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

PLOS ONE, Dec 2019

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.

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

et al. (2012) Pharmacokinetic Analysis of 111In-Labeled Liposomal Doxorubicin in Murine Glioblastoma after Blood-Brain Barrier Disruption by Focused Ultrasound. PLoS ONE 7(9): e45468. doi:10.1371/journal.pone.0045468 111 Pharmacokinetic Analysis of In-Labeled Liposomal Doxorubicin in Murine Glioblastoma after Blood-Brain Barrier Disruption by Focused Ultrasound Feng-Yi Yang 0 Hsin-Ell Wang 0 Ren-Shyan Liu 0 Ming-Che Teng 0 Jia-Je Li 0 Maggie Lu 0 Ming- 0 . Cheng Wei 0 Tai-Tong Wong 0 Dominique Heymann, Faculte de medecine de Nantes, France 0 1 Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University , Taipei, Taiwan , 2 Department of Nuclear Medicine, National Yang-Ming University Medical School, Taipei Veterans General Hospital , Taipei, Taiwan , 3 Drug Delivery Lab, Biomedical Technology and Device Research Laboratories, Industrial Technology Research Institute, HsinChu, Taiwan, 4 Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital , Taipei , Taiwan 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 (BBBD) 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 111InAP-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. - Funding: 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. Competing Interests: The authors have declared that no competing interests exist. . These authors contributed equally to this work. 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. Despite the fact that the BTB is in itself more permeable than the bloodbrain barrier (BBB), therapeutics are rarely effective in patients with brain tumors because the selective permeability of the BTB still blocks many antitumor agents and stops them approaching their target [1]. Glioblastoma multiforme (GBM) is one of the most common forms of glioma and is hard to treat completely by surgical resection due to the diffuse nature of the glioma. As a result, residual microscopic tumor cells usually need to be eliminated by additional chemotherapy or radiotherapy [2]. Liposomes are polymeric nanoparticles that consist of phospholipid bilayer structure and can be used to effectively encapsulate chemotherapeutic agents. These encapsulated agents exhibit improved pharmacokinetics, better biodistribution, and lower tissue toxicity. 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]. One negative aspect of traditional liposomes is that they are easily taken up by reticuloendothelial system (RES). Polyethylene glycol (PEG) conjugated liposomes were developed to evade this rapid clearance by the RES and allow long-term circulation of the liposomal drugs in order to prolong the period of treatment [6,7]. 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]. It has been reported that human brain tumor cell lines overexpress (...truncated)


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Feng-Yi Yang, Hsin-Ell Wang, Ren-Shyan Liu, Ming-Che Teng, Jia-Je Li, Maggie Lu, Ming-Cheng Wei, Tai-Tong Wong. Pharmacokinetic Analysis of 111In-Labeled Liposomal Doxorubicin in Murine Glioblastoma after Blood-Brain Barrier Disruption by Focused Ultrasound, PLOS ONE, 2012, Volume 7, Issue 9, DOI: 10.1371/journal.pone.0045468