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CAIX aptamer-functionalized targeted nanobubbles for ultrasound molecular imaging of various tumors

Authors Zhu L, Wang L, Liu Y, Xu D, Fang K, Guo Y

Received 5 June 2018

Accepted for publication 3 August 2018

Published 16 October 2018 Volume 2018:13 Pages 6481—6495

DOI https://doi.org/10.2147/IJN.S176287

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Cristina Weinberg

Peer reviewer comments 2

Editor who approved publication: Dr Linlin Sun


Lianhua Zhu,1 Luofu Wang,2 Yu Liu,1 Dan Xu,1 Kejing Fang,1 Yanli Guo1

1Department of Ultrasound, Southwest Hospital, Third Military Medical University (Army Medical University), Shapingba District, Chongqing, China; 2Department of Urology, Daping Hospital, Third Military Medical University (Army Medical University), Yuzhong District, Chongqing, China

Purpose: Targeted nanobubbles can penetrate the tumor vasculature and achieve ultrasound molecular imaging (USMI) of tumor parenchymal cells. However, most targeted nanobubbles only achieve USMI of tumor parenchymal cells from one organ, and their distribution, loading ability, and binding ability in tumors are not clear. Therefore, targeted nanobubbles loaded with carbonic anhydrase IX (CAIX) aptamer were fabricated for USMI of various tumors, and the morphological basis of USMI with targeted nanobubbles was investigated.
Materials and methods: The specificity of CAIX aptamer at the cellular level was measured by immunofluorescence and flow cytometry. Targeted nanobubbles loaded with CAIX aptamer were prepared by a maleimide-thiol coupling reaction, and their binding ability to CAIX-positive tumor cells was analyzed in vitro. USMI of targeted and non-targeted nanobubbles was performed in tumor-bearing nude mice. The distribution, loading ability, and binding ability of targeted nanobubbles in xenograft tumor tissues were demonstrated by immunofluorescence.
Results: CAIX aptamer could specifically bind to CAIX-positive 786-O and Hela cells, rather than CAIX-negative BxPC-3 cells. Targeted nanobubbles loaded with CAIX aptamer had the advantages of small size, uniform distribution, regular shape, and high safety, and they could specifically accumulate around 786-O and Hela cells, while not binding to BxPC-3 cells in vitro. Targeted nanobubbles had significantly higher peak intensity and larger area under the curve than non-targeted nanobubbles in 786-O and Hela xenograft tumor tissues, while there was no significant difference in the imaging effects of targeted and non-targeted nanobubbles in BxPC-3 xenograft tumor tissues. Immunofluorescence demonstrated targeted nanobubbles could still load CAIX aptamer after penetrating the tumor vasculature and specifically binding to CAIX-positive tumor cells in xenograft tumor tissues.
Conclusion: Targeted nanobubbles loaded with CAIX aptamer have a good imaging effect in USMI of tumor parenchymal cells, and can improve the accuracy of early diagnosis of malignant tumors from various organs.

Keywords: targeted ultrasound contrast agents, molecular imaging, malignant tumors, aptamers, morphological basis

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