Advantages Of Local Delivery Strategies

Traditional systemic delivery modalities share a common limitation by relying on diffusion across the BBB to distribute a therapeutic agent throughout the CNS (3). Diffusion, especially through solid tissue, is slow and relies on concentration gradients to disperse molecules (95). The increased time needed to establish dispersion reduces the bioavailability of drugs by increasing the potential for drug catabolism and tissue clearance. Methods that rely on diffusion require a high concentration source to establish a sufficient concentration gradient for adequate distribution. The high concentration sources needed to

From: Minimally Invasive Neurosurgery, edited by: M.R. Proctor and P.M. Black © Humana Press Inc., Totowa, NJ

establish sufficient concentration gradients across the BBB can be toxic to both the surrounding cerebral tissue and systemic organ systems (81).

The major advantage of local treatment modalities is that drugs do not have to cross the BBB to reach target destinations (2). Although the BBB has been shown to be disrupted in cerebral tumors and may not be an absolute barrier to therapy, some form of BBB remains either within the tumor or in peritumoral brain (3,81,83). Local treatment avoids this limitation, achieving higher local drug concentrations in the surrounding parenchyma (5,71,81).

An example of the application of local therapy is in the treatment of malignant gliomas, in which tumor dissemination and local recurrence are problematic. Up to 90% of gliomas recur within 2 cm of resection, providing the rationale for local delivery by increasing intratumoral and peritumoral concentrations of therapeutic agent (1,9,51,28). Although this theoretical advantage for decreased tumor recurrence is challenged by some investigators (28), local treatment modalities have been shown to increase significantly patient survival (53,55,56).

Local treatment modalities achieve a higher local drug concentration (13,51), sustain longer target exposure times, and minimize toxicity (75,77). One of the disadvantages of systemic treatment is the brief time a drug is in contact with a targeted area of the CNS. Arterial delivery has been tried in an effort to increase CNS penetration, but its pulsatile nature, its potential for binding tissues outside the CNS, and its increasing tissue clearance before and after reaching the CNS combine to limit the time and dose of exposure. By contrast, local delivery can maintain drug concentration and exposure more uniformly and consistently (3,5) through increased drug half-life (3,75) by limiting a drug's exposure to tissues, carrier proteins, and cells outside the CNS (75).

Technological advances have produced products engineered to facilitate local delivery strategies. Direct injection with pumps, reservoirs, and catheters offers several advantages when one is attempting to treat patients requiring complex and prolonged delivery schemes with multiple drugs (20). Different rates of drug infusion can be programmed for treatment (4), and refillable pumps and reservoirs avoid the need for multiple injections, surgeries, or invasive procedures. Among the most versatile and effective local delivery strategies is CED, which can treat localized lesions while potentially reaching areas of invaded brain tissue (71,75,80,83). The more uniform concentrations attained with CED achieve a desired therapeutic window for a drug (75,95) and provide flexibility for controlling the concentrations over a longer period of treatment time (81). Adjustment of volumes and flow rates allows local concentrations to be altered in a temporal fashion with greater accuracy (2,80). CED also achieves maximal volume of distribution in a shorter time (75,77,80,95). The reduced time translates into less drug catabolism, less nonspecific tissue binding, reduced tissue clearance, and prolonged exposure to the drug (95).

Local delivery modalities provide the advantage of delivering a variety of new classes of therapeutic compounds from neurohormones, trophic factors, neurotransmitters, viruses, immunotherapy, and drugs to a specific site within the CNS (22). This advantage of customizing drug delivery expands the reper toire of drugs that can be used when treating CNS disorders (11,51). The flexibility to apply novel classes of compounds to cellular and molecular targets will help local delivery modalities keep pace with evolving pharmaceutical developments that would otherwise not be feasible with systemic delivery.

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