Challenges in drug delivery to tumors of the central nervous system: An overview of pharmacological and surgical considerations☆

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Abstract

The majority of newly diagnosed brain tumors are treated with surgery, radiation, and the chemotherapeutic temozolomide. Development of additional therapeutics to improve treatment outcomes is complicated by the blood–brain barrier (BBB), which acts to protect healthy tissue from chemical insults. The high pressure found within brain tumors adds a challenge to local delivery of therapy by limiting the distribution of bolus injections. Here we discuss various drug delivery strategies, including convection-enhanced delivery, intranasal delivery, and intrathecal delivery, as well as pharmacological strategies for improving therapeutic efficacy, such as blood–brain barrier disruption.

Section snippets

The blood–brain barrier (BBB) in normal brain and in brain tumors

The central nervous system is uniquely protected by the Blood–brain Barrier (BBB), which separates circulating blood and from the CNS. Composed of endothelial cells lacking intracellular fenestrations and linked by tight junctions, the BBB serves to dramatically restrict the types of compounds that can freely diffuse into the brain from the bloodstream [1], [2], [3]. While there is evidence of transcytosis of positively charged serum proteins, such as albumin, the movement of simple molecules,

Convection-enhanced delivery (CED)

Intraoperative injection of anti-cancer agents into brain tumors has experienced minor success as a result of diffusion-limited drug distribution as well as infusate leakage away from the target site. Convection-enhanced delivery (CED) is a type of direct administration that uses positive pressure to increase circulation of drug throughout the tumor, and to reduce the influence of therapeutic molecular weight on distribution. Practically, this is obtained either in acute infusions by attaching

Pharmacological methods for improving drug delivery to CNS tumors

While bypassing the BBB, through physical methods, has achieved a degree of preclinical and clinical success, CED and ITD remain invasive approaches that carry significant risks for patients. The development of pharmacological strategies to reduce BBB effects have been sought not only for their potential in decreasing patient risk, but also for the potential of these approaches in achieving greater therapeutic distribution in tumors, and for compatibility with repeated drug administration.

Conclusion

Delivering drugs for effective treatment of CNS cancer has long been hampered by a lack of effective approaches that either modulate or circumvent the BBB. Despite these obstacles, significant progress has been made in alternative routes of administration, especially CED and ITD, as well as with regard to novel drug formulations, and this progress is being actively investigated in numerous clinical trials. Collectively, the related research that has been conducted in recent years provides

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    ☆

    This review is part of the Advanced Drug Delivery Reviews theme issue on “Delivery of Therapeutics to the Central Nervous System”.

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    Copyright © 2012 Elsevier B.V. All rights reserved.