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

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:

• repeated focused ultrasound
• interleukin-4 receptor
• blood-brain barrier
• brain tumor
• target drug delivery

Acknowledgments

This study was supported by grants from the National Science Council of Taiwan (100-2321-B-010-010 and 99-- 2321-B-010-017), Cheng Hsin General Hospital Foundation (100F117CY25), Veterans General Hospital University System of Taiwan Joint Research Program (VGHUST100-G1-3-3 and V100E6-007), Yen Tjing Ling Medical Foundation (CI-100-17), and Department of Health of Taiwan (DOH101- TD-PB-111-TM012 and DOH101-TD-C-111-007).

Disclosure

The authors report no conflicts of interest in this work.