Abstract
The blood–brain barrier (BBB) is a specialized vascular interface that restricts the entry of many compounds into brain. This is accomplished through the sealing of vascular endothelial cells together with tight junction proteins to prevent paracellular diffusion. In addition, the BBB has a high degree of expression of numerous efflux transporters which actively extrude compounds back into blood. However, when a metastatic lesion develops in brain the vasculature is typically compromised with increases in passive permeability (blood-tumor barrier; BTB). What is not well documented is to what degree active efflux retains function at the BTB despite the changes observed in passive permeability. In addition, there have been previous reports documenting both increased and decreased expression of P-glycoprotein (P-gp) in lesion vasculature. Herein, we simultaneously administer a passive diffusion marker (14C-AIB) and a tracer subject to P-gp efflux (rhodamine 123) into a murine preclinical model of brain metastases of breast cancer. We observed that the metastatic lesions had similar expression (p > 0.05; n = 756–1214 vessels evaluated) at the BBB and the BTB. Moreover, tissue distribution of R123 was not significantly (p > 0.05) different between normal brain and the metastatic lesion. It is possible that the similar expression of P-gp on the BBB and the BTB contribute to this phenomenon. Additionally we observed P-gp expression at the metastatic cancer cells adjacent to the vasculature which may also contribute to reduced R123 uptake into the lesion. The data suggest that despite the disrupted integrity of the BTB, efflux mechanisms appear to be intact, and may be functionally comparable to the normal BBB. The BTB is a significant hurdle to delivering drugs to brain metastasis.
Highlights
The successful treatment of central nervous system (CNS) tumors and metastases using chemotherapy depends on the ability of therapeutic concentrations of drug to cross the blood–brain barrier (BBB)
To determine if P-gp expression is present in the vasculature of brain metastases, we analyzed the brains of tumor bearing mice using immunofluorescence staining for both P-gp and the vascular marker CD31 to quantify the amount of colocalization (Figure 1)
To determine blood-tumor barrier (BTB) passive permeability and whether P-gp influences Rhodamine 123 (R123) uptake into brain metastases of breast cancer, tumor-bearing mice were injected with 14C-AIB which was allowed to circulate for 10 min before a 2 min R123 perfusion, which was followed by sacrifice (Figure 3)
Summary
The successful treatment of central nervous system (CNS) tumors and metastases using chemotherapy depends on the ability of therapeutic concentrations of drug to cross the blood–brain barrier (BBB). More than 98% of potential CNS active anticancer drugs fail in preclinical work and or clinical trials because of inadequate BBB penetration (Pardridge, 2007) This results in many anticancer agents failing to substantially reduce tumor burden and or significantly prolong survival (Deeken and Loscher, 2007). It has been shown that the blood-tumor barrier (BTB) vasculature has disrupted integrity compared to the intact BBB. This disruption can allow small molecule to accumulate into lesions up to 30–100-fold more than the accumulation of the molecule in normal brain (Lockman et al, 2010; Taskar et al, 2012). P-gp is highly functional in limiting the lesion accumulation of the P-gp substrate, Rhodamine 123 (R123) despite significant passive permeability increases
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