Trastuzumab distribution in an in-vivo and in-vitro model of brain metastases of breast cancer
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Tori B. Terrell-Hall1, Mohamed Ismail Nounou2,3, Fatema El-Amrawy2, Jessica I.G. Griffith1 and Paul R. Lockman1
1Department of Basic Pharmaceutical Sciences, School of Pharmacy, West Virginia University HSC, Morgantown, West Virginia 26506, USA
2Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt
3Department of Pharmaceutical Sciences, School of Pharmacy, University of Saint Joseph (USJ), Hartford, Connecticut 06103, USA
Paul R. Lockman, email: firstname.lastname@example.org
Keywords: drug delivery, metastasis, microfluidic device, blood brain barrier, permeability
Received: March 15, 2017 Accepted: July 03, 2017 Published: July 26, 2017
Background: 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.
Methods: We 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.
Results: Tissue 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 X 104) and BTB (1.29 ± 0.93 X 104) showed to be significantly greater than 0 (p < 0.05). The BTB devices showed significant heterogenetic tendencies, as seen in in-vivo.
Conclusions: 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.
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