Treating glioblastoma multiforme with selective high-dose liposomal doxorubicin chemotherapy induced by repeated focused ultrasound

Int J Nanomedicine. 2012;7:965-74. doi: 10.2147/IJN.S29229. Epub 2012 Feb 21.

Abstract

Background: High-dose tissue-specific delivery of therapeutic agents would be a valuable clinical strategy. We have previously shown that repeated transcranial focused ultrasound is able to increase the delivery of Evans blue significantly into brain tissue. The present study shows that repeated pulsed high-intensity focused ultrasound (HIFU) can be used to deliver high-dose atherosclerotic plaque-specific peptide-1 (AP-1)-conjugated liposomes selectively to brain tumors.

Methods: Firefly luciferase (Fluc)-labeled human GBM8401 glioma cells were implanted into NOD-scid mice. AP-1-conjugated liposomal doxorubicin or liposomal doxorubicin alone was administered followed by pulsed HIFU and the doxorubicin concentration in the treated brains quantified by fluorometer. Growth of the labeled glioma cells was monitored through noninvasive bioluminescence imaging and finally the brain tissue was histologically examined after sacrifice.

Results: Compared with the control group, the animals treated with 5 mg/kg injections of AP-1 liposomal doxorubicin or untargeted liposomal doxorubicin followed by repeated pulsed HIFU not only showed significantly enhanced accumulation of drug at the sonicated tumor site but also a significantly elevated tumor-to-normal brain drug ratio (P < 0.001). Combining repeated pulsed HIFU with AP-1 liposomal doxorubicin or untargeted liposomal doxorubicin has similar antitumor effects.

Conclusion: This study demonstrates that targeted or untargeted liposomal doxorubicin, followed by repeated pulsed HIFU, is a promising high-dose chemotherapy method that allows the desired brain tumor region to be targeted specifically.

Keywords: blood-brain barrier; brain tumor; interleukin-4 receptor; repeated focused ultrasound; target drug delivery.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology*
  • Blood-Brain Barrier / metabolism
  • Brain Neoplasms / diagnostic imaging
  • Brain Neoplasms / drug therapy
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / therapy*
  • Combined Modality Therapy
  • Doxorubicin / pharmacokinetics
  • Doxorubicin / pharmacology*
  • Flow Cytometry
  • Glioblastoma / diagnostic imaging
  • Glioblastoma / drug therapy
  • Glioblastoma / metabolism
  • Glioblastoma / pathology
  • Glioblastoma / therapy*
  • Histocytochemistry
  • Humans
  • Liposomes / pharmacokinetics
  • Liposomes / pharmacology*
  • Luminescent Measurements
  • Magnetic Resonance Imaging
  • Male
  • Mice
  • Mice, SCID
  • Receptors, Interleukin-4 / metabolism
  • Sonication / methods
  • Ultrasonic Therapy / methods*
  • Ultrasonography
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Liposomes
  • Receptors, Interleukin-4
  • Doxorubicin