Noninvasive measurement of pharmacokinetics by near-infrared fluorescence imaging in the eye of mice

Dobosz, Michael; Strobel, Steffen; Stubenrauch, Kay-Gunnar; Osl, Franz; Scheuer, Werner

doi:10.1117/1.jbo.19.1.016022

Cited by 9 publications

(7 citation statements)

References 31 publications

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“…Serum stability of liposomes was further verified in vivo by imaging the fluorescence emission of the eyes of nude mice lacking tumors, at designated time points post i.v. injection of probes as reported earlier [ 41 ]. The HER2-IL which revealed a comparably higher dye release in in vitro serum incubations than the Bi-FAP/HER2-IL and FAP-IL showed a slight increase in fluorescence intensities from 2 to 10 h post i.v.…”

Section: Resultsmentioning

confidence: 99%

“…To monitor the serum stability of liposomes in vivo by imaging the eyes of mice as reported elsewhere [ 41 ], the respective liposomes (20 µmol final lipids/kg body weight) were applied intravenously in female nude mice and the eyes were imaged at designated time points on the Maestro™ in vivo fluorescence imaging system (CRi-InTAS, Woburn, MA, USA) using the red filterset as stated above. Further evaluation and determination of the fluorescence intensities of the eyes was done as similar to the whole body NIRF images stated above.…”

Section: Methodsmentioning

confidence: 99%

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Rapid Target Binding and Cargo Release of Activatable Liposomes Bearing HER2 and FAP Single-Chain Antibody Fragments Reveal Potentials for Image-Guided Delivery to Tumors

et al. 2020

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Liposomes represent suitable tools for the diagnosis and treatment of a variety of diseases, including cancers. To study the role of the human epidermal growth factor receptor 2 (HER2) as target in cancer imaging and image-guided deliveries, liposomes were encapsulated with an intrinsically quenched concentration of a near-infrared fluorescent dye in their aqueous interior. This resulted in quenched liposomes (termed LipQ), that were fluorescent exclusively upon degradation, dye release, and activation. The liposomes carried an always-on green fluorescent phospholipid in the lipid layer to enable tracking of intact liposomes. Additionally, they were functionalized with single-chain antibody fragments directed to fibroblast activation protein (FAP), a marker of stromal fibroblasts of most epithelial cancers, and to HER2, whose overexpression in 20–30% of all breast cancers and many other cancer types is associated with a poor treatment outcome and relapse. We show that both monospecific (HER2-IL) and bispecific (Bi-FAP/HER2-IL) formulations are quenched and undergo HER2-dependent rapid uptake and cargo release in cultured target cells and tumor models in mice. Thereby, tumor fluorescence was retained in whole-body NIRF imaging for 32–48 h post-injection. Opposed to cell culture studies, Bi-FAP/HER2-IL-based live confocal microscopy of a high HER2-expressing tumor revealed nuclear delivery of the encapsulated dye. Thus, the liposomes have potentials for image-guided nuclear delivery of therapeutics, and also for intraoperative delineation of tumors, metastasis, and tumor margins.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Rapid Target Binding and Cargo Release of Activatable Liposomes Bearing HER2 and FAP Single-Chain Antibody Fragments Reveal Potentials for Image-Guided Delivery to Tumors

et al. 2020

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“…The half-life of intravenously injected anti-CCSP-2 scFv-FITC was measured at 0, 2, 4, 6, and 8 h after injection using mouse whole-body fluorescence images 44 .…”

Section: Methodsmentioning

confidence: 99%

Biomolecular imaging of colorectal tumor lesions using a FITC-labeled scFv-Cκ fragment antibody

Kim

et al. 2021

Sci Rep

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For the sensitive diagnosis of colorectal cancer lesions, advanced molecular imaging techniques using cancer-specific targets have emerged. However, issues regarding the clearance of unbound probes and immunogenicity remain unresolved. To overcome these limitations, we developed a small-sized scFv antibody fragment conjugated with FITC for the real-time detection of colorectal cancer by in vivo molecular endoscopy imaging. A small-sized scFv fragment can target colon cancer secreted protein-2 (CCSP-2), highly expressed in colorectal adenocarcinoma tissues; moreover, its full-length IgG probe has been used for molecular imaging previously. To assess the efficacy of anti-CCSP-2 scFv-FITC, surgical specimens were obtained from 21 patients with colorectal cancer for ex vivo molecular fluorescence analysis, histology, and immunohistochemistry. Orthotopic mice were administered with anti-CCSP-2 scFv-FITC topically and intravenously, and distinct tumor lesions were observed by real-time fluorescence colonoscopy. The fluorescence imaging of human colon cancer specimens allowed the differentiation of malignant tissues from non-malignant tissues (p < 0.05), and the CCSP-2 expression level was found to be correlated with the fluorescence intensity. Here, we demonstrated the feasibility and safety of anti-CCSP-2 scFv-FITC for molecular imaging as well as its potential in real-time fluorescence colonoscopy for the differential diagnosis of tumor lesions.

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“…For example, the PK behavior of antibodies or fragments can be monitored non-invasively in the blood by measuring fluorescence signal intensities in the eye of mice. 70 Combination of fluorescence and bioluminescence can be measured simultaneously by using luciferase-transfected tumor cells 71 or tumor cells equipped with split-luciferase. 72,73 The latter allows monitoring of apoptosis induction non-invasively.…”

Section: Discussionmentioning

confidence: 99%

Improved decision making for prioritizing tumor targeting antibodies in human xenografts: Utility of fluorescence imaging to verify tumor target expression, antibody binding and optimization of dosage and application schedule

Dobosz¹,

Haupt²,

Scheuer³

2016

mAbs

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Preclinical efficacy studies of antibodies targeting a tumor-associated antigen are only justified when the expression of the relevant antigen has been demonstrated. Conventionally, antigen expression level is examined by immunohistochemistry of formalin-fixed paraffin-embedded tumor tissue section. This method represents the diagnostic "gold standard" for tumor target evaluation, but is affected by a number of factors, such as epitope masking and insufficient antigen retrieval. As a consequence, variances and discrepancies in histological staining results can occur, which may influence decision-making and therapeutic outcome. To overcome these problems, we have used different fluorescence-labeled therapeutic antibodies targeting human epidermal growth factor receptor (HER) family members and insulin-like growth factor-1 receptor (IGF1R) in combination with fluorescence imaging modalities to determine tumor antigen expression, drug-target interaction, and biodistribution and tumor saturation kinetics in non-small cell lung cancer xenografts. For this, whole-body fluorescence intensities of labeled antibodies, applied as a single compound or antibody mixture, were measured in Calu-1 and Calu-3 tumor-bearing mice, then ex vivo multispectral tumor tissue analysis at microscopic resolution was performed. With the aid of this simple and fast imaging method, we were able to analyze the tumor cell receptor status of HER1-3 and IGF1R, monitor the antibody-target interaction and evaluate the receptor binding sites of anti-HER2-targeting antibodies. Based on this, the most suitable tumor model, best therapeutic antibody, and optimal treatment dosage and application schedule was selected. Predictions drawn from obtained imaging data were in excellent concordance with outcome of conducted preclinical efficacy studies. Our results clearly demonstrate the great potential of combined in vivo and ex vivo fluorescence imaging for the preclinical development and characterization of monoclonal antibodies.

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Noninvasive measurement of pharmacokinetics by near-infrared fluorescence imaging in the eye of mice

Abstract: The combination of eye and whole body fluorescence imaging enables the simultaneous measurement of blood PKs and biodistribution of fluorescent-labeled compounds.

Cited by 9 publications

References 31 publications

Rapid Target Binding and Cargo Release of Activatable Liposomes Bearing HER2 and FAP Single-Chain Antibody Fragments Reveal Potentials for Image-Guided Delivery to Tumors

Rapid Target Binding and Cargo Release of Activatable Liposomes Bearing HER2 and FAP Single-Chain Antibody Fragments Reveal Potentials for Image-Guided Delivery to Tumors

Biomolecular imaging of colorectal tumor lesions using a FITC-labeled scFv-Cκ fragment antibody

Improved decision making for prioritizing tumor targeting antibodies in human xenografts: Utility of fluorescence imaging to verify tumor target expression, antibody binding and optimization of dosage and application schedule

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