Synthesis and Investigation of a Radioiodinated F3 Peptide Analog as a SPECT Tumor Imaging Radioligand

Bhojani, Mahaveer S.; Ranga, Rajesh; Luker, Gary D.; Rehemtulla, Alnawaz; Ross, Brian D.; Dort, Marcian E. Van

doi:10.1371/journal.pone.0022418

Cited by 26 publications

(19 citation statements)

References 29 publications

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“…34 A cysteine residue was incorporated into the C-terminus of F3 peptide to facilitate its conjugation onto UiO-66 nMOF (via thiol maleimide reaction with pyrene-PEG-maleimide). 35 …”

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confidence: 99%

In Vivo Targeting and Positron Emission Tomography Imaging of Tumor with Intrinsically Radioactive Metal–Organic Frameworks Nanomaterials

et al. 2017

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Nanoscale metal–organic frameworks (nMOF) materials represent an attractive tool for various biomedical applications. Due to the chemical versatility, enormous porosity, and tunable degradability of nMOFs, they have been adopted as carriers for delivery of imaging and/or therapeutic cargos. However, the relatively low stability of most nMOFs has limited practical in vivo applications. Here we report the production and characterization of an intrinsically radioactive UiO-66 nMOF (89Zr-UiO-66) with incorporation of positron-emitting isotope zirconium-89 (89Zr). 89Zr-UiO-66 was further functionalized with pyrene-derived polyethylene glycol (Py–PGA-PEG) and conjugated with a peptide ligand (F3) to nucleolin for targeting of triple-negative breast tumors. Doxorubicin (DOX) was loaded onto UiO-66 with a relatively high loading capacity (1 mg DOX/mg UiO-66) and served as both a therapeutic cargo and a fluorescence visualizer in this study. Functionalized 89Zr-UiO-66 demonstrated strong radiochemical and material stability in different biological media. Based on the findings from cellular targeting and in vivo positron emission tomography (PET) imaging, we can conclude that 89Zr-UiO-66/Py–PGA-PEG-F3 can serve as an image-guidable, tumor-selective cargo delivery nanoplatform. In addition, toxicity evaluation confirmed that properly PEGylated UiO-66 did not impose acute or chronic toxicity to the test subjects. With selective targeting of nucleolin on both tumor vasculature and tumor cells, this intrinsically radioactive nMOF can find broad application in cancer theranostics.

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“…34 A cysteine residue was incorporated into the C-terminus of F3 peptide to facilitate its conjugation onto UiO-66 nMOF (via thiol maleimide reaction with pyrene-PEG-maleimide). 35 …”

mentioning

confidence: 99%

In Vivo Targeting and Positron Emission Tomography Imaging of Tumor with Intrinsically Radioactive Metal–Organic Frameworks Nanomaterials

et al. 2017

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“…The F3 peptide [60] and F3 peptide-conjugated nanoparticles [35, 61] have previously been studied as imaging probes for tumors. F3 peptide-conjugated oligonucleotides [34] and nanoparticles [62] have also been reported as having therapeutic effects in cancer.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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Nucleolin (NCL) plays an important role in tumor vascular development. An increased endothelial expression level of NCL has been related to cancer aggressiveness and prognosis and has been detected clinically in advanced tumors. Here, with a peptide targeted to NCL (F3 peptide), we created an NCL-targeted microbubble (MB) and compared the performance of F3-conjugated MBs with non-targeted (NT) MBs both in vitro and in vivo. In an in vitro study, F3-conjugated MBs bound 433 times more than NT MBs to an NCL-expressing cell line, while pretreating cells with 0.5 mM free F3 peptide reduced the binding of F3-conjugated MBs by 84%, n=4, p<0.001. We then set out to create a method to extract both the tumor wash-in and wash-out kinetics and tumor accumulation following a single injection of targeted MBs. In order to accomplish this, a series of ultrasound frames (a clip) was recorded at the time of injection and subsequent time points. Each pixel within this clip was analyzed for the minimum intensity projection (MinIP) and average intensity projection (AvgIP). We found that the MinIP robustly demonstrates enhanced accumulation of F3-conjugated MBs over the range of tumor diameters evaluated here (2 to 8 mm), and the difference between the AvgIP and the MinIP quantifies inflow and kinetics. The inflow and clearance were similar for unbound F3-conjugated MBs, control (non-targeted) and scrambled control agents. Targeted agent accumulation was confirmed by a high amplitude pulse and by a two-dimensional Fourier Transform technique. In summary, F3-conjugated MBs provide a new imaging agent for ultrasound molecular imaging of cancer vasculature, and we have validated metrics to assess performance using low mechanical index strategies that have potential for use in human molecular imaging studies.

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“…Furthermore, in vivo the conjugate arrested tumor growth, though tumor uptake was modest and most of the radioactivity was found in the blood and the kidneys (46). The F3 peptide has also been radiolabeled with 125 I, which also internalized in vitro, albeit no biological effects were evaluated (47). Tc conjugated to bombesin binds gastrin-releasing peptide receptor (GRP-r), which is overexpressed on the surface of several types of cancer cells (48).…”

Section: Peptidesmentioning

confidence: 99%

Novel radioisotope-based nanomedical approaches

Olsen¹,

Thisgaard²,

Vogel

et al. 2013

European Journal of Nanomedicine

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Radioisotope therapy of cancer is on the rise applying mainly β-emitting radionuclides. However, due to exposure of healthy tissues, the maximum achievable radiation dose with these is limited. Auger-electron emitters (AEs) represent a promising alternative because of their mode of decay within a short nanometer range. The challenge is that their therapeutic efficacy relies on a close vicinity to DNA. To overcome this and to minimize toxicity, the construction of smart nanomedical devices is required, which ascertain tumor cell targeting with succeeding cellular uptake and nuclear translocation. In this review we describe the potential of AEs with focus on their delivery down to the DNA level and their cellular effects. Reported efforts comprise different tumor-targeting strategies, including the use of antibodies or peptides with nuclear localizing sequences. Recently, attention has shifted to various nanoparticle formats for overcoming delivery problems. To this end, these approaches have mostly been tested in cell lines in vitro applying AEs more suited for imaging than therapy. This defines a demand for nanomedical formulations with documented in vivo activity, using AEs selected for their therapeutic potential to come closer to real clinical settings.

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Synthesis and Investigation of a Radioiodinated F3 Peptide Analog as a SPECT Tumor Imaging Radioligand

Cited by 26 publications

References 29 publications

In Vivo Targeting and Positron Emission Tomography Imaging of Tumor with Intrinsically Radioactive Metal–Organic Frameworks Nanomaterials

In Vivo Targeting and Positron Emission Tomography Imaging of Tumor with Intrinsically Radioactive Metal–Organic Frameworks Nanomaterials

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

Novel radioisotope-based nanomedical approaches

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