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Brain tumor-targeted delivery and therapy by focused ultrasound introduced doxorubicin-loaded cationic liposomes

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Abstract

Brain tumor lacks effective delivery system for treatment. Focused ultrasound (FUS) can reversibly open BBB without impacts on normal tissues. As a potential drug carrier, cationic liposomes (CLs) have the ability to passively accumulate in tumor tissues for their positive charge. In this study, FUS introduced doxorubicin-loaded cationic liposomes (DOX-CLs) were applied to improve the efficiency of glioma-targeted delivery. Doxorubicin-loaded CLs (DOX-CLs) and quantum dot-loaded cationic liposomes (QD-CLs) were prepared using extrusion technology, and their characterizations were evaluated. With the advantage of QDs in tracing images, the glioma-targeted accumulation of FUS + CLs was evaluated by fluorescence imaging and flow cytometer. Cell survival rate, tumor volume, animal survival time, and brain histology in C6 glioma model were investigated to evaluate the glioma-targeted delivery of FUS + DOX-CLs. DOX-CLs and QD-CLs had suitable nanoscale sizes and high entrapment efficiency. The combined strategy of FUS introduced CLs significantly increased the glioma-targeted accumulation for load drugs. FUS + DOX-CLs showed the strongest inhibition on glioma based on glioma cell in vitro and glioma model in vivo experiments. From MRI and histological analysis, FUS + DOX-CLs group strongly suppressed the glioma progression and extended the animal survival time to 81.2 days. Among all the DOX treatment groups, FUS + DOX-CLs group showed the best cell viability and highest level of tumor apoptosis and necrosis. Combining the advantages of BBB reversible opening by FUS and glioma-targeted binding by CLs, ultrasound introduced cationic liposomes could achieve glioma-targeted delivery, which might be developed as a potential strategy for future brain tumor therapy.

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Abbreviations

DOX:

Doxorubicin

CLs:

Cationic liposomes

FUS:

Focused ultrasound

MRI:

Magnetic resonance images

DOX-CLs:

Doxorubicin-loaded cationic liposomes

QD:

Quantum dots

QD-CLs:

QD-loaded cationic liposomes

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Acknowledgments

This research was supported by the National Natural Science Foundation of China (Grant Nos. 81360195, 81301982, 81571392, and 81272160), Zhejiang Provincial Natural Science Foundation of China (Grant No. LY12H31003), Zhejiang Provincial Foundation for Health Department (Grant No. 2015ZDA023), Medicine Grant from Wenzhou Bureau of Science and Technology (Grant Nos. Y2014730 and Y20140726). Major Scientific Project of Guangdong Province(Grant No. 2012A080201010). Science and Technology Program of Guangzhou, China (201508020001).

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Author notes

  1. Ying-Zheng Zhao

    Present address: College of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang Province, China

  2. Cui-Tao Lu

    Present address: The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang Province, China

Authors and Affiliations

  1. College of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang Province, China

    Qian Lin, Kai-Li Mao, Fu-Rong Tian, Jing-Jing Yang, Pian-Pian Chen, Jie Xu, Zi-Liang Fan & Cui-Tao Lu

  2. The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang Province, China

    Qian Lin & Ya-Ping Zhao

  3. The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang Province, China

    Wen-Feng Li & Lei Zheng

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Electronic supplementary material

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280_2015_2926_MOESM1_ESM.tif

Fig. S1 Kaplan–Meier survival curves for the animals in different experimental groups. Supplementary material 1 (TIFF 20 kb)

280_2015_2926_MOESM2_ESM.tif

Fig. S2 TUNEL staining analysis for different experimental groups. *P < 0.05 and **P < 0.01 versus control group. Supplementary material 2 (TIFF 20 kb)

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Lin, Q., Mao, KL., Tian, FR. et al. Brain tumor-targeted delivery and therapy by focused ultrasound introduced doxorubicin-loaded cationic liposomes. Cancer Chemother Pharmacol 77, 269–280 (2016). https://doi.org/10.1007/s00280-015-2926-1

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  • DOI: https://doi.org/10.1007/s00280-015-2926-1

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