title: Targeting microbubbles-carrying TGFβ1 inhibitor combined with ultrasound sonication induce BBB/BTB disruption to enhance nanomedicine treatment for brain tumors.
abstract: The clinical application of chemotherapy for brain cancer tumors remains a challenge due to difficulties in the transport of therapeutic agents across the blood-brain barrier/blood-tumor barrier (BBB/BTB). In this study, we developed des-octanoyl ghrelin-conjugated microbubbles (GMB) loaded with TGFβ1 inhibitor (LY364947) (GMBL) to induce BBB/BTB disruption for ultrasound (US) sonication with GMBL. The in-vitro stability study showed that GMB was pretty stable over one month. The in-vivo study showed that the accumulation of superparamagnetic iron oxide nanoparticles (SPION) in the sonicated tumor was significantly higher for focused US sonication in the presence of GMBL, indicating that GMBL/US can locally disrupt BBB/BTB to promote vascular permeability of nanoparticles. In addition, the combination of folate-conjugated polymersomal doxorubicin (FPD) and GMBL/US (FPD+GMBL/US) achieved the best anti-glioma effect and significant improvement in the overall survival time for brain tumor-bearing mice. When combined with focused US, GMBL facilitated local BBB/BTB disruption and simultaneously released LY364947 to decrease the pericyte coverage of the endothelium at the targeted brain tumor sites, resulting in enhanced accumulation and antitumor activity of FPD. The overall results indicate that GMBL/US owns a great potential for non-invasive targeting delivery of nanomedicine across the BBB to treat central nervous system (CNS) diseases.
authors.affiliation: Institute of Biomedical Engineering, College of Medicine and College of Engineering, National Taiwan University, Taipei, Taiwan; Biomedical Technology and Device Research Labs, Industrial Technology Research Institute, Hsinchu, Taiwan.
authors.forename: Yung-Chu
authors.initials: YC
authors.lastname: Chen
authors.affiliation: Institute of Biomedical Engineering, College of Medicine and College of Engineering, National Taiwan University, Taipei, Taiwan.
authors.forename: Chi-Feng
authors.initials: CF
authors.lastname: Chiang
authors.affiliation: Institute of Biomedical Engineering, College of Medicine and College of Engineering, National Taiwan University, Taipei, Taiwan.
authors.forename: Sheng-Kai
authors.initials: SK
authors.lastname: Wu
authors.affiliation: Divison of Neurosurgery, Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Li-Fang
authors.initials: LF
authors.lastname: Chen
authors.affiliation: Biomedical Technology and Device Research Labs, Industrial Technology Research Institute, Hsinchu, Taiwan. Electronic address: hsiehw@itri.org.tw.
authors.forename: Wen-Yuan
authors.initials: WY
authors.lastname: Hsieh
authors.affiliation: Institute of Biomedical Engineering, College of Medicine and College of Engineering, National Taiwan University, Taipei, Taiwan; Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Miaoli, Taiwan. Electronic address: winli@ntu.edu.tw.
authors.forename: Win-Li
authors.initials: WL
authors.lastname: Lin
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D001932:Brain Neoplasms / Q000378:metabolism / Q000628:therapy*; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology; D016503:Drug Delivery Systems / Q000379:methods; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D016513:Mice, SCID; D045423:Microbubbles; D050997:Nanomedicine / Q000379:methods*; D011720:Pyrazoles / Q000008:administration & dosage; D011758:Pyrroles / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D013010:Sonication / Q000379:methods*; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011804:Quinolines
chemical_list: D011720:Pyrazoles; D011758:Pyrroles; D053773:Transforming Growth Factor beta1; C506615:HTS 466284; D011804:Quinolines; C508961:Tgfb1 protein, mouse
keywords: Blood–brain/blood–tumor barrier (BBB/BTB); Des-octanoyl ghrelin; Folate; Microbubbles; TGFβ1 inhibitor; Targeted delivery; Ultrasound