Local drug delivery for treatment of brain tumor associated edema

Abstract

Brain tumor associated edema, a common feature of malignant brain neoplasms, is a significant cause of morbidity from brain tumor. Systemic administration of corticosteroids, the standard of care, is highly effective but can introduce serious systemic complications. Agents that inhibit the vascular endothelial growth factor (VEGF) pathway, such as cediranib, are promising alternatives, but are also associated with systemic toxicity as VEGF is essential for normal physiological functions. A miniature drug delivery device was developed for local drug delivery in rodents. It comprises of a drug reservoir and a cap with orifice(s) through which drug is released. Drug release kinetics is dependent on the payload, the drug solubility, and the surface area for diffusion. Sustained releases of dexamethasone (DXM), dexamethasone sodium phosphate (DSP), and solid dispersion of cediranib (AZD/PVP) were achieved. Employing the solid dispersion technique to increase the solubility of cediranib was necessary to enhance its release. Therapeutic efficacy and systemic toxicity of local drug administration via our devices were examined in an intracranial 9L gliosarcoma rat model. Local delivery of DSP was effective in reducing edema but led to DXM induced weight loss at high doses in a pilot study. DXM, which is much less water-soluble than DSP, was used subsequently to reduce the dose delivered. The use of DXM enabled long-term, sustained zero-order release and a higher payload than DSP. Local deliveries of DXM and AZD/PVP were demonstrated to be as effective as systemic dosing in alleviating edema. Edema reduction was associated with survival benefit, despite continuous tumor progression. Animals treated with locally delivered DXM did not suffer from body weight loss and corticosterone suppression, which are adverse effects induced by systemic DXM. Local drug administration using our device is superior to traditional systemic administration as it minimizes systemic toxicity and allows increased drug concentration in the tumor by circumventing the blood brain barrier. A much lower dose can therefore be utilized to achieve similar efficacy. Our drug delivery system can be used with other therapeutic agents targeting brain tumor to achieve therapeutic efficacy without systemic toxicity.