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Pharmaceutical Research

, Volume 32, Issue 9, pp 2889–2900 | Cite as

Combined Microdialysis-Tumor Homogenate Method for the Study of the Steady State Compartmental Distribution of a Hydrophobic Anticancer Drug in Patient-Derived Xenografts

  • Carles Monterrubio
  • Sonia Paco
  • Monica Vila-Ubach
  • Eva Rodríguez
  • Romina Glisoni
  • Cinzia Lavarino
  • Paula Schaiquevich
  • Alejandro Sosnik
  • Jaume Mora
  • Angel M. CarcabosoEmail author
Research Paper

Abstract

Purpose

To develop a reproducible microdialysis-tumor homogenate method for the study of the intratumor distribution of a highly hydrophobic anticancer drug (SN-38; 7-ethyl-10-hydroxycamptothecin) in neuroblastoma patient-derived xenografts.

Methods

We studied the nonspecific binding of SN-38 to the microdialysis tubing in the presence of 2-hydroxypropyl-beta-cyclodextrin (HPBCD) in the perfusate. We calibrated the microdialysis probes by the zero flow rate (ZFR) method and calculated the enhancement factor (f = extrapolated SN-38 concentration at the ZFR / SN-38 concentration in the dialysed solution) of HPBCD. We characterized the extravasation of HPBCD to tumors engrafted in mice. In vivo microdialysis and terminal homogenate data at the steady state (subcutaneous pump infusions) were used to calculate the volume of distribution of unbound SN-38 (Vu,tumor) in neuroblastoma.

Results

HPBCD (10% w/v) in the perfusate prevented the nonspecific binding of SN-38 to the microdialysis probe and enhanced SN-38 recovery (f = 1.86). The extravasation of HPBCD in the tumor during microdialysis was lower than 1%. Vu,tumor values were above 3 mL/g tumor for both neuroblastoma models and suggested efficient cellular penetration of SN-38.

Conclusions

The method contributes to overcome the limitations of the microdialysis technique in hydrophobic drugs and provides a powerful tool to characterize compartmental anticancer drug distribution in xenografts.

KEY WORDS

drug distribution drug penetration hydrophobic anticancer drugs microdialysis neuroblastoma patient-derived xenograft (PDX) SN-38 solid tumor steady state tumor homogenate tumor microenvironment 

ABBREVIATIONS

ECF

Extracellular fluid

ER

Enhanced recovery

f

Enhancement factor

FEP

Fluorinated ethylene propylene

HPBCD

2-hydroxypropyl-beta-cyclodextrin

PDX

Patient-derived xenograft

RR

Relative recovery

SN-38 C

SN-38 Carboxylate

SN-38 L

SN-38 Lactone

tECF

Tumor extracellular fluid

ZFR

Zero flow rate

Notes

Acknowledgments

AMC acknowledges funding from the AECC Scientific Foundation, MINECO (SAF2011-22660), Fundacion BBVA, European Union Seventh Framework Programme (FP7/2007-2013) under Marie Curie International Reintegration Grant (PIRG-08-GA-2010-276998) and ISCIII-FEDER (CP13/00189). AS thanks the European Union's - Seventh Framework Programme under grant agreement #612675-MC-NANOTAR. Work supported by the Xarxa de Bancs de Tumors de Catalunya (XBTC) sponsored by Pla Director d’Oncologia de Catalunya. We thank Dr. Mireia Camos for performing erythrocyte counts.

Supplementary material

11095_2015_1671_MOESM1_ESM.docx (18 kb)
ESM 1 (DOCX 18 kb)

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Carles Monterrubio
    • 1
    • 2
  • Sonia Paco
    • 1
    • 2
  • Monica Vila-Ubach
    • 1
    • 2
  • Eva Rodríguez
    • 1
    • 2
  • Romina Glisoni
    • 3
  • Cinzia Lavarino
    • 1
    • 2
  • Paula Schaiquevich
    • 4
  • Alejandro Sosnik
    • 5
  • Jaume Mora
    • 1
    • 2
  • Angel M. Carcaboso
    • 1
    • 2
    Email author
  1. 1.Department of Pediatric Hematology and OncologyHospital Sant Joan de Déu BarcelonaEsplugues de LlobregatSpain
  2. 2.Preclinical Therapeutics and Drug Delivery Research Program, Developmental Tumor Biology LaboratoryFundació Sant Joan de DéuEsplugues de LlobregatSpain
  3. 3.CONICET-Department of Pharmaceutical Technology, Faculty of Pharmacy and BiochemistryUniversidad de Buenos AiresBuenos AiresArgentina
  4. 4.CONICET-Clinical Pharmacokinetics UnitHospital de Pediatria JP GarrahanBuenos AiresArgentina
  5. 5.Department of Materials Science and EngineeringTechnion-Israel Institute of TechnologyHaifaIsrael

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