A5018219579- Radiopharmaceutical Chemistry and Applications
- Lung Cancer Research Studies
- Neuroendocrine Tumor Research Advances
- Monoclonal and Polyclonal Antibodies Research
- Neuroblastoma Research and Treatments
- Medical Imaging Techniques and Applications
- HER2/EGFR in Cancer Research
- Lung Cancer Treatments and Mutations
- Peptidase Inhibition and Analysis
- Prostate Cancer Treatment and Research
- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- Cell Adhesion Molecules Research
- Medical Imaging and Pathology Studies
- Immunotherapy and Immune Responses
- Nanoplatforms for cancer theranostics
- Pancreatic and Hepatic Oncology Research
- Advanced Biosensing Techniques and Applications
- Lanthanide and Transition Metal Complexes
- Radiation Therapy and Dosimetry
- Cancer, Hypoxia, and Metabolism
- Boron Compounds in Chemistry
- Glycosylation and Glycoproteins Research
- Hepatocellular Carcinoma Treatment and Prognosis
- Cancer-related gene regulation
National Institutes of Health
2015-2025
National Cancer Institute
2014-2023
Center for Cancer Research
2010-2023
Illinois Institute of Technology
2008
Physical Sciences (United States)
2008
Alpha-particle emitters have a high linear energy transfer and short range, offering the potential for treating micrometastases while sparing normal tissues. We developed urea-based, 211At-labeled small molecule targeting prostate-specific membrane antigen (PSMA) treatment of due to prostate cancer (PC).PSMA-targeted (2S)-2-(3-(1-carboxy-5-(4-211At-astatobenzamido)pentyl)ureido)-pentanedioic acid (211At- 6: ) was synthesized. Cellular uptake clonogenic survival were tested in PSMA-positive...
Targeted alpha therapy is an emerging strategy for the treatment of disseminated cancer. [223Ra]RaCl2 only clinically approved particle-emitting drug, and it used to treat castrate-resistant prostate cancer bone metastases, which [223Ra]Ra2+ localizes. To specifically direct non-osseous disease sites, chelation conjugation a cancer-targeting moiety necessary. Although previous efforts stably chelate this purpose have had limited success, here we report biologically stable radiocomplex with...
The objective of this study was to characterize the in vitro and vivo properties F(ab')(2) fragment panitumumab investigate its potential for imaging radioimmunotherapy.The generated by enzymatic pepsin digestion. After integrity immunoreactivity evaluated, radiolabeled. In studies included direct quantitation tumor targeting normal organ distribution radiolabeled as well planar γ-scintigraphy PET imaging.The successfully produced peptic digest. modified with CHX-A"-DTPA chelate efficiently...
Targeted radiopharmaceutical therapy (TRT) using α-particle radiation is a promising approach for treating both large and micrometastatic lesions. We developed prostate-specific membrane antigen (PSMA)–targeted low-molecular-weight agents <sup>212</sup>Pb-based TRT of patients with prostate cancer (PC) by evaluating the matching γ-emitting surrogate, <sup>203</sup>Pb. <b>Methods:</b> Five rationally designed ligands (L1-L5) were synthesized lysine-urea-glutamate scaffold, PSMA inhibition...
The monoclonal antibody, cetuximab, binds to epidermal growth-factor receptor and thus provides an opportunity create both imaging therapies that target this receptor. potential of cetuximab as a radioimmunoconjugate, using the acyclic bifunctional chelator, CHX-A″-DTPA, was investigated. pharmacokinetic behavior in blood determined mice with without tumors. Tumor targeting scintigraphic were evaluated bearing xenografts LS-174T (colorectal), SHAW (pancreatic), SKOV3 (ovarian), DU145...
Abstract Bevacizumab is a humanized monoclonal antibody that binds to tumor‐secreted vascular endothelial growth factor (VEGF)‐A and inhibits tumor angiogenesis. In 2004, the was approved by US Food Drug Administration (FDA) for treatment of metastatic colorectal carcinoma in combination with chemotherapy. This report describes preclinical evaluation radioimmunoconjugate, 86 Y‐CHX‐A″‐DTPA‐bevacizumab, potential use Positron Emission Tomography (PET) imaging VEGF‐A angiogenesis as surrogate...
Actinium-225 (225Ac) is one of the most promising radionuclides for targeted alpha therapy (TAT). With a half-life 9.92 days and decay chain that emits four high-energy α particles, 225Ac well-suited TAT when conjugated to macromolecular targeting vectors exhibit extended in vivo circulation times. The implementation these constructs, however, requires suitable chelator can bind retain this radionuclide vivo. Previous work has demonstrated suitability diaza-18-crown-6 macrocyclic H2macropa...
Abstract Radiopharmaceutical therapy (RPT) is a promising approach to treating solid tumors, but therapeutic advances are impeded by the lack of broadly expressed targets and shared molecular vulnerability across different tumor types. Here, we evaluate VLA-4 (integrin α4β1) as potential target for RPT in tumors use radiolabeled copper-64 ([64Cu]Cu-) copper-67 ([67Cu]Cu-CB-TE1A1P-PEG4-LLP2A) LLP2A, peptidomimetic ligand VLA-4, preclinical imaging testing. Expression ITGA4, gene encoding...
A novel lysine-based trifunctional chelate 3 was designed, synthesized, and characterized bears both a chelating moiety (CHX-A' ') for sequestering radiometals (86Y or 111In) the near-infrared dye Cy5.5 dual modality PET (or SPECT) fluorescence imaging, respectively. Successful conjugation of to monoclonal antibody trastuzumab (Herceptin) achieved by efficient thiol-maleimide chemistry, thereby yielding immunoconjugate 2. Analysis 2 flow cytometry competitive binding assay demonstrates that...
The increased use of copper radioisotopes in radiopharmaceutical applications has created a need for bifunctional chelators (BFCs) that form stable radiocopper complexes and allow covalent attachment to biological molecules. Previous studies have established 4,11-bis-(carbo- tert-butoxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (H 2CB-TE2A), member the ethylene "cross-bridged" cyclam (CB-cyclam) class bicyclic tetraaza macrocycles, forms highly kinetically with Cu(II) is less...
Panitumumab, a human monoclonal antibody that binds to the epidermal growth factor receptor (<i>HER1</i>), was approved by Food and Drug Administration in 2006 for treatment of patients with <i>HER1</i>-expressing carcinoma. In this article, we describe preclinical development <sup>86</sup>Y-CHX-A″-diethylenetriaminepentaacetic acid (DTPA)-panitumumab quantitative PET Panitumumab conjugated CHX-A″-DTPA radiolabeled <sup>86</sup>Y. vivo biodistribution, PET, blood clearance, area under curve,...
Malignant mesothelioma (MM), a rare form of cancer is often associated with previous exposure to fibrous minerals, such as asbestos. Asbestos increases HER1-activity and expression in pre-clinical models. Additionally, HER1 over-expression observed the majority MM cases. In this study, utility HER1-targeted chimeric IgG1, cetuximab, human IgG2, panitumumab, radiolabeled 86Y, were evaluated for PET imaging detect non-invasively vivo, select an antibody candidate radioimmunotherapy (RIT)....
In preclinical studies, targeted radioimmunotherapy using (212)Pb-TCMC-trastuzumab as an in vivo generator of the high-energy α-particle emitting radionuclide (212)Bi is proving efficacious modality for treatment disseminated peritoneal cancers. To elucidate mechanisms associated with this therapy, mice bearing human colon cancer LS-174T intraperitoneal xenografts were treated and compared nonspecific control (212)Pb-TCMC-HuIgG, unlabeled trastuzumab, HuIgG, well untreated controls. induced...
Abstract Aryliodonium salts have become precursors of choice for the synthesis 18 F‐labeled tracers nuclear imaging. However, little is known on reactivity these compounds with heavy halides, that is, radioiodide and astatide, at radiotracer scale. In first comparative study radiohalogenation aryliodonium 125 I − 211 At , initial experiments a model compound highlight higher astatide compared to iodide, which could not be anticipated from trends previously observed within halogen series....
Glypican-3 (GPC3) is expressed in 75% of hepatocellular carcinoma (HCC), but not normal liver, making it a promising HCC therapeutic target. GC33 full-length humanized monoclonal IgG1 specific to GPC3 that can localize vivo. alone failed demonstrate efficacy when evaluated patients with HCC; however, we posit cytotoxic functionalization the antibody radionuclides, may be warranted. Alpha particles, which are emitted by radioisotopes such as Actinium-225 (Ac-225) exhibit high linear energy...
The potential of the HER2-targeting antibody trastuzumab as a radioimmunoconjugate useful for both imaging and therapy was investigated. Conjugation with acyclic bifunctional chelator CHX-A"-DTPA yielded chelate:protein ratio 3.4±0.3; immunoreactivity unaffected. Radiolabeling efficient, routinely yielding product high specific activity. Tumor targeting evaluated in mice bearing subcutaneous (s.c.) xenografts colorectal, pancreatic, ovarian, prostate carcinomas. High uptake...
A new bifunctional ligand 3p-C-DEPA was synthesized and evaluated for use in targeted α-radioimmunotherapy. efficiently prepared via regiospecific ring opening of an aziridinium ion conjugated with trastuzumab. The 3p-C-DEPA-trastuzumab conjugate extremely rapid binding (205/6)Bi, the corresponding (205/6)Bi-3p-C-DEPA-trastuzumab complex stable human serum. Biodistribution studies were performed to evaluate vivo stability tumor targeting bearing athymic mice. displayed excellent as evidenced...
Studies from this laboratory have demonstrated the potential of targeting HER2 for therapeutic and imaging applications with medically relevant radionuclides. To expand repertoire trastuzumab as a radioimmunoconjugate (RIC) vector, use (177)Lu was investigated. The combination 6.7 d half-life, lower energy β(-)-emissions (500 keV max; 130 ave), an imagable γ-emission make attractive candidate radioimmunotherapy (RIT) regimens treatment larger tumor burdens not possible α-zparticle radiation....
Although the epidermal growth factor receptor (EGFR), also known as HER1, has been studied for over a decade, it continues to be molecule of great interest and focus investigators development targeted therapies. The marketed monoclonal antibody cetuximab binds thus might serve basis creation imaging or therapies that target this receptor. potential vehicle delivery α-particle radiation was investigated in an intraperitoneal tumor mouse model. effective working dose 10 μCi 212Pb-cetuximab...
<sup>86</sup>Y (half-life = 14.74 h, 33% β<sup>+</sup>) is within an emerging class of positron-emitting isotopes with relatively long physical half-lives that enables extended imaging biologic processes. We report the synthesis and evaluation 3 low-molecular-weight compounds labeled for prostate-specific membrane antigen (PSMA) using PET. Impetus study derives from need to perform dosimetry estimates corresponding <sup>90</sup>Y-labeled radiotherapeutics. <b>Methods:</b> Multistep syntheses...
Abstract Purpose: Studies herein explore paclitaxel enhancement of the therapeutic efficacy α-particle-targeted radiation therapy. Experimental Design: Athymic mice bearing 3 day i.p. LS-174T xenografts were treated with 300 or 600 μg at 24 h before, concurrently, after [213Bi] [212Pb]trastuzumab. Results: Paclitaxel (300 μg) followed later [213Bi]trastuzumab (500 μCi) provided no enhancement. administered concurrently [213Bi]HuIgG resulted in median survival 93 and 37 days, respectively;...