Abstract
BackgroundDrug and antibody delivery to brain metastases has been highly debated in the literature. The blood-tumor barrier (BTB) is more permeable than the blood-brain barrier (BBB), and has shown to have highly functioning efflux transporters and barrier properties, which limits delivery of targeted therapies.MethodsWe characterized the permeability of 125I-trastuzumab in an in-vivo, and fluorescent trastuzumab-Rhodamine123 (t-Rho123) in a novel microfluidic in-vitro, BBB and BTB brain metastases of breast cancer model. In-vivo: Human MDA-MB-231-HER2+ metastatic breast cancer cells were grown and maintained under static conditions. Cells were harvested at 80% confluency and prepped for intra-cardiac injection into 20 homozygous female Nu/Nu mice. In-vitro: In a microfluidic device (SynVivo), human umbilical vein endothelial cells were grown and maintained under shear stress conditions in the outer compartment and co-cultured with CTX-TNA2 rat brain astrocytes (BBB) or Met-1 metastatic HER2+ murine breast cancer cells (BTB), which were maintained in the central compartment under static conditions.ResultsTissue distribution of 125I-trastuzumab revealed only ~3% of injected dose reached normal brain, with ~5% of injected dose reaching brain tumors. No clear correlation was observed between size of metastases and the amount of 125I-trastuzumab localized in-vivo. This heterogeneity was paralleled in-vitro, where the distribution of t-Rho123 from the outer chamber to the central chamber of the microfluidic device was qualitatively and quantitatively analyzed over time. The rate of t-Rho123 linear uptake in the BBB (0.27 ± 0.33 × 104) and BTB (1.29 ± 0.93 × 104) showed to be significantly greater than 0 (p < 0.05). The BTB devices showed significant heterogenetic tendencies, as seen in in-vivo.ConclusionsThis study is one of the first studies to measure antibody movement across the blood-brain and blood-tumor barriers, and demonstrates that, though in small and most likely not efficacious quantities, trastuzumab does cross the blood-brain and blood-tumor barriers.
Highlights
Brain metastases are a fatal neurological complication of breast cancer which have historically been a major cause of morbidity
No clear correlation was observed between size of metastases and the amount of 125I-trastuzumab localized in-vivo
This study demonstrates that trastuzumab crosses the blood-tumor barrier (BTB) and the accumulates in tumor in our preclinical model of brain metastases of breast cancer and is accompanied by confirmatory microfluidic in-vitro experiments
Summary
Brain metastases are a fatal neurological complication of breast cancer which have historically been a major cause of morbidity. Among the many associated risk factors in the development of brain metastases from breast cancer, hormone receptor status is significant [8]. Within the HER2-positive (HER2+) subset, hormone receptor status is associated with CNS relapse. Up to 37% of patients with HER2+ breast cancer relapse is associated with intracranial metastases, despite control of the peripheral tumors [13,14,15]. A limiting factor in the treatment of brain metastases is the inability of chemotherapy to reach the desired tumor location. This is due, in large part, to the presence of a strictly controlled and complex vascular network known as the blood-brain barrier (BBB). The blood-tumor barrier (BTB) is more permeable than the blood-brain barrier (BBB), and has shown to have highly functioning efflux transporters and barrier properties, which limits delivery of targeted therapies
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