Pharmacokinetic analysis of 111 in-labeled liposomal Doxorubicin in murine glioblastoma after blood-brain barrier disruption by focused ultrasound

PLoS One. 2012;7(9):e45468. doi: 10.1371/journal.pone.0045468. Epub 2012 Sep 18.

Abstract

The goal of this study was to evaluate the pharmacokinetics of targeted and untargeted (111)In-doxorubicin liposomes after these have been intravenously administrated to tumor-bearing mice in the presence of blood-brain barrier disruption (BBB-D) induced by focused ultrasound (FUS). An intracranial brain tumor model in NOD-scid mice using human brain glioblastoma multiforme (GBM) 8401 cells was developed in this study. (111)In-labeled human atherosclerotic plaque-specific peptide-1 (AP-1)-conjugated liposomes containing doxorubicin (Lipo-Dox; AP-1 Lipo-Dox) were used as a microSPECT probe for radioactivity measurements in the GBM-bearing mice. Compared to the control tumors treated with an injection of (111)In-AP-1 Lipo-Dox or (111)In-Lipo-Dox, the animals receiving the drugs followed by FUS exhibited enhanced accumulation of the drug in the brain tumors (p<0.05). Combining sonication with drugs significantly increased the tumor-to-normal brain doxorubicin ratio of the target tumors compared to the control tumors. The tumor-to-normal brain ratio was highest after the injection of (111)In-AP-1 Lipo-Dox with sonication. The (111)In-liposomes micro-SPECT/CT should be able to provide important information about the optimum therapeutic window for the chemotherapy of brain tumors using sonication.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood-Brain Barrier / metabolism*
  • Blood-Brain Barrier / pathology
  • Brain / metabolism
  • Brain / pathology
  • Brain Neoplasms / diagnosis
  • Brain Neoplasms / drug therapy
  • Brain Neoplasms / metabolism*
  • Cell Line, Tumor
  • Doxorubicin / administration & dosage
  • Doxorubicin / adverse effects
  • Doxorubicin / pharmacokinetics*
  • Glioblastoma / diagnosis
  • Glioblastoma / drug therapy
  • Glioblastoma / metabolism*
  • Humans
  • Indium Radioisotopes
  • Male
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Multimodal Imaging
  • Positron-Emission Tomography
  • Sonication*
  • Tomography, X-Ray Computed
  • Xenograft Model Antitumor Assays

Substances

  • Indium Radioisotopes
  • Doxorubicin

Grant support

This study was supported by grants from the National Science Council of Taiwan (no. NSC 100-2321-B-010-010 and NSC 99-2321-B-010-017), Department of Health of Taiwan (DOH101-TD-PB-111-TM012 and DOH101-TD-C-111-007), Veterans General Hospitals University System of Taiwan Joint Research Program (#VGHUST100-G1-3-3), Yen Tjing Ling Medical Foundation (grant CI-100-17), and Cheng Hsin General Hospital Foundation (no. 100F117CY25). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.