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

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.

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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

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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.

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Correspondence to Angel M. Carcaboso.

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Monterrubio, C., Paco, S., Vila-Ubach, M. et al. Combined Microdialysis-Tumor Homogenate Method for the Study of the Steady State Compartmental Distribution of a Hydrophobic Anticancer Drug in Patient-Derived Xenografts. Pharm Res 32, 2889–2900 (2015). https://doi.org/10.1007/s11095-015-1671-9

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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