Pharmacokinetic Analysis of 111In-Labeled Liposomal Doxorubicin in Murine Glioblastoma after Blood-Brain Barrier Disruption by Focused Ultrasound

Feng-Yi Yang,Ming-Che Teng,Ming-Cheng Wei,Ren-Shyan Liu,Maggie Lu,Tai-Tong Wong,Hsin-Ell Wang,Jia-Je Li,Dominique Heymann

doi:10.1371/journal.pone.0045468

Abstract

The goal of this study was to evaluate the pharmacokinetics of targeted and untargeted 111In-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. 111In-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 111In-AP-1 Lipo-Dox or 111In-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 111In-AP-1 Lipo-Dox with sonication. The 111In-liposomes micro-SPECT/CT should be able to provide important information about the optimum therapeutic window for the chemotherapy of brain tumors using sonication.

Highlights

Malignant brain tumors remain difficult to treat using chemotherapy because the blood-tumor barrier (BTB) limits the amount of potent agents that can be delivered to the tumor; the result is that the drug is usually unable to reach a therapeutic level
blood–brain barrier (BBB) disruption in the left sonicated tumor can be clearly seen in terms of uptake of 111In-Lipo-Dox or 111In-atherosclerotic plaque-specific peptide-1 (AP-1) Lipo-Dox at 48 hr after administration
The histology images (Fig. 3) showed that at 12 days after implantation there was local displacement and widening of intercellular gaps in the tumor tissues treated with AP1 Lipo-Dox followed by sonication relative to the control tumors or tumors treated with AP-1 Lipo-Dox alone

Summary

Introduction

Malignant brain tumors remain difficult to treat using chemotherapy because the blood-tumor barrier (BTB) limits the amount of potent agents that can be delivered to the tumor; the result is that the drug is usually unable to reach a therapeutic level. Liposomes are polymeric nanoparticles that consist of phospholipid bilayer structure and can be used to effectively encapsulate chemotherapeutic agents. Long-circulating liposomes were found to accumulate in tumor by enhanced permeability and retention (EPR) effect. They are delivered mainly to the regions of interest and the above properties enhance the therapeutic effectiveness of a given drug [3,4,5]. Compared to conventional liposome formulations, the PEGylated liposomal formulation of doxorubicin produces a marked improvement in antitumor effects, enhances cancer cell targeting and improves treatment efficacy [8,9]

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