Trastuzumab distribution in an in-vivo and in-vitro model of brain metastases of breast cancer

• Published in: Oncotarget Vol. 8; no. 48; pp. 83734 - 83744
• Main Authors: Terrell-Hall, Tori B, Nounou, Mohamed Ismail, El-Amrawy, Fatema, Griffith, Jessica I G, Lockman, Paul R
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 13.10.2017
• Subjects: Research Paper; blood brain barrier; microfluidic device; drug delivery; metastasis; permeability
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.19634

Drug 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. We characterized the permeability of I-trastuzumab in an , and fluorescent trastuzumab-Rhodamine123 (t-Rho123) in a novel microfluidic , BBB and BTB brain metastases of breast cancer model. : 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 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. Tissue distribution of I-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 I-trastuzumab localized . This heterogeneity was paralleled , 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 × 10 ) and BTB (1.29 ± 0.93 × 10 ) showed to be significantly greater than 0 (p < 0.05). The BTB devices showed significant heterogenetic tendencies, as seen in . This 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.