First-In-Human Study Demonstrating Tumor-Angiogenesis by PET/CT Imaging with68Ga-NODAGA-THERANOST, a High-Affinity Peptidomimetic for αvβ3Integrin Receptor Targeting

BaumRichard, P; KulkarniHarshad, R; MüllerDirk,; SatzStanley,; DanthiNarasimhan,; KimYoung-Seung,; BrechbielMartin, W

doi:10.1089/cbr.2014.1747

Cited by 23 publications

(17 citation statements)

References 28 publications

(41 reference statements)

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“…By including radiolabels on fluorescence tracers, so-called dual-modality (bimodal or hybrid) tracers are generated that allow quantitative mapping of the pharmacokinetic properties (7). This concept has been successfully applied to nanoparticles, antibody analogs, and peptides (8)(9)(10)(11)(12)(13), as exemplified by the plurality of hybrid tracers in the literature (14)(15)(16)(17). For example, for the arginylglycylaspartic acid (RGD) vector, it has been documented that the introduction of different pendant moieties on an otherwise stable conjugated system influences the pharmacokinetics (18)(19)(20)(21)(22).…”

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confidence: 99%

Tracers for Fluorescence-Guided Surgery: How Elongation of the Polymethine Chain in Cyanine Dyes Alters the Pharmacokinetics of a Dual-Modality c[RGDyK] Tracer

et al. 2018

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The potential of receptor-mediated fluorescence-based image-guided surgery tracers is generally linked to the near-infrared emission profile and good-manufacturing-production availability of fluorescent dyes. Surprisingly, little is known about the critical interaction between the structural composition of the dyes and the pharmacokinetics of the tracers. In this study, a dual-modality tracer design was used to systematically and quantitatively evaluate the influence of elongation of the polymethine chain in a fluorescent cyanine dye on the imaging potential of a targeted tracer. As a model system, the integrin marker αβ was targeted using arginylglycylaspartisc acid [RGD]-based vectors functionalized with a In-diethylenetriaminepentaacetic acid (DTPA) chelate and a fluorescent dye: (Cy3-(SO)methyl-COOH [emission wavelength (λ), 580 nm], Cy5-(SO)methyl-COOH [λ, 680 nm], or Cy7-(SO)methyl-COOH [λ, 780 nm]). Tracers were analyzed for differences in photophysical properties, serum protein binding, chemical or optical stability, and signal penetration through tissue. Receptor affinities were evaluated using saturation and competition experiments. In vivo biodistribution (SPECT imaging and percentage injected dose per gram of tissue) was assessed in tumor-bearing mice and complemented with in vivo and ex vivo fluorescence images obtained using a clinical-grade multispectral fluorescence laparoscope. Two carbon-atom-step variations in the polymethine chain of the fluorescent cyanine dyes were shown to significantly influence the chemical and photophysical characteristics (e.g., stability, brightness, and tissue penetration) of the hybrid RGD tracers. DTPA-Cy5-(SO)methyl-COOH-c[RGDyK] structurally outperformed its Cy3 and Cy7 derivatives. Radioactivity-based evaluation of in vivo tracer pharmacokinetics yielded the lowest nonspecific uptake and highest tumor-to-background ratio for DTPA-Cy5-(SO)methyl-COOH-c[RGDyK] (13.2 ± 1.7), with the Cy3 and Cy7 analogs trailing at respective tumor-to-background ratios of 5.7 ± 0.7 and 4.7 ± 0.7. Fluorescence-based assessment of tumor visibility revealed a similar trend. These findings underline that variations in the polymethine chain lengths of cyanine dyes have a profound influence on the photophysical properties, stability, and in vivo targeting capabilities of fluorescent imaging tracers. In a direct comparison, the intermediate-length dye (Cy5) yielded a superior c[RGDyK] tracer, compared with the shorter (Cy3) and longer (Cy7) analogs.

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confidence: 99%

Tracers for Fluorescence-Guided Surgery: How Elongation of the Polymethine Chain in Cyanine Dyes Alters the Pharmacokinetics of a Dual-Modality c[RGDyK] Tracer

et al. 2018

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“…The current need for early diagnosis, stratification, and treatment response assessment has led to innovative techniques for nuclear medicine and molecular imaging. Medical imaging has an advantage as a biomarker by being a noninvasive method that can provide a variety of information about the tumor (24). Integrated PET/CT using 18 F-FDG, the most widespread image radiotracer, can visualize tumor viability, tumor anatomy, and the surrounding normal tissues.…”

Section: Discussionmentioning

confidence: 99%

Response Assessment of ⁶⁸Ga-DOTA-E-[c(RGDfK)]² PET/CT in Lung Adenocarcinoma Patients Treated with Nintedanib Plus Docetaxel

et al. 2017

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Nintedanib is an oral angiokinase inhibitor used as second-line treatment for non-small cell lung cancer. New radiotracers, such as Ga-DOTA-E-[c(RGDfK)], that target αβ integrin might have an impact as a noninvasive method for assessing angiogenesis inhibitors. From July 2011 through October 2015, 38 patients received second-line nintedanib plus docetaxel. All patients underwent PET/CT withGa-DOTA-E-[c(RGDfK)] radiotracer and blood-sample tests to quantify angiogenesis factors (fibroblast growth factor, vascular endothelial growth factor, and platelet-derived growth factor AB) before and after completing 2 therapy cycles. Of the 38 patients, 31 had available baseline and follow-up PET/CT. Baseline lung tumor volume addressed withGa-DOTA-E-[c(RGDfK)] PET/CT correlated with serum vascular endothelial growth factor levels, whereas baseline lung/liver SUV index correlated with platelet-derived growth factor AB. After treatment, the overall response rate and disease control rate were 7.9% and 47.3%, respectively. A greater decrease in lung tumor volume (-37.2% vs. -27.6%) was associated with a better disease control rate in patients ( = 0.005). Median progression-free survival was 3.7 mo. Nonsmokers and patients with a higher baseline lung tumor volume were more likely to have a higher progression-free survival (6.4 vs. 3.74 [ = 0.023] and 6.4 vs. 2.1 [ = 0.003], respectively). Overall survival was not reached. Patients with a greater decrease in lung SUV (not reached vs. 7.1 mo; = 0.016) and a greater decrease in the lung/spleen SUV index (not reached vs. 7.1; = 0.043) were more likely to have a longer overall survival.Ga-DOTA-E-[c(RGDfK)] PET/CT is a potentially useful tool for assessing responses to angiogenesis inhibitors. Further analysis and novel studies are warranted to identify patients who might benefit from this therapy.

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“…The second patient (61-year-old male with neuroendocrine neoplasm of the right lower lobe of the lung) received 496 MBq of [ 68 Ga]Ga-NODAGA-THERANOST™ which demonstrated αvβ3 receptor expression and angiogenesis. [ 68 Ga]Ga-NODAGA-THERANOST™ revealed high uptake, specificity and sensitivity in tumors and metastatic sites 60 min post injection [80]. A clinical trial is currently in progress with 120 participants with an estimated completion date in 2020 and the results may provide compelling evidence for further investigation of petidomimetics [81].…”

Section: Personlised Imaging Techniques—peptides and Peptidomimeticsmentioning

confidence: 99%

Radiolabelled Aptamers for Theranostic Treatment of Cancer

Khalid

Henri

et al. 2018

Pharmaceuticals

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Cancer has a high incidence and mortality rate worldwide, which continues to grow as millions of people are diagnosed annually. Metastatic disease caused by cancer is largely responsible for the mortality rates, thus early detection of metastatic tumours can improve prognosis. However, a large number of patients will also present with micrometastasis tumours which are often missed, as conventional medical imaging modalities are unable to detect micrometastases due to the lack of specificity and sensitivity. Recent advances in radiochemistry and the development of nucleic acid based targeting molecules, have led to the development of novel agents for use in cancer diagnostics. Monoclonal antibodies may also be used, however, they have inherent issues, such as toxicity, cost, unspecified binding and their clinical use can be controversial. Aptamers are a class of single-stranded RNA or DNA ligands with high specificity, binding affinity and selectivity for a target, which makes them promising for molecular biomarker imaging. Aptamers are presented as being a superior choice over antibodies because of high binding affinity and pH stability, amongst other factors. A number of aptamers directed to cancer cell markers (breast, lung, colon, glioblastoma, melanoma) have been radiolabelled and characterised to date. Further work is ongoing to develop these for clinical applications.

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First-In-Human Study Demonstrating Tumor-Angiogenesis by PET/CT Imaging with⁶⁸Ga-NODAGA-THERANOST, a High-Affinity Peptidomimetic for α_vβ₃Integrin Receptor Targeting

Cited by 23 publications

References 28 publications

Tracers for Fluorescence-Guided Surgery: How Elongation of the Polymethine Chain in Cyanine Dyes Alters the Pharmacokinetics of a Dual-Modality c[RGDyK] Tracer

Tracers for Fluorescence-Guided Surgery: How Elongation of the Polymethine Chain in Cyanine Dyes Alters the Pharmacokinetics of a Dual-Modality c[RGDyK] Tracer

Response Assessment of ⁶⁸Ga-DOTA-E-[c(RGDfK)]² PET/CT in Lung Adenocarcinoma Patients Treated with Nintedanib Plus Docetaxel

Radiolabelled Aptamers for Theranostic Treatment of Cancer

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First-In-Human Study Demonstrating Tumor-Angiogenesis by PET/CT Imaging with68Ga-NODAGA-THERANOST, a High-Affinity Peptidomimetic for αvβ3Integrin Receptor Targeting

Cited by 23 publications

References 28 publications

Tracers for Fluorescence-Guided Surgery: How Elongation of the Polymethine Chain in Cyanine Dyes Alters the Pharmacokinetics of a Dual-Modality c[RGDyK] Tracer

Tracers for Fluorescence-Guided Surgery: How Elongation of the Polymethine Chain in Cyanine Dyes Alters the Pharmacokinetics of a Dual-Modality c[RGDyK] Tracer

Response Assessment of 68Ga-DOTA-E-[c(RGDfK)]2 PET/CT in Lung Adenocarcinoma Patients Treated with Nintedanib Plus Docetaxel

Radiolabelled Aptamers for Theranostic Treatment of Cancer

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Product

Resources

About

First-In-Human Study Demonstrating Tumor-Angiogenesis by PET/CT Imaging with⁶⁸Ga-NODAGA-THERANOST, a High-Affinity Peptidomimetic for α_vβ₃Integrin Receptor Targeting

Response Assessment of ⁶⁸Ga-DOTA-E-[c(RGDfK)]² PET/CT in Lung Adenocarcinoma Patients Treated with Nintedanib Plus Docetaxel