In vitro characterization and in vivo ultrasound molecular imaging of nucleolin-targeted microbubbles

Zhang, Hua; Ingham, Elizabeth S.; Gagnon, M. Karen J.; Mahakian, Lisa M.; Liu, Jingfei; Foiret, Josquin; Willmann, Jüergen K.; Ferrara, Katherine W.

doi:10.1016/j.biomaterials.2016.11.026

Cited by 37 publications

(21 citation statements)

References 65 publications

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“…Targeted UCAs are mostly on the micron scale, and their binding targets are mainly membrane proteins of tumor vascular endothelial cells, such as vascular endothelial growth factor receptor-2, endothelin, nucleolin, and so on. [3][4][5][6] Therefore, they only specifically bind to tumor vasculature and achieve USMI of tumor blood pool. It is a challenge for targeted UCAs to penetrate the tumor vasculature and achieve extravascular USMI of malignant tumors.…”

Section: Introductionmentioning

confidence: 99%

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

Zhu¹,

Wang²,

Liu³

et al. 2018

IJN

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PurposeTargeted 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 methodsThe 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 maleimidethiol 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.ResultsCAIX 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.ConclusionTargeted 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.

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Section: Introductionmentioning

confidence: 99%

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

Zhu¹,

Wang²,

Liu³

et al. 2018

IJN

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“…Currently, various novel diagnostic and therapeutic targets for lung cancer are being studied (3,4). Recent evidence suggests that nucleolin, also known as C23, is a potent therapeutic target for the treatment of tumors (5)(6)(7). Nucleolin is a highly conserved multifunctional protein located in the nucleus.…”

Section: Introductionmentioning

confidence: 99%

Phosphorylation of nucleolin is indispensable to its involvement in the proliferation and migration of non-small cell lung cancer cells

Huang

Tan

et al. 2018

Oncol Rep

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Non-small cell lung cancer (NSCLC) is one of the mostly deadly malignancies in the world. Nucleolin is a multifunctional protein that mainly regulates ribosome biogenesis but also has other functions including modulating the transcription of mRNAs and repressing RNA polymerase II. Nucleolin is overexpressed in various cancer cells, including NSCLC cells. It can confer resistance to apoptosis and promote cell migration and blood vessel formation by directly taking part in various tumor signal transduction pathways. The activities of nucleolin are regulated mainly by intracellular localization and post-translational modifications, including phosphorylation, glycosylation, methylation, and ADP-ribosylation. Phosphorylation of nucleolin (P-nucleolin) in NSCLC cells is still not well characterized. In the present study, the levels of nucleolin and P-nucleolin were examined in lung tissue and cells and it was demonstrated that levels of the two forms of nucleolin were significantly increased in NSCLC compared with non-cancerous tissues and cells. In addition, it was demonstrated that high expression levels of nucleolin and P-nucleolin were significantly associated with poor overall survival of NSCLC patients. Doxorubicin (DOX) is a type of anthracycline that has been used in the treatment of various types of cancer, including NSCLC. Upregulation of nucleolin through exogenous expression of nucleolin promoted A549 cell proliferation and migration, while downregulation of nucleolin through expression of small interfering RNA-nucleolin attenuated A549 cell proliferation and migration. Following stimulation with DOX, A549 cell proliferation and migration decreased and the expression of P-nucleolin also decreased. In order to investigate whether P-nucleolin is indispensable to the proliferation and migration of NSCLC cells, a plasmid encoding mutant nucleolin, in which the phosphorylation site at threonine-76 was mutated to alanine, was constructed. Compared with the A549 cells transfected with wild-type nucleolin, P-nucleolin expression and cell proliferation and migration were significantly decreased in A549 cells transfected with mutant nucleolin. These results indicate that targeting P-nucleolin may be a promising strategy for treating NSCLC patients.

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“…These markers could be good targets for cancer detection. In this respect, E-selectin [ 86 , 87 ], secreted frizzled related protein 2 (SFRP2) [ 113 ], B7–H3 [ 54 ], nucleolin [ 55 ] and thymocyte differentiation antigen 1 (Thy1) [ 56 ] were tested for cancerous tissue detection and showed promising results. Since angiogenesis is an early event in tumor development [ 114 ], angiogenesis targeted MB should be able to detect tumors at early stages.…”

Section: Targeted Contrast Agentsmentioning

confidence: 99%

Molecular Ultrasound Imaging

2020

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In the last decade, molecular ultrasound imaging has been rapidly progressing. It has proven promising to diagnose angiogenesis, inflammation, and thrombosis, and many intravascular targets, such as VEGFR2, integrins, and selectins, have been successfully visualized in vivo. Furthermore, pre-clinical studies demonstrated that molecular ultrasound increased sensitivity and specificity in disease detection, classification, and therapy response monitoring compared to current clinically applied ultrasound technologies. Several techniques were developed to detect target-bound microbubbles comprising sensitive particle acoustic quantification (SPAQ), destruction-replenishment analysis, and dwelling time assessment. Moreover, some groups tried to assess microbubble binding by a change in their echogenicity after target binding. These techniques can be complemented by radiation force ultrasound improving target binding by pushing microbubbles to vessel walls. Two targeted microbubble formulations are already in clinical trials for tumor detection and liver lesion characterization, and further clinical scale targeted microbubbles are prepared for clinical translation. The recent enormous progress in the field of molecular ultrasound imaging is summarized in this review article by introducing the most relevant detection technologies, concepts for targeted nano- and micro-bubbles, as well as their applications to characterize various diseases. Finally, progress in clinical translation is highlighted, and roadblocks are discussed that currently slow the clinical translation.

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In vitro characterization and in vivo ultrasound molecular imaging of nucleolin-targeted microbubbles

Cited by 37 publications

References 65 publications

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

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

Phosphorylation of nucleolin is indispensable to its involvement in the proliferation and migration of non-small cell lung cancer cells

Molecular Ultrasound Imaging

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