title: Methotrexate-loaded PLGA nanobubbles for ultrasound imaging and Synergistic Targeted therapy of residual tumor during HIFU ablation.
abstract: High intensity focused ultrasound (HIFU) has attracted the great attention in tumor ablation due to its non-invasive, efficient and economic features. However, HIFU ablation has its intrinsic limitations for removing the residual tumor cells, thus the tumor recurrence and metastasis cannot be avoided in this case. Herein, we developed a multifunctional targeted poly(lactic-co-glycolic acid) (PLGA) nanobubbles (NBs), which not only function as an efficient ultrasound contrast agent for tumor imaging, but also a targeted anticancer drug carrier and excellent synergistic agent for enhancing the therapeutic efficiency of HIFU ablation. Methotrexate (MTX)-loaded NBs were synthesized and filled with perfluorocarbon gas subsequently using a facile but general double emulsion evaporation method. The active tumor-targeting monoclonal anti-HLA-G antibodies (mAbHLA-G) were further conjugated onto the surface of nanobubbles. The mAbHLA-G/MTX/PLGA NBs could enhance the ultrasound imaging both in vitro and in vivo, and the targeting efficiency to HLA-G overexpressing JEG-3 cells has been demonstrated. The elaborately designed mAbHLA-G/MTX/PLGA NBs can specifically target to the tumor cells both in vitro and in vivo, and their blood circulation time in vivo was much longer than non-targeted MTX/PLGA NBs. Further therapeutic evaluations showed that the targeted NBs as a synergistic agent can significantly improve the efficiency of HIFU ablation by changing the acoustic environment, and the focused ultrasound can promote the on-demand MTX release both in vitro and in vivo. The in vivo histopathology test and immunohistochemical analysis showed that the mAbHLA-G/MTX/PLGA NBs plus HIFU group presented most serious coagulative necrosis, the lowest proliferation index and the highest apoptotic index. Therefore, the successful introduction of targeted mAbHLA-G/MTX/PLGA NBs provides an excellent platform for the highly efficient, imaging-guided and non-invasive HIFU synergistic therapy of cancer with the supplementary functions of killing residual tumor cells and preventing tumor recurrence/metastasis.
authors.affiliation: Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Institution of Ultrasound Imaging, Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, PR China. Electronic address: zhengyuanyi@gmail.com.
authors.forename: Yuanyi
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Institution of Ultrasound Imaging, Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, PR China.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Huang
authors.affiliation: State Laboratory of High Performance Ceramics, Chinese Academy of Sciences, Shanghai 200050, PR China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Orthopaedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Jiang
authors.affiliation: Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China.
authors.forename: Mingxia
authors.initials: M
authors.lastname: Ding
authors.affiliation: Department of Pathology, Chongqing Medical University, Chongqing 400016, PR China.
authors.forename: Qingshu
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China.
authors.forename: Xiaoqiu
authors.initials: X
authors.lastname: Xiao
authors.affiliation: Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China.
authors.forename: Xin
authors.initials: X
authors.lastname: Luo
authors.affiliation: College of Biomedical Engineering, Chongqing Medical University, Chongqing 400016, PR China.
authors.forename: Zhibiao
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China. Electronic address: qihongbocq@gmail.com.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Qi
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003287:Contrast Media / Q000737:chemistry*; D003952:Diagnostic Imaging / Q000379:methods; D005260:Female; D057086:High-Intensity Focused Ultrasound Ablation; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry*; D008727:Methotrexate / Q000737:chemistry*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D045423:Microbubbles; D018365:Neoplasm, Residual / Q000175:diagnosis*; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer
chemical_list: D003287:Contrast Media; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D008727:Methotrexate
keywords: Cancer therapy; HIFU; Methotrexate; Nanobubbles; Ultrasound imaging