Robert Nickles

University of Wisconsin-Madison, Medical Physicss Department, Faculty Member

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Papers by Robert Nickles

Re-assessing the enhanced permeability and retention effect in peripheral arterial disease using radiolabeled long circulating nanoparticles

Biomaterials, Sep 1, 2016

As peripheral arterial disease (PAD) results in muscle ischemia and neovascularization, it has be... more As peripheral arterial disease (PAD) results in muscle ischemia and neovascularization, it has been claimed that nanoparticles can passively accumulate in ischemic tissues through the enhanced permeability and retention (EPR) effect. At this time, a quantitative evaluation of the passive targeting capabilities of nanoparticles has not been reported in PAD. Using a murine model of hindlimb ischemia, we quantitatively assessed the passive targeting capabilities of 64 Cu-labeled PEGylated reduced graphene oxide -iron oxide nanoparticles ( 64 Cu-RGO-IONP-PEG) through the EPR effect using positron emission tomography (PET) imaging. Serial laser Doppler imaging was performed to monitor changes in blood perfusion upon surgical induction of ischemia. Nanoparticle accumulation was assessed at 3, 10, and 17 days post-surgery and found to be highest at 3 days post-surgery, with the ischemic hindlimb displaying an accumulation of 14.7 ± 0.5 percent injected dose per gram (%ID/g). Accumulation of 64 Cu-RGO-IONP-PEG was lowest at 17 days post-surgery, with the ischemic hindlimb displaying only 5.1 ± 0.5 %ID/g. Furthermore, nanoparticle accumulation was confirmed by photoacoustic imaging (PA). The combination of PET and serial Doppler imaging showed that nanoparticle accumulation in the ischemic hindlimb negatively correlated with blood perfusion. Thus, we quantitatively confirmed that 64 Cu-RGO-IONP-PEG passively accumulated in ischemic tissue via the EPR effect, which is reduced as the perfusion normalizes. As 64 Cu-RGO-IONP-PEG displayed substantial accumulation in the ischemic tissue, this nanoparticle platform may function as a future theranostic agent, providing both imaging and therapeutic applications.

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In vitro characterization of a novel prostate cancer therapeutic radiopharmaceutical

The Journal of Nuclear Medicine, May 1, 2016

Segmented PET Attenuation with Positron Floodlight

In vivo tumor targeting of CD146 with antibody-conjugated hollow mesoporous silica nanoparticles

Novel RGD peptide derivatives with enhanced pharmacokinetics for PET imaging

Whole Body Dosimetry of (H2O)-O-14, O-12 (2), and (CHF)-H-3-F-17

In vivo tumor vasculature targeting and imaging with VEGF-conjugated nanographene oxide

Facile synthesis of 69Ge-labeled nanoparticles for dual-modality PET/MRI

FluoroDOPA PET shows the nondopaminergic as well as dopaminergic destinations of levodopa

Neurology, Oct 1, 1999

To evaluate the visible and quantitative anatomic distribution of fluorine-18-labeled L-DOPA in t... more To evaluate the visible and quantitative anatomic distribution of fluorine-18-labeled L-DOPA in the healthy human brain, to thereby expand the understanding of extrastriatal sites of levodopa function, and to provide a broader foundation for clinical and research studies of fluoroDOPA accumulation in patients. The authors performed dynamic three-dimensional fluoroDOPA PET imaging in 10 healthy volunteers and analyzed the images visually and quantitatively. Twenty-eight regions of interest were applied to parametric images of the uptake rate constant (using the multiple-time graphic plot method with cortical input function) and also were used to quantitate regional radioactivity at 80 to 90 minutes. The authors correlated the uptake constants with published human regional neurotransmitter and decarboxylation data. PET imaging with fluoroDOPA demonstrates trapping of labeled dopamine or its metabolites in substantial quantities in many areas of the brain other than the mesostriatal pathways, including considerable uptake in the serotonergic and noradrenergic areas of the hypothalamus and brainstem as well as in extrastriatal cerebral sites. Total fluoroDOPA uptake correlates best with the sum of catecholamine and indolamine concentrations in the brain and moderately well with regional activity of aromatic L-amino acid decarboxylase, but correlates poorly with extrastriatal dopamine concentration. Neither L-DOPA nor its radiolabeled analog fluoroDOPA is metabolized or accumulates specifically in dopaminergic or even catecholaminergic neurons. Substantial dopamine production within serotonin and norepinephrine neurons may play a role in either therapeutic effects or adverse effects of therapy with L-DOPA.

PET Imaging of VEGFR-2 Expression in Lung Cancer with 64Cu-Labeled Ramucirumab

The Journal of Nuclear Medicine, Nov 5, 2015

Lung cancer accounts for 17% of cancer-related deaths worldwide, and most patients present with l... more Lung cancer accounts for 17% of cancer-related deaths worldwide, and most patients present with locally advanced or metastatic disease. Novel PET imaging agents for assessing vascular endothelial growth factor receptor-2 (VEGFR-2) expression can be used for detecting VEGFR-2-positive malignancies and subsequent monitoring of therapeutic response to VEGFR-2-targeted therapies. Here, we report the synthesis and characterization of an antibodybased imaging agent for PET imaging of VEGFR-2 expression in vivo. Methods: Ramucirumab (named RamAb), a fully humanized IgG1 monoclonal antibody, was conjugated to 2-S-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA) and labeled with 64 Cu. Flow cytometry analysis and microscopy studies were performed to compare the VEGFR-2 binding affinity of RamAb and NOTA-RamAb. PET imaging and biodistribution studies were performed in nude mice bearing HCC4006 and A549 xenograft tumors. Ex vivo histopathology was performed to elucidate the expression patterns of VEGFR-2 in different tissues and organs to validate in vivo results. Results: Flow cytometry examination revealed the specific binding capacity of fluorescein isothiocyanate-RamAb to VEGFR-2, and no difference in VEGFR-2 binding affinity was seen between RamAb and NOTA-RamAb. After being labeled with 64 Cu, PET imaging revealed specific and prominent uptake of 64 Cu-NOTA-RamAb in VEGFR-2-positive HCC4006 tumors (9.4 ± 0.5 percentage injected dose per gram at 48 h after injection; n 5 4) and significantly lower uptake in VEGFR-2-negative A549 tumors (4.3 ± 0.2 percentage injected dose per gram at 48 h after injection; n 5 3). Blocking experiments revealed significantly lower uptake in HCC4006 tumors, along with histology analysis, further confirming the VEGFR-2 specificity of 64 Cu-NOTA-RamAb. Conclusion: This study provides initial evidence that 64 Cu-NOTA-RamAb can function as a PET imaging agent for visualizing VEGFR-2 expression in vivo, which may also find potential applications in monitoring the treatment response of VEGFR-2-targeted cancer therapy.

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Intrinsic and Stable Conjugation of Thiolated Mesoporous Silica Nanoparticles with Radioarsenic

ACS Applied Materials & Interfaces, Feb 16, 2017

The development of new image-guided drug delivery tools to improve the therapeutic efficacy of ch... more The development of new image-guided drug delivery tools to improve the therapeutic efficacy of chemotherapeutics remains an important goal in nanomedicine. Using labeling strategies that involve radioelements that have theranostic pairs of diagnostic positron-emitting isotopes and therapeutic electron-emitting isotopes has promise in achieving this goal and further enhancing drug performance through radiotherapeutic effects. The isotopes of radioarsenic offer such theranostic potential and would allow for the use of positron emission tomography (PET) for image-guided drug delivery studies of the arsenic-based chemotherapeutic arsenic trioxide (ATO). Thiolated mesoporous silica nanoparticles (MSN) are shown to effectively and stably bind cyclotron-produced radioarsenic. Labeling studies elucidate that this affinity is a result of specific binding between trivalent arsenic and nanoparticle thiol surface modification. Serial PET imaging of the in vivo murine biodistribution of radiolabeled silica nanoparticles shows very good stability toward dearsenylation that is directly proportional to silica porosity. Thiolated MSNs are found to have a macroscopic arsenic loading capacity of 20 mg of ATO per gram of MSN, sufficient for delivery of chemotherapeutic quantities of the drug. These results show the great potential of *

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PET radiometals for antibody labeling

Journal of Labelled Compounds and Radiopharmaceuticals, Mar 12, 2018

Recent advances in molecular characterization of tumors have made possible the emergence of new t... more Recent advances in molecular characterization of tumors have made possible the emergence of new types of cancer therapies where traditional cytotoxic drugs and nonspecific chemotherapy can be complemented with targeted molecular therapies. One of the main revolutionary treatments is the use of monoclonal antibodies (mAbs) that selectively target the disseminated tumor cells while sparing normal tissues. mAbs and related therapeutics can be efficiently radiolabeled with a wide range of radionuclides to facilitate preclinical and clinical studies. Non-invasive molecular imaging techniques, such as Positron Emission Tomography (PET), using radiolabeled mAbs provide useful information on the whole-body distribution of the biomolecules, which may enable patient stratification, diagnosis, selection of targeted therapies, evaluation of treatment response, and prediction of dose limiting tissue and adverse effects. In addition, when mAbs are labeled with therapeutic radionuclides, the combination of immunological and radiobiological cytotoxicity may result in enhanced treatment efficacy. The pharmacokinetic profile of antibodies demands the use of long half-life isotopes for longitudinal scrutiny of mAb biodistribution and precludes the use of well-stablished short half-life isotopes. Herein, we review the most promising PET radiometals with chemical and physical characteristics that make the appealing for mAb labeling, highlighting those with theranostic radioisotopes. Monoclonal antibodies (mAbs) have become indispensable tools for the modern clinical management of cancer. Currently, approximately 76 mAbs or antibody-related therapeutics have been approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of several primary and metastatic cancer types. Some of the advantages of mAbs as therapeutic agents include an exquisite affinity and specificity for their cognate antigen, relatively long circulation half-lives, and the ability to

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<sup>18</sup>F-labeled resin microspheres as surrogates for<sup>90</sup>Y resin microspheres used in the treatment of hepatic tumors: a radiolabeling and PET validation study

Physics in Medicine and Biology, Dec 5, 2007

90Y-labeled resin microspheres (SIR-Spheres) are currently used to treat patients with primary an... more 90Y-labeled resin microspheres (SIR-Spheres) are currently used to treat patients with primary and metastatic solid liver tumors. This treatment is typically palliative since patients have exhausted all other standard treatment options. Improving the quality of life and extending patient survival are typical benchmarks for tracking patient response. However, the current method for predicting microsphere biodistributions with 99mTc-labeled macroaggregated albumin (MAA)

M-Neurology-M-20-PET Studies in Rhesus Monkeys Using 6-(18F)-fluoro-meta-tyrosine, and Aromatic L-amino Acid Decarboxylase Tracer

The Noncatechol Tracer 6-Fluoro-m-Tyrosine

Elsevier eBooks, 1996

This chapter presents results from positron emission tomography (PET) scans in rhesus monkeys usi... more This chapter presents results from positron emission tomography (PET) scans in rhesus monkeys using a dihydroxyphenylalanine (DOPA) analog, which is not catecholic and not methylated, and therefore has much higher specific-to-nonspecific activity in PET studies of the brain. This allows the delineation of areas of small concentrations of dopaminergic neurons and terminals. Because of the decarboxylating enzyme that acts on DOPA, 18 F-6-fluoro-L-DOPA (FDOPA), and 18 F-6-fluoro-meta-tyrosine (FMT) present in all catecholaminergic and serotonergic neurons, small concentrations of nondopaminergic neurons are also demonstrated. This tracer may be particularly useful in the evaluation of diseases, such as schizophrenia, that involve extrastriatal dopamine systems. Dopamine is the dominant monoaminergic neurotransmitter in the striatum, and dopaminergic neurons may be responsible for much of the limbic, diencephalic, and mesencephalic uptake as well. However, the presence of specific FMT uptake diffusely through the brain stem, including large areas without dopaminergic cell bodies or terminals, demonstrates accumulation in other monoamine neurons. Lack of the 3-O-methyl metabolite after FMT administration will markedly simplify dopaminergic PET scans performed for the evaluation of the nigrostriatal system in patients with movement disorders. More striking, however, is the possibility that smaller concentrations of extrastriatal Dopaminergic terminals may be now measurable in vivo by PET, which may be important in studying diseases such as schizophrenia. Even the “confounding” specific accumulation of FMT in nondopaminergic neurons may find eventual scientific or clinical use. Studies should be carried out soon to assess both the chemoarchitectural features and potential clinical significance of this tracer in the human brain.

Radioactive Gases in the Evaluation of Left Ventricular Function

The hydrodynamic performance of heart chambers can be noninvasively investigated by quantitative ... more The hydrodynamic performance of heart chambers can be noninvasively investigated by quantitative evaluation of tracer dilution curves. The application of nuclear medical procedures to cardiac dynamic measurements must begin with two fundamental decisions concerning the radiotracer and the detection system, chosen to measure the desired cardiac parameter with the greatest sensitivity. After these choices have been made, the statistical quality of the data will dictate the level of refinement that is justified in the quantitative modeling of the heart as a pump. In particular, the measurement of atrial and ventricular ejection fractions and detection of valvular insufficiencies stand apart from most nuclear medical procedures due to the severe demands placed on spatial and temporal resolution. Accurate diagnosis can hinge on seeing count-rate differences of several percent in successive 10 cm2 × 10 msec image slices, suggesting that observed data rates from the heart alone should be of the order of 1 MHz. The fundamental tracer/ detector choices determine how far short of this ideal a practical procedure will fall.

Carbon-10 Dioxide: A new tracer for Human Brain Mapping with PET

NeuroImage, May 1, 1998

Radiochemical isolation method for the production of 52gMn from natCr for accelerator targets

Applied Radiation and Isotopes, Apr 1, 2019

We report a novel, precipitation-based method for the isolation of Mn from Cr targets for cyclotr... more We report a novel, precipitation-based method for the isolation of Mn from Cr targets for cyclotron production of 52gMn. The separation produces no-carrier-added 52gMn with a decay corrected radiochemical yield of 85 ± 3% and apparent molar activity for DOTA of 1.3 GBq/μmol. This method reduces stable metallic impurities in the purified 52gMn compared to previously reported chromatographic methods.

Improved production of 76Br, 77Br and 80mBr via CoSe cyclotron targets and vertical dry distillation

Nuclear Medicine and Biology, 2020

INTRODUCTION The radioisotopes of bromine are uniquely suitable radiolabels for small molecule th... more INTRODUCTION The radioisotopes of bromine are uniquely suitable radiolabels for small molecule theranostic radiopharmaceuticals but are of limited availability due to production challenges. Significantly improved methods were developed for the production and radiochemical isolation of clinical quality 76Br, 77Br, and 80mBr. The radiochemical quality of the radiobromine produced using these methods was tested through the synthesis of a novel 77Br-labeled inhibitor of poly (ADP-ribose) polymerase-1 (PARP-1), a DNA damage response protein. METHODS 76Br, 77Br, and 80mBr were produced in high radionuclidic purity via the proton irradiation of novel isotopically-enriched Co76Se, Co77Se, and Co80Se intermetallic targets, respectively. Radiobromine was isolated through thermal chromatographic distillation in a vertical furnace assembly. The 77Br-labeled PARP inhibitor was synthesized via copper-mediated aryl boronic ester radiobromination. RESULTS Cyclotron production yields were 103 ± 10 MBq∙μA-1∙h-1 for 76Br, 88 ± 10 MBq∙μA-1∙h-1 for 80mBr at 16 MeV and 17 ± 1 MBq∙μA-1∙h-1 for 77Br at 13 MeV. Radiobromide isolation yields were 76 ± 11% in a small volume of aqueous solution. The synthesized 77Br-labeled PARP-1 inhibitor had a measured apparent molar activity up to 700 GBq/μmol at end of synthesis. CONCLUSIONS A novel selenium alloy target enabled clinical-scale production of 76Br, 77Br, and 80mBr with high apparent molar activities, which was used to for the production of a new 77Br-labeled inhibitor of PARP-1. ADVANCES IN KNOWLEDGE New methods for the cyclotron production and isolation of radiobromine improved the production capacity of 77Br by a factor of three and 76Br by a factor of six compared with previous methods. IMPLICATIONS FOR PATIENT CARE Preclinical translational research of 77Br-based Auger electron radiotherapeutics, such as those targeting PARP-1, will require the production of GBq-scale 77Br, which necessitates next-generation, high-yielding, isotopically-enriched cyclotron targets, such as the novel intermetallic Co77Se.

Production of Radiohalogens: Bromine and Astatine for Imaging and Therapy

Robert Nickles

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