule. The capsule is placed subcutaneously under the scalp to prevent infection and the reservoir can be filled by subcutaneous injections. Eventually, pump devices that could be subcutaneously implanted were developed to facilitate drug delivery at a constant rate (5). There are two categories of pumps, vapor pressure and programmable. More recent pumps can electronically control the rate of drug delivery: constant flow, periodic flow, or multiple flow rates (20). Programmable pumps have the advantage of being refillable, so that a sustained treatment regimen can be followed. The pump system has several disadvantages, however; the tubes and materials of the pumps are subject to corrosion (20), and the accumulation of tissue debris, tissue fibrosis, solution residue, and material can block the flow from the pumps. Protein solutions are generally avoided because of the possibility of denaturation within the device. Additional disadvantages include pump failure, infection, and surgical risks associated with improper placement of the catheter (16). A further limitation of the pump system is the limited biodistribution of drug with an exponential drop in concentration from the catheter tip (4,19,35).

Clinical Applications of Direct Injection

Direct injection has a significant history in the treatment of various CNS disorders. The use of catheters (4,35), pumps, and reservoirs continues in conventional patient care. Current pump applications include patient-controlled analgesia (PCA) (4,20,22) and treatment of Alzheimer's disease (4,22), spasticity (22), carcinomatous meningitis (2,4,37), leukemia (4), infectious meningitis (4), and malignant gliomas (2,22). Ommaya reservoirs are used in the treatment of meningeal leukemia, meningeal carcinomatosis (3), and infectious meningitis (4). Reservoir technology has been used in experimental immunotheraputic (27 )protocols to infuse interferon-y locally into surgical cavities of malignant gliomas. Although no significant improvement in survival occurred, this local treatment was found to be safe and well tolerated in patients (27).

More conventionally, intrathecal delivery via Ommaya reservoirs is used for treatment of leptomeningeal metastases and has resulted in increased survival time and improvement of symptoms. Catheter malposition must be avoided, as it can result in leukencephalopathy in surrounding neurological structures. Other complications include increased intracranial pressure (ICP), infection, and intracranial hemorrhage (15,16). Reservoirs, however, offer significant advantages over multiple lumbar punctures to deliver chemotherapy including improved patient comfort, diminished risk in patients with thrombocytopenia, and a more predictable concentration of drug delivery (16).

Ommaya reservoirs have also been used in the treatment of pediatric tumors, including intralesional chemotherapy of cystic craniopharyngiomas (17,26). Local chemotherapy with bleomycin can avoid systemic side effects, although local toxicity can include hypothalamic dysfunction with hypersomnia, mental change, visual disturbances, thermal dysfunction, and memory impairment. Leakage of bleomycin from the cyst has also been associated with arterial infarcts and subsequent cerebral function (17).

More versatile than reservoirs, implantable pumps have diverse applications in neurosurgery, particularly in the treatment of chronic pain (5,22). Intraspinal morphine, hydromorphone, bupivicane, and analgesic peptides have all been used to control patient pain in inpatient and outpatient settings (4,22). Implantable pumps have also been used for the treatment of spasticity with the intraspinal administration of baclofen (20,22,37). A more recent application of pump technology is in the treatment of Alzheimer's disease. Multicenter double-blind studies in Alzheimer's patients revealed a measurable improvement in behavior and neuropsychological test scores following bethanechol infusion (20,22). Finally, pumps have been used in the treatment of malignant glioma, in which postresection cavities have been targeted. Studies with methotrexate (19) achieved higher intratumoral concentrations than could be achieved with systemic administration (19,22). Side effects from intrathecal administration included arachnoiditis; however, intratumoral treatment with methotrexate was well tolerated (19).

Simple direct injection has been used to deliver cells into the CNS. One such study utilized lymphokine-activated killer (LAK) cells engineered with recombinant DNA technology to produce various cytokines (6). LAK cells and cytokines were injected into tumor resection cavities to amplify local tumor immune responses. Clinical efforts have focused on interleukin-2 (IL-2) as a candidate cytokine because of its ability to induce T-cell growth and potentially to amplify T-cell tumoricidal activity (14,21,23,24,28). Side effects of the injection included debilitating fatigue, headaches, and lethargy that were attributed to increased ICP and edema surrounding the injection site. Many side effects were controllable with systemic corticosteroids (21,23). Postmortem biopsy specimens revealed extensive necrosis, gliosis, and infiltration of lymphocytes and macrophages in the area surrounding the injection sites (23,24).

The first gene therapy trial for malignant glioma utilized a direct injection strategy. Patients received stereotactically guided injections of murine fibrob-lasts that produced retroviruses carrying the herpes simplex virus-thymidine kinase (HSV-tk) gene. The retroviruses would transduce the tumor cells and express the thymidine kinase gene. Patients were then given systemic ganci-clovir, which entered transduced tumor cells, where it was phosphorylated by the thymidine kinase gene. The phosphorylated ganciclovir would block DNA replication and be selectively lethal to proliferating cells. The first clinical trial involved 15 patients, 12 with recurrent malignant gliomas, 2 with metastatic melanoma, and 1 with metastatic breast carcinoma. Reduction of the tumor mass occurred in five patients, and survival time improved to more than 11 mo in three patients. Although there were several adverse events (including seizures, meningeal inflammation, headache, and pancytopenia), the study demonstrated the feasibility of intratumoral injection of retrovirus-producing cells for patients with malignant gliomas. Interestingly, no replication-competent retroviruses were found in the systemic circulation of the patients treated with direct injection (48,49). Similar phase I and II studies have verified the usefulness of the HSV-tk strategy for the treatment of malignant gliomas (42,45,46,48).

CNS disorders other than malignant gliomas may be treated with direct injection, as suggested by recent research in Parkinson's disease (44). Injection of dopaminergic neuroprotection and regeneration chemicals and studies with neurotophic factors in clinical trials (88) are under way. Although therapeutic efficacy has yet to be shown, these studies do not suggest an increased risk of toxicity with intracerebral injections.

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