Authors: Monterrubio, Carles; Paco, Sonia; Vila Ubach, Mónica; Rodríguez, Eva; Glisoni, Romina Julieta; Lavarino, Cinzia; Schaiquevich, Paula Susana; Sosnik, Alejandro; Mora, Jaume; Carcaboso, Ángel M.
Publication Date: 2014.
Language: English.
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.
Author affiliation: Monterrubio, Carles. Hospital Sant Joan de Déu Barcelona; España. Fundació Sant Joan de Déu; España
Author affiliation: Paco, Sonia. Hospital Sant Joan de Déu Barcelona; España. Fundació Sant Joan de Déu; España
Author affiliation: Vila Ubach, Mónica. Hospital Sant Joan de Déu Barcelona; España. Fundació Sant Joan de Déu; España
Author affiliation: Rodríguez, Eva. Hospital Sant Joan de Déu Barcelona; España. Fundació Sant Joan de Déu; España
Author affiliation: Glisoni, Romina Julieta. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Tecnología Farmacéutica; Argentina
Author affiliation: Lavarino, Cinzia. Technion - Israel Institute of Technology; Israel
Author affiliation: Schaiquevich, Paula Susana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría ; Argentina
Author affiliation: Sosnik, Alejandro. Hospital Sant Joan de Déu Barcelona; España. Fundació Sant Joan de Déu; España
Author affiliation: Mora, Jaume. Hospital Sant Joan de Déu Barcelona; España. Fundació Sant Joan de Déu; España
Author affiliation: Carcaboso, Ángel M.. Hospital Sant Joan de Déu Barcelona; España. Fundació Sant Joan de Déu; España
Keywords: microdialysis; oncology; Drug distribution; Drug penetration; Hydrophobic anticancer drugs; Microdialysis; Neuroblastoma; Patient-derived xenograft (PDX); SN-38; Solid tumor; Steady state; Tumor homogenate; Tumor microenvironment; Inmunología; Medicina Básica; CIENCIAS MÉDICAS Y DE LA SALUD.
Repository: CONICET Digital (CONICET). Consejo Nacional de Investigaciones Científicas y Técnicas