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Old 08-05-2017, 07:24 PM   #1
Lani
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Join Date: Mar 2006
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for those with her2+ brain mets

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Oncotarget. 2017 Jul 26. doi: 10.18632/oncotarget.19634. [Epub ahead of print]
Trastuzumab distribution in an in-vivo and in-vitro model of brain metastases of breast cancer.
Terrell-Hall TB1, Nounou MI2,3, El-Amrawy F2, Griffith JIG1, Lockman PR1.
Author information

1
Department of Basic Pharmaceutical Sciences, School of Pharmacy, West Virginia University HSC, Morgantown, West Virginia 26506, USA.
2
Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt.
3
Department of Pharmaceutical Sciences, School of Pharmacy, University of Saint Joseph (USJ), Hartford, Connecticut, 06103, USA.
Abstract
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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