Construction of Nucleolin-Targeted Lipid Nanobubbles and Contrast-Enhanced Ultrasound Molecular Imaging in Triple-Negati
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RESEARCH PAPER
Construction of Nucleolin-Targeted Lipid Nanobubbles and Contrast-Enhanced Ultrasound Molecular Imaging in Triple-Negative Breast Cancer Kejing Fang 1,2 & Luofu Wang 3 & Haiyun Huang 1 & Minmin Lan 1 & Daijia Shen 1 & Shiwu Dong 2 & Yanli Guo 1
Received: 17 March 2020 / Accepted: 2 July 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
ABSTRACT Purpose To construct aptamer AS1411-functionalized targeted lipid nanobubbles that could simultaneously target abnormally highly expressed nucleolin (NCL) on tumor tissue and neovasculature. Additionally, the study of their contrast-enhanced ultrasound molecular imaging capabilities in vitro and in vivo to explore new methods and approaches for the early and accurate diagnosis of triple-negative breast cancer (TNBC). Methods First, the targeted lipid-nucleic acid molecules were constructed by an amide reaction. Then, the targeted lipid nanobubbles (AS1411-NBs) and nontargeted lipid nanobubbles (NBs) were prepared by membrane hydration, mechanical vibration and centrifugal floatation. The physicochemical characteristics and contrast-enhanced ultrasound imaging capabilities of AS1411-NBs and NBs were compared and analyzed in vitro and in vivo. Results There were no significant differences between the AS1411-NBs and NBs in their concentration, average particle size or ultrasound imaging capabilities in vitro (P > 0.05). However, AS1411-NBs could simultaneously target NCL in tumor tissue and neovasculature to effectively prolong the duration of contrast-enhanced ultrasound imaging compared to NBs in vivo. The area under the time-intensity curve was significantly different between AS1411-NBs and NBs (P < 0.001), and the
* Shiwu Dong [email protected] * Yanli Guo [email protected] 1
Department of Ultrasound, Southwest Hospital Army Medical University, Chongqing 400038, China
2
Department of Biomedical Materials Science Army Medical University, Chongqing 400038, China
3
Department of Urology Army Characteristic Medical Center, Chongqing 400042, China
drug loading capacity of the AS1411-NBs was also significantly higher than that of the NBs (P < 0.05). Conclusions Aptamer AS1411-functionalized targeted lipid nanobubbles could significantly prolong the duration of contrast-enhanced ultrasound imaging to achieve dualtargeted ultrasound molecular imaging of tumor tissue and neovasculature. AS1411-NBs also have higher drug loading and targeted drug delivery capabilities compared with NBs, which can provide new methods and approaches for the early accurate diagnosis and effective treatment of TNBC.
KEYWORDS targeted lipid nanobubbles . nucleolin . aptamer AS1411 . ultrasound molecular imaging . triple-negative breast cancer
ABBREVIATIONS AS1411-NBs
Aptamer AS1411-functionalized targeted lipid nanobubbles AUC Area under the curve CD31 Platelet endothelial cell adhesion molecule 1 DAPI 2-(4-Amidinophenyl)-6-indolecarbamidine dihydrochloride DiI 1,1′-Dioctadecyl-3,3,3′,3′tetramethylindocarbocyanine perchlorate DL Drug loading DMEM
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