Hypoxia-Targeting Fluorescent Nanobodies for Optical Molecular Imaging of Pre-Invasive Breast Cancer

Brussel, Aram S. A. van; Adams, Arthur L.L.; Oliveira, Sabrina; Dorresteijn, Bram; Khattabi, Mohamed El; Vermeulen, Jeroen F.; Wall, Elsken van der; Mali, Willem P.Th.M.; Derksen, Patrick W.B.; Diest, Paul J. van; Henegouwen, Paul M.P. van Bergen en

doi:10.1007/s11307-015-0909-6

Cited by 55 publications

(47 citation statements)

References 35 publications

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“…Carbonic anhydrase IX (CAIX) plays an important role in the growth and metastasis of numerous tumors (including renal cancer, cervical cancer, colon cancer, prostate cancer, breast cancer, head and neck tumors, and so on), and has been used for the diagnosis, treatment, and prognosis of malignant tumors. [18][19][20][21][22][23] Targeted ligands against CAIX include monoclonal antibodies, nanobodies, and affibodies, as well as polypeptides that we studied earlier. 18,22,24,25 Aptamers are single-stranded DNA or RNA oligonucleotides that specifically bind to biological macromolecules or cells through a specific spatial structure.…”

Section: Introductionmentioning

confidence: 99%

“…[18][19][20][21][22][23] Targeted ligands against CAIX include monoclonal antibodies, nanobodies, and affibodies, as well as polypeptides that we studied earlier. 18,22,24,25 Aptamers are single-stranded DNA or RNA oligonucleotides that specifically bind to biological macromolecules or cells through a specific spatial structure. Compared with other ligands, aptamers have several attractive features, including diverse structure, high specificity, high stability, rapid tissue penetration, no immunogenicity, and easy synthesis and modification.…”

Section: Introductionmentioning

confidence: 99%

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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%

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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“…To avoid ionizing radiation, nanobodies can also be conjugated to near-infrared fluorophores such as IRDye800CW to perform optical tumor imaging, a technique that is cost-effective, flexible, sensitive and fast. As such, a nanobody against the hypoxia marker enzyme CAIX and an anti-EGFR nanobody were used for molecular imaging of (pre-) invasive breast cancer and orthotopic oral squamous cell carcinoma (OSCC), respectively ( van Brussel et al, 2015 , van Driel et al, 2014 ) ( Table 1 ). The brightest future of this technique lies in imaging-guided surgery, which was first shown with anti-HER2 nanobodies.…”

Section: Nanobodies In Molecular Imagingmentioning

confidence: 99%

Nanobodies as Versatile Tools to Understand, Diagnose, Visualize and Treat Cancer

2016

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Since their discovery, nanobodies have been used extensively in the fields of research, diagnostics and therapy. These antigen binding fragments, originating from Camelid heavy-chain antibodies, possess unusual hallmarks in terms of (small) size, stability, solubility and specificity, hence allowing cost-effective production and sometimes outperforming monoclonal antibodies. In this review, we evaluate the current status of nanobodies to study, diagnose, visualize or inhibit cancer-specific proteins and processes. Nanobodies are highly adaptable tools for cancer research as they enable specific modulation of targets, enzymatic and non-enzymatic proteins alike. Molecular imaging studies benefit from the rapid, homogeneous tumor accumulation of nanobodies and their fast blood clearance, permitting previously unattainable fast tumor visualization. Moreover, they are endowed with considerable therapeutic potential as inhibitors of receptor-ligand pairs and deliverers of drugs or drug-loaded nanoparticles towards tumors. More in vivo and clinical studies are however eagerly awaited to unleash their full potential.

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“…With this diversity in mind, it raises the possibility that non-invasive MIBA that targets well-chosen biomarkers of cancer could improve early diagnosis and prediction of treatment efficacy. A variety of NIR fluorescent molecular imaging probes are available, and/or are reported, for powerful biological characterization of tumor biology, including probes for pH [16,17], hypoxia [18,19], protease activity [20][21][22], vascular leak [23,24], integrin expression [21,25], metabolic markers [26,27], hormone receptors [28,29], and well-characterized tumor markers [30][31][32]. However, their utilities as tools for MI vs. MIBA can be as much dependent on proper study design as on probe performance, with controls, treatment design, and imaging time points dictating whether results are geared toward just overt outcomes or toward gathering useful biological information.…”

Section: Miba Strategies In Cancermentioning

confidence: 99%

Paradigms in Fluorescence Molecular Imaging: Maximizing Measurement of Biological Changes in Disease, Therapeutic Efficacy, and Toxicology/Safety

Peterson

2018

Mol Imaging Biol

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Fluorescence molecular imaging (MI) is an important concept in preclinical research that focuses on the visualization of cellular and biological function in a non-invasive fashion to better understand in vivo disease processes and treatment effects. MI differs fundamentally from traditional preclinical imaging strategies in that it generally relies on reporter probes specific for particular targets or pathways that can be used to reveal biological changes in situ, at the site(s) of disease. In contrast, the more established imaging modalities, like magnetic resonance imaging, X-ray, micro X-ray computed tomography, and ultrasound, historically have relied primarily on late-stage anatomical or physiologic changes. The practical application of fluorescence MI, however, has drifted somewhat from the emphasis on quantifying biology, and based on the publication record, it now appears to include any imaging in which a probe or contrast agent is used to non-invasively acquire in vivo endpoint information. Unfortunately, the mere use of a defined biologically specific probe, in the absence of careful study design, does not guarantee that any useful biological information is actually gained, although often useful endpoint results still can be achieved. This review proposes to add subcategories of MI, termed MI biological assessment (or MIBA), that emphasize a focus on obtaining early and clear biological changes associated with disease development, therapeutic efficacy, and drug-induced tissue changes. Proper selection of probes and careful study design are critical for maximizing the non-invasive assessment of in vivo biological changes, and applications of these critical elements are described.

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Hypoxia-Targeting Fluorescent Nanobodies for Optical Molecular Imaging of Pre-Invasive Breast Cancer

Cited by 55 publications

References 35 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

Nanobodies as Versatile Tools to Understand, Diagnose, Visualize and Treat Cancer

Paradigms in Fluorescence Molecular Imaging: Maximizing Measurement of Biological Changes in Disease, Therapeutic Efficacy, and Toxicology/Safety

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