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Local Drug Delivery in the Treatment of Glioblastoma
The prognosis following diagnosis of glioblastoma remains poor. Historically, there have been many notable attempts to use local drug delivery to treat glioblastoma, including convection-enhanced delivery (CED), direct tumor injection, and the use of to deliver chemotherapeutics. The use of polymer wafers resulted in the only US Food and Drug Administration (FDA)–approved intracranial drug implant for treatment of recurrent and de novo glioblastoma, Gliadel. Over a period of several decades, the delivery of the chemotherapeutic 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) from biodegradable polyanhydride polymeric wafers was developed and tested for efficacy and safety, culminating in the wafer’s approval for recurrent glioblastoma in 1996 and de novo glioblastoma in 2003. To date, this polymeric delivery vehicle is the most extensively tested and also one of the few drug-eluting systems created for intracranial drug delivery. This chapter reviews the scientific challenges and evolution of local compounds for glioblastoma, including BCNU wafers, CED, direct injection, and hydrogel-based delivery.
Background to intracranial drug delivery
The impetus for local drug delivery is fundamentally based on the ability to bypass the blood-brain barrier (BBB). The BBB is composed of endothelial cells in brain capillaries forming nearly impenetrable tight junctions (zonula occludens), with limited to almost no detectable pathways for transendothelial transport of molecules of greater than 200 Da. Beyond a physical barrier, the BBB also forms a metabolic gate, inactivating passive compounds via intracellular and extracellular enzymes. Elsewhere in this publication, techniques and modalities specialized for bypassing the BBB for more efficacious systemic administration of drugs are described. More specifically, this chapter addresses the tools, materials, and techniques used in the direct bypass of the BBB by local, intracranial drug delivery.
The implantation of drug-eluting biomaterials within the brain is limited by several factors. The first and most important is that any implantable material must maintain a highly favorable safety profile. All implantable devices within the brain parenchyma are subject to interaction between the device and brain tissue and must be (1) completely biocompatible without eliciting a biological reaction, (2) unable to migrate and cause mechanical damage to the ventricular system or anatomic structures, and (3) limited in its ability to cause severe side effects from leakage of the dissolving or migrating compound.
A major barrier to the implementation of local and topical drugs for the treatment of glioblastoma is the cellular infiltrative nature of the disease, which extends beyond where a resection may take place surgically, or where a topical agent can be applied. Local drug delivery can provide controlled, sustained release of the compound, or can enhance the permeability of the BBB in some cases to promote uptake of the therapeutic, but does not change the underlying pathophysiologic nature of diffuse cellular infiltration.
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