Pharmaceutical Research

, Volume 33, Issue 12, pp 2904–2919 | Cite as

Vinorelbine Delivery and Efficacy in the MDA-MB-231BR Preclinical Model of Brain Metastases of Breast Cancer

  • Ramakrishna Samala
  • Helen R. Thorsheim
  • Satyanarayana Goda
  • Kunal Taskar
  • Brunilde Gril
  • Patricia S. Steeg
  • Quentin R. SmithEmail author
Research Paper



To evaluate vinorelbine drug exposure and activity in brain metastases of the human MDA-MB-231BR breast cancer model using integrated imaging and analysis.


Brain and systemic metastases were created by administration of cancer cells in female NuNu mice. After metastases developed, animals were administered vinorelbine at the maximal tolerated dose (12 mg/kg), and were evaluated thereafter for total and unbound drug pharmacokinetics, biomarker TUNEL staining, and barrier permeability to Texas red.


Median brain metastasis drug exposure was 4-fold greater than normal brain, yet only ~8% of non-barrier systemic metastases, which suggests restricted brain exposure. Unbound vinorelbine tissue/plasma partition coefficient, Kp,uu, equaled ~1.0 in systemic metastases, but 0.03–0.22 in brain metastases, documenting restricted equilibration. In select sub-regions of highest drug-uptake brain metastases, Kp,uu approached 1.0, indicating complete focal barrier breakdown. Most vinorelbine-treated brain metastases exhibited little or no positive early apoptosis TUNEL staining in vivo. The in vivo unbound vinorelbine IC50 for TUNEL-positive staining (56 nM) was 4-fold higher than that measured in vitro (14 nM). Consistent with this finding, P-glycoprotein expression was observed to be substantially upregulated in brain metastasis cells in vivo.


Vinorelbine exposure at maximum tolerated dose was less than one-tenth that in systemic metastases in >70% of brain metastases, and was associated with negligible biomarker effect. In small subregions of the highest uptake brain metastases, compromise of blood-tumor barrier appeared complete. The results suggest that restricted delivery accounts for 80% of the compromise in drug efficacy for vinorelbine against this model.


blood–brain barrier brain metastases breast cancer permeability vinorelbine 



Area under the curve


Brain adjacent to tumor


Blood–brain barrier


Blood-tumor barrier


Central nervous system


Unbound fraction


Unbound fraction in diluted homogenate


Integrated total drug partition coefficient between tissue and plasma


Integrated unbound drug partition coefficient between tissue and plasma




P-glycoprotein (ABCB1)





This work was supported by grants from the Department of Defense Breast Cancer Program (W81XWH-06-2-0033) and the Cancer Prevention Research Institute of Texas (RP120489 and RP110786)

Supplementary material

11095_2016_2012_MOESM1_ESM.pdf (411 kb)
ESM 1 (PDF 411 kb)


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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Ramakrishna Samala
    • 1
  • Helen R. Thorsheim
    • 1
  • Satyanarayana Goda
    • 1
    • 2
  • Kunal Taskar
    • 1
    • 3
  • Brunilde Gril
    • 4
  • Patricia S. Steeg
    • 4
  • Quentin R. Smith
    • 1
    Email author
  1. 1.Department of Pharmaceutical Sciences, School of PharmacyTexas Tech University Health Sciences CenterAmarilloUSA
  2. 2.Formurex, Inc.StocktonUSA
  3. 3.Mechanistic Safety and DispositionIVIVT, GlaxoSmithKlineWareUK
  4. 4.Women’s Malignancies Branch, Center for Cancer ResearchNational Cancer InstituteBethesdaUSA

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