Abstract
// Ying-Zheng Zhao 1, 2, 3 , Li-Juan Chen 4 , Qian Lin 1 , Jun Cai 5 , Wen-Ze Yu 1 , Ya-Ping Zhao 2 , Chong-Yong Xu 2 , Kai-Li Mao 1 , Fu-Rong Tian 1 , Wen-Feng Li 6 , Ho Lun Wong 7 , Cui-Tao Lu 1, 2 1 College of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang Province 325035, China 2 The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province 325000, China 3 Hainan Medical College, Haikou City, Hainan Province 570102, China 4 Dispensary of Traditional Chinese Medicine, Wenzhou Central Hospital, Wenzhou, Zhejiang Province 325000, China 5 Departments of Pediatrics and Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, Kentucky 40202, USA 6 The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province 325000, China 7 School of Pharmacy, Temple University, Philadelphia, Pennsylvania 19140, USA Correspondence to: Ho Lun Wong, e-mail: ho-lun.wong@temple.edu Cui-Tao Lu, e-mail: lctuua@sina.com Keywords: chemotherapy, focused ultrasound, nanotechonology, BBB opening, glioma Received: July 09, 2015 Accepted: August 20, 2015 Published: September 02, 2015 ABSTRACT Purpose: Blood-brain barrier and blood-tumor barrier (BBB/BTB) are the main limitations for chemotherapeutics in glioma therapy. Focused ultrasound (FUS) combined novel Doxorubicin-loaded liposomes (LIP-DOX) was applied to open the BBB/BTB and improve the efficiency of glioma-targeted chemotherapy. Experimental designs: Particle size, Zeta potential and drug encapsulation efficiency were evaluated. C6 glioma model rats were established to evaluate the BBB/BTB disruption and the glioma inhibition in vivo . With Evans Blue (EB) as the model, the permeability of BBB/BTB was evaluated. The glioma inhibition of FUS+LIP-DOX was investigated by magnetic resonance images (MRI) and confocal laser microscope. The activities of β1-intergrin and claudin-5 proteins in response to FUS-mediated BBB/BTB opening were explored. Results: LIP-DOX has suitable nanoscale size and good polydispersity index. From EB extravasation experiment, FUS increased the BBB/BTB penetration and accumulation of EB in the glioma. LIP-DOX combined with FUS could efficiently enhance DOX penetrate into the model rat brains, realizing strong glioma inhibition in vivo . Among DOX-administrated groups, FUS+LIP-DOX group showed the beat inhibition on glioma. FUS+LIP-DOX group reduced the tumor progression ratio from 1.18 to −0.20, extending the median survival from 23d to 57.5d. β1-intergrin and claudin-5 were significantly decreased after FUS treatment, which explained the molecular mechanisms of BBB-opening by FUS. Conclusions: Glioma-targeted inhibition can be realized by using FUS induced BBB/BTB-opening technique combined with LIP-DOX. This combined technology will be developed as a potential strategy for glioma-targeted therapy.
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