Combined Microdialysis-Tumor Homogenate Method for the Study of the Steady State Compartmental Distribution of a Hydrophobic Anticancer Drug in Patient-Derived Xenografts
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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.
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.
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.
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 WORDSdrug distribution drug penetration hydrophobic anticancer drugs microdialysis neuroblastoma patient-derived xenograft (PDX) SN-38 solid tumor steady state tumor homogenate tumor microenvironment
Fluorinated ethylene propylene
- SN-38 C
- SN-38 L
Tumor extracellular fluid
Zero flow rate
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.
- 7.Tuntland T, Ethell B, Kosaka T, Blasco F, Zang RX, Jain M, et al. Implementation of pharmacokinetic and pharmacodynamic strategies in early research phases of drug discovery and development at Novartis Institute of Biomedical Research. Front Pharmacol. 2014;5:174.PubMedCentralPubMedCrossRefGoogle Scholar
- 13.Lindberger M, Tomson T, Lars S. Microdialysis sampling of carbamazepine, phenytoin and phenobarbital in subcutaneous extracellular fluid and subdural cerebrospinal fluid in humans: an in vitro and in vivo study of adsorption to the sampling device. Pharmacol Toxicol. 2002;91(4):158–65.PubMedCrossRefGoogle Scholar
- 24.D'argenio DZ, Schumitzky A. ADAPT 5 User’s guide: pharmacokinetic/ pharmacodynamic systems analysis software. Los Angeles: Biomedical Simulations Resource; 2009.Google Scholar