The blood-brain and blood-tumor barriers: A review of strategies for increasing drug delivery

Abstract

Drug delivery to brain tumors has been a controversial subject. Some believe the blood-brain barrier is not important, while others believe it is the major obstacle in treatment and have devised innovative approaches to circumvent it. These approaches can be divided into two categories: those that attempt to increase drug delivery of intravascularly administered drugs by manipulating either the drugs or capillary permeability, and those that attempt to increase drug delivery by local administration. Several strategies have been developed to increase the fraction of intravascular drug reaching the tumor, including intra-arterial administration, barrier disruption, new ways of packaging drugs, and, most recently, inhibiting drug efflux from tumor. When given intravascularly, all drugs have a common drawback: the body acts as a sink, and, even in the best situations, only a small fraction of administered drug actually reaches the tumor. A consequence is that systemic toxicity is usually the dose-limiting factor. When given locally, such as into the cerebrospinal fluid or directly into the tumor, 100% of an administered dose is delivered to the target site. However, local delivery is associated with variable and unpredictable spatial distribution and variation in drug concentration. The major dose-limiting factor of most local delivery methods will be neurotoxicity. The relative advantages and disadvantages of the different methods of circumventing the blood-brain barrier are presented in this review, and special attention is given to convection-enhanced delivery, which has particular promise for the local delivery of large therapeutic agents such as monoclonal antibodies, antisense oligonucleotides, or viral vectors.

Drug delivery to brain tumors

“…ATP-adenosine triphosphate; BCRP-breast cancer resistance protein; CED-convection-enhanced delivery; MRP-multidrug resistance protein; P-gp-P glycoprotein. port systems that have low affinity and capacity, such that basal levels of the endogenous substrate may interfere with binding of engineered ligands [12].…”

“…However, there have been some promising results, including in traditionally difficult tumors such as brainstem gliomas [21]. BBBD and concentrated chemotherapy approaches hold the most promise for anticancer agents that are likely to bind to tumor tissue (and hence, not be rapidly effluxed) and for chemosensitive tumors such as primary CNS lymphoma and germ cell tumors [12,22,23]. The side effects associated with BBB disruption and IA drug delivery are generally ischemic in nature and likely related to catheterization of the vessel for delivery as well as the irritative effects of the chemotherapy [20].…”

“…Intuitively, a greater number of catheters placed throughout heterogeneous tumors may result in increased delivery; however, this may be technically difficult and has not been demonstrated in clinical practice. This is likely because other factors such as rate of efflux from the CNS, proximity to white matter tracks, and patterns of bulk flow influence the delivery, and therefore the efficacy, of the infused agent [12]. Because the major limitation of CED is the area of drug distribution, imaging techniques such as fluorodeoxyglucose-positron emission tomography (FDG-PET), diffusion-weighted imaging (DWI), MRI, and single photo emission computed tomography (SPECT) are increasingly being used to image agents within the brain after CED.…”

Sleeping sickness and the brain

“…One approach is to target endogenous blood-brain barrier transport systems as in the case of the anti-retroviral reverse transcriptase inhibitor azidothymidine. Other CNS drug delivery strategies [125] include barrier disruption, novel ways of packaging drugs, inhibition of drug efflux from the brain or manipulation of the brain capillary endothelium permeability to therapeutic agents. Development of inhibitors of efflux pumps, also used to reverse P-glycoprotein-mediated multi-drug resistance in cancer cells [115], may greatly improve the retention in the brain of valuable drugs that are otherwise removed [126].…”

Convection-enhanced delivery of liposomal doxorubicin in intracranial brain tumor xenografts

“…Poor penetration of most anticancer drugs across the blood-brain barrier (BBB) into the central nervous system (CNS), when systemically administered, is one of the major reasons why improvement of survival is limited. Even with drugs that penetrate the BBB, it is difficult to reach sufficient drug concentrations in brain tumor tissue without causing systemic side effects [1].…”