title: Combined Microdialysis-Tumor Homogenate Method for the Study of the Steady State Compartmental Distribution of a Hydrophobic Anticancer Drug in Patient-Derived Xenografts.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Pediatric Hematology and Oncology, Hospital Sant Joan de Déu Barcelona, Esplugues de Llobregat, Spain.
authors.forename: Carles
authors.initials: C
authors.lastname: Monterrubio
authors.forename: Sonia
authors.initials: S
authors.lastname: Paco
authors.forename: Monica
authors.initials: M
authors.lastname: Vila-Ubach
authors.forename: Eva
authors.initials: E
authors.lastname: Rodríguez
authors.forename: Romina
authors.initials: R
authors.lastname: Glisoni
authors.forename: Cinzia
authors.initials: C
authors.lastname: Lavarino
authors.forename: Paula
authors.initials: P
authors.lastname: Schaiquevich
authors.forename: Alejandro
authors.initials: A
authors.lastname: Sosnik
authors.forename: Jaume
authors.initials: J
authors.lastname: Mora
authors.forename: Angel M
authors.initials: AM
authors.lastname: Carcaboso
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology; D002166:Camptothecin / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D064593:Heterografts / Q000378:metabolism*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D000077146:Irinotecan; D051379:Mice; D008819:Mice, Nude; D017551:Microdialysis / Q000379:methods; D009447:Neuroblastoma / Q000188:drug therapy / Q000378:metabolism*; D047392:beta-Cyclodextrins / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000077146:Irinotecan; D002166:Camptothecin