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Liposomal Irinotecan Accumulates in Metastatic Lesions, Crosses the Blood-Tumor Barrier (BTB), and Prolongs Survival in an Experimental Model of Brain Metastases of Triple Negative Breast Cancer.
Mohammad, Afroz S; Griffith, Jessica I; Adkins, Chris E; Shah, Neal; Sechrest, Emily; Dolan, Emma L; Terrell-Hall, Tori B; Hendriks, Bart S; Lee, Helen; Lockman, Paul R.
Afiliación
  • Mohammad AS; School of Pharmacy, Department of Pharmaceutical Sciences, West Virginia University Health Sciences Center, 1 Medical Center Drive, Morgantown, West Virginia, 26506-9050, USA.
  • Griffith JI; School of Pharmacy, Department of Pharmaceutical Sciences, West Virginia University Health Sciences Center, 1 Medical Center Drive, Morgantown, West Virginia, 26506-9050, USA.
  • Adkins CE; School of Pharmacy, Department of Pharmaceutical Sciences, West Virginia University Health Sciences Center, 1 Medical Center Drive, Morgantown, West Virginia, 26506-9050, USA.
  • Shah N; School of Pharmacy, Department of Pharmaceutical Sciences, West Virginia University Health Sciences Center, 1 Medical Center Drive, Morgantown, West Virginia, 26506-9050, USA.
  • Sechrest E; School of Pharmacy, Department of Pharmaceutical Sciences, West Virginia University Health Sciences Center, 1 Medical Center Drive, Morgantown, West Virginia, 26506-9050, USA.
  • Dolan EL; School of Pharmacy, Department of Pharmaceutical Sciences, West Virginia University Health Sciences Center, 1 Medical Center Drive, Morgantown, West Virginia, 26506-9050, USA.
  • Terrell-Hall TB; School of Pharmacy, Department of Pharmaceutical Sciences, West Virginia University Health Sciences Center, 1 Medical Center Drive, Morgantown, West Virginia, 26506-9050, USA.
  • Hendriks BS; Merrimack Pharmaceuticals, Cambridge, Massachusetts, 02139, USA.
  • Lee H; Merrimack Pharmaceuticals, Cambridge, Massachusetts, 02139, USA.
  • Lockman PR; School of Pharmacy, Department of Pharmaceutical Sciences, West Virginia University Health Sciences Center, 1 Medical Center Drive, Morgantown, West Virginia, 26506-9050, USA. prlockman@hsc.wvu.edu.
Pharm Res ; 35(2): 31, 2018 Jan 09.
Article en En | MEDLINE | ID: mdl-29368289
PURPOSE: The blood-tumor barrier (BTB) limits irinotecan distribution in tumors of the central nervous system. However, given that the BTB has increased passive permeability we hypothesize that liposomal irinotecan would improve local exposure of irinotecan and its active metabolite SN-38 in brain metastases relative to conventional irinotecan due to enhanced-permeation and retention (EPR) effect. METHODS: Female nude mice were intracardially or intracranially implanted with human brain seeking breast cancer cells (brain metastases of breast cancer model). Mice were administered vehicle, non-liposomal irinotecan (50 mg/kg), liposomal irinotecan (10 mg/kg and 50 mg/kg) intravenously starting on day 21. Drug accumulation, tumor burden, and survival were evaluated. RESULTS: Liposomal irinotecan showed prolonged plasma drug exposure with mean residence time (MRT) of 17.7 ± 3.8 h for SN-38, whereas MRT was 3.67 ± 1.2 for non-liposomal irinotecan. Further, liposomal irinotecan accumulated in metastatic lesions and demonstrated prolonged exposure of SN-38 compared to non-liposomal irinotecan. Liposomal irinotecan achieved AUC values of 6883 ± 4149 ng-h/g for SN-38, whereas non-liposomal irinotecan showed significantly lower AUC values of 982 ± 256 ng-h/g for SN-38. Median survival for liposomal irinotecan was 50 days, increased from 37 days (p<0.05) for vehicle. CONCLUSIONS: Liposomal irinotecan accumulates in brain metastases, acts as depot for sustained release of irinotecan and SN-38, which results in prolonged survival in preclinical model of breast cancer brain metastasis.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Encéfalo / Neoplasias Encefálicas / Inhibidores de Topoisomerasa I / Neoplasias de la Mama Triple Negativas / Irinotecán Límite: Animals / Female / Humans Idioma: En Revista: Pharm Res Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Encéfalo / Neoplasias Encefálicas / Inhibidores de Topoisomerasa I / Neoplasias de la Mama Triple Negativas / Irinotecán Límite: Animals / Female / Humans Idioma: En Revista: Pharm Res Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos