Publications by authors named "Justin J Wilson"

65 Publications

Py-Macrodipa: A Janus Chelator Capable of Binding Medicinally Relevant Rare-Earth Radiometals of Disparate Sizes.

J Am Chem Soc 2021 Jul 30;143(27):10429-10440. Epub 2021 Jun 30.

Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, United States.

Nuclear medicine leverages different types of radiometals for disease diagnosis and treatment, but these applications usually require them to be stably chelated. Given the often-disparate chemical properties of these radionuclides, it is challenging to find a single chelator that binds all of them effectively. Toward addressing this problem, we recently reported a macrocyclic chelator macrodipa with an unprecedented "dual-size-selectivity" pattern for lanthanide (Ln) ions, characterized by its high affinity for both the large and the small Ln ( , 2020, 142, 13500). Here, we describe a second-generation "macrodipa-type" ligand, py-macrodipa. Its coordination chemistry with Ln was thoroughly investigated experimentally and computationally. These studies reveal that the Ln-py-macrodipa complexes exhibit enhanced thermodynamic and kinetic stabilities compared to Ln-macrodipa, while retaining the unusual dual-size selectivity. Nuclear medicine applications of py-macrodipa for chelating radiometals with disparate chemical properties were assessed using the therapeutic La and diagnostic Sc radiometals representing the two size extremes within the rare-earth series. Radiolabeling and stability studies demonstrate that the rapidly formed complexes of these radionuclides with py-macrodipa are highly stable in human serum. Thus, in contrast to gold standard chelators like DOTA and macropa, py-macrodipa can be harnessed for the simultaneous, efficient binding of radiometals with disparate ionic radii like La and Sc, signifying a substantial achievement in nuclear medicine. This concept could enable the facile incorporation of a breadth of medicinally relevant radiometals into chemically identical radiopharmaceutical agents. The fundamental coordination chemistry learned from py-macrodipa provides valuable insight for future chelator development.
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http://dx.doi.org/10.1021/jacs.1c05339DOI Listing
July 2021

Biocompatible metal-organic frameworks for the storage and therapeutic delivery of hydrogen sulfide.

Chem Sci 2021 Apr 30;12(22):7848-7857. Epub 2021 Apr 30.

Department of Chemistry and Chemical Biology, Cornell University Ithaca NY 14850 USA

Hydrogen sulfide (HS) is an endogenous gasotransmitter with potential therapeutic value for treating a range of disorders, such as ischemia-reperfusion injury resulting from a myocardial infarction or stroke. However, the medicinal delivery of HS is hindered by its corrosive and toxic nature. In addition, small molecule HS donors often generate other reactive and sulfur-containing species upon HS release, leading to unwanted side effects. Here, we demonstrate that HS release from biocompatible porous solids, namely metal-organic frameworks (MOFs), is a promising alternative strategy for HS delivery under physiologically relevant conditions. In particular, through gas adsorption measurements and density functional theory calculations we establish that HS binds strongly and reversibly within the tetrahedral pockets of the fumaric acid-derived framework MOF-801 and the mesaconic acid-derived framework Zr-mes, as well as the new itaconic acid-derived framework CORN-MOF-2. These features make all three frameworks among the best materials identified to date for the capture, storage, and delivery of HS. In addition, these frameworks are non-toxic to HeLa cells and capable of releasing HS under aqueous conditions, as confirmed by fluorescence assays. Last, a cellular ischemia-reperfusion injury model using H9c2 rat cardiomyoblast cells corroborates that HS-loaded MOF-801 is capable of mitigating hypoxia-reoxygenation injury, likely due to the release of HS. Overall, our findings suggest that HS-loaded MOFs represent a new family of easily-handled solid sources of HS that merit further investigation as therapeutic agents. In addition, our findings add Zr-mes and CORN-MOF-2 to the growing lexicon of biocompatible MOFs suitable for drug delivery.
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http://dx.doi.org/10.1039/d1sc00691fDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8188460PMC
April 2021

Towards the stable chelation of radium for biomedical applications with an 18-membered macrocyclic ligand.

Chem Sci 2021 Jan 29;12(10):3733-3742. Epub 2021 Jan 29.

Department of Radiology, Washington University in St. Louis School of Medicine St. Louis MO 63110 USA

Targeted alpha therapy is an emerging strategy for the treatment of disseminated cancer. [Ra]RaCl is the only clinically approved alpha particle-emitting drug, and it is used to treat castrate-resistant prostate cancer bone metastases, to which [Ra]Ra localizes. To specifically direct [Ra]Ra to non-osseous disease sites, chelation and conjugation to a cancer-targeting moiety is necessary. Although previous efforts to stably chelate [Ra]Ra for this purpose have had limited success, here we report a biologically stable radiocomplex with the 18-membered macrocyclic chelator macropa. Quantitative labeling of macropa with [Ra]Ra was accomplished within 5 min at room temperature with a radiolabeling efficiency of >95%, representing a significant advancement over conventional chelators such as DOTA and EDTA, which were unable to completely complex [Ra]Ra under these conditions. [Ra][Ra(macropa)] was highly stable in human serum and exhibited dramatically reduced bone and spleen uptake in mice in comparison to bone-targeted [Ra]RaCl, signifying that [Ra][Ra(macropa)] remains intact . Upon conjugation of macropa to a single amino acid β-alanine as well as to the prostate-specific membrane antigen-targeting peptide DUPA, both constructs retained high affinity for Ra, complexing >95% of Ra in solution. Furthermore, [Ra][Ra(macropa-β-alanine)] was rapidly cleared from mice and showed low Ra bone absorption, indicating that this conjugate is stable under biological conditions. Unexpectedly, this stability was lost upon conjugation of macropa to DUPA, which suggests a role of targeting vectors in complex stability for this system. Nonetheless, our successful demonstration of efficient radiolabeling of the β-alanine conjugate with Ra and its subsequent stability establishes for the first time the possibility of delivering [Ra]Ra to metastases outside of the bone using functionalized chelators, marking a significant expansion of the therapeutic utility of this radiometal in the clinic.
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http://dx.doi.org/10.1039/d0sc06867eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8179459PMC
January 2021

Tuning the Kinetic Inertness of Bi Complexes: The Impact of Donor Atoms on Diaza-18-Crown-6 Ligands as Chelators for Bi Targeted Alpha Therapy.

Inorg Chem 2021 Jun 8;60(12):9199-9211. Epub 2021 Jun 8.

Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, United States.

The radionuclide Bi can be applied for targeted α therapy (TAT): a type of nuclear medicine that harnesses α particles to eradicate cancer cells. To use this radionuclide for this application, a bifunctional chelator (BFC) is needed to attach it to a biological targeting vector that can deliver it selectively to cancer cells. Here, we investigated six macrocyclic ligands as potential BFCs, fully characterizing the Bi complexes by NMR spectroscopy, mass spectrometry, and elemental analysis. Solid-state structures of three complexes revealed distorted coordination geometries about the Bi center arising from the stereochemically active 6s lone pair. The kinetic properties of the Bi complexes were assessed by challenging them with a 1000-fold excess of the chelating agent diethylenetriaminepentaacetic acid (DTPA). The most kinetically inert complexes contained the most basic pendent donors. Density functional theory (DFT) and quantum theory of atoms in molecules (QTAIM) calculations were employed to investigate this trend, suggesting that the kinetic inertness is not correlated with the extent of the 6s lone pair stereochemical activity, but with the extent of covalency between pendent donors. Lastly, radiolabeling studies of Bi (30-210 kBq) with three of the most promising ligands showed rapid formation of the radiolabeled complexes at room temperature within 8 min for ligand concentrations as low as 10 M, corresponding to radiochemical yields of >80%, thereby demonstrating the promise of this ligand class for use in Bi TAT.
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http://dx.doi.org/10.1021/acs.inorgchem.1c01269DOI Listing
June 2021

Cobalt amine complexes and Ru265 interact with the DIME region of the mitochondrial calcium uniporter.

Chem Commun (Camb) 2021 Jun;57(50):6161-6164

Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY, USA.

We report our investigation into the MCU-inhibitory activity of Co3+ complexes in comparison to Ru265. These compounds reversibly inhibit the MCU with nanomolar potency. Mutagenesis studies and molecular docking simulations suggest that the complexes operate through interactions with the DIME motif of the MCU pore.
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http://dx.doi.org/10.1039/d1cc01623gDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240128PMC
June 2021

Nontoxic Cobalt(III) Schiff Base Complexes with Broad-Spectrum Antifungal Activity.

Chemistry 2021 Jan 24;27(6):2021-2029. Epub 2020 Nov 24.

Centre for Superbug Solutions, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD, 4072, Australia.

Resistance to currently available antifungal drugs has quietly been on the rise but overshadowed by the alarming spread of antibacterial resistance. There is a striking lack of attention to the threat of drug-resistant fungal infections, with only a handful of new drugs currently in development. Given that metal complexes have proven to be useful new chemotypes in the fight against diseases such as cancer, malaria, and bacterial infections, it is reasonable to explore their possible utility in treating fungal infections. Herein we report a series of cobalt(III) Schiff base complexes with broad-spectrum antifungal activity. Some of these complexes show minimum inhibitory concentrations (MIC) in the low micro- to nanomolar range against a series of Candida and Cryptococcus yeasts. Additionally, we demonstrate that these compounds show no cytotoxicity against both bacterial and human cells. Finally, we report the first in vivo toxicity data on these compounds in Galleria mellonella, showing that doses as high as 266 mg kg are tolerated without adverse effects, paving the way for further in vivo studies of these complexes.
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http://dx.doi.org/10.1002/chem.202003545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855930PMC
January 2021

Tuning the Separation of Light Lanthanides Using a Reverse-Size Selective Aqueous Complexant.

Inorg Chem 2020 Nov 24;59(22):16522-16530. Epub 2020 Oct 24.

Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, United States.

Efficiently separating the chemically similar lanthanide ions into elementally pure compositions is one of the greatest scientific challenges of the 21st century. Although extensive research efforts have focused on the development of organic extractants for this purpose, the implementation of aqueous complexants possessing distinct coordination chemistries has scarcely been explored as an approach to enhancing intralanthanide separations. In this study, we investigate the lanthanide coordination chemistry of macrophosphi, a novel analogue of the reverse-size selective expanded macrocycle macropa. Our studies reveal that substitution of the pyridyl-2-carboxylic acid pendent arms of macropa with pyridyl-2-phosphinic acid arms of macrophosphi gives rise to a dramatic enhancement in the ability to discriminate between light lanthanides, reflected by a binding affinity of macrophosphi for La that is over 5 orders of magnitude higher than that for Gd. Furthermore, upon implementation of macrophosphi as an aqueous complexant in a biphasic extraction system containing the industrial extractant bis(2-ethylhexyl)phosphoric acid, separation factors of up to 45 were achieved for the Ce/La pair. These results represent a remarkable separation of adjacent lanthanides, demonstrating the significant potential of reverse-size selective aqueous complexants in lanthanide separation schemes.
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http://dx.doi.org/10.1021/acs.inorgchem.0c02413DOI Listing
November 2020

Aquation and Anation Kinetics of Rhenium(I) Dicarbonyl Complexes: Relation to Cell Toxicity and Bioavailability.

Inorg Chem 2020 Nov 21;59(21):15888-15897. Epub 2020 Oct 21.

Department of Chemistry, University of the Free State, Bloemfontein, South Africa 9301.

The aquation reactions of four rhenium(I) dicarbonyl complexes, [Re(CO)(NN)(PR)(Cl)], where NN = 1,10-phenanthroline (Phen) and 2,9-dimethyl-1,10-phenanthroline (DMPhen) and PR = 1,3,5-triaza-7-phosphaadamantane (PTA) and 1,4-diacetyl-1,3,7-triaza-5-phosphabicylco[3.3.1]nonane (DAPTA). Additionally, the anation reactions of the corresponding aqua complexes with Cl were investigated. Single crystals of [Re(CO)(DMPhen)(PTA)(Cl)]·DMF and [Re(CO)(DMPhen)(DAPTA)(Cl)] were obtained, and their structures were determined using X-ray diffraction. The Re-Cl interatomic distances are 2.4991(13) and 2.4922(6) Å, respectively, indicating a mild trans influence effect of the phosphine ligands. The rate constants, , for the aquation reactions of these complexes spanned a range of (3.7 ± 0.3) × 10 to (15.7 ± 0.3) × 10 s with the two Phen complexes having rate constants that are 2.5 times greater than those of the DMPhen complexes at 298 K. Similarly, the second-order anation rate constants () of the resulting aqua complexes, [Re(CO)(NN)(PR)(HO)], with Cl ions at 298 K varied between (2.99 ± 0.05) × 10 and (6.79 ± 0.09) × 10 M s. Likewise, these rate constants for the Phen complexes were almost 2 times faster than those of the DMPhen complexes. The p values of the four aqua complexes were determined to be greater than 9.0 for all of the complexes with [Re(CO)(Phen)(PTA)(HO)] having the highest p value of 9.28 ± 0.03. From the p values and the ratios of the aquation and anation rate contants, which give thermodynamic Cl binding constants, the speciation of the rhenium(I) complexes in blood plasma, the cytoplasm, and the cell nucleus were estimated. The data suggest that the aqua complexes would be the dominant species in all three environments. This result may have important implications on the potential biological activity of these complexes.
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http://dx.doi.org/10.1021/acs.inorgchem.0c02389DOI Listing
November 2020

A Dinuclear Persulfide-Bridged Ruthenium Compound is a Hypoxia-Selective Hydrogen Sulfide (H S) Donor.

Angew Chem Int Ed Engl 2021 01 16;60(3):1588-1592. Epub 2020 Nov 16.

Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY, 14853, USA.

Hydrogen sulfide (H S) is a gaseous molecule that has received attention for its role in biological processes and therapeutic potential in diseases, such as ischemic reperfusion injury. Despite its clinical relevance, delivery of H S to biological systems is hampered by its toxicity at high concentrations. Herein, we report the first metal-based H S donor that delivers this gas selectively to hypoxic cells. We further show that H S release from this compound protects H9c2 rat cardiomyoblasts from an in vitro model of ischemic reperfusion injury. These results validate the utility of redox-activated metal complexes as hypoxia-selective H S-releasing agents for use as tools to study the role of this gaseous molecule in complex biological systems.
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http://dx.doi.org/10.1002/anie.202012620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855780PMC
January 2021

Macrocyclic Ligands with an Unprecedented Size-Selectivity Pattern for the Lanthanide Ions.

J Am Chem Soc 2020 08 22;142(31):13500-13506. Epub 2020 Jul 22.

Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, United States.

Lanthanides (Ln) are critical materials used for many important applications, often in the form of coordination compounds. Tuning the thermodynamic stability of these compounds is a general concern, which is not readily achieved due to the similar coordination chemistry of lanthanides. Herein, we report two 18-membered macrocyclic ligands called macrodipa and macrotripa that show for the first time a dual selectivity toward both the light, large Ln ions and the heavy, small Ln ions, as determined by potentiometric titrations. The lanthanide complexes of these ligands were investigated by NMR spectroscopy and X-ray crystallography, which revealed the occurrence of a significant conformational toggle between a 10-coordinate Conformation A and an 8-coordinate Conformation B that accommodates Ln ions of different sizes. The origin of this selectivity pattern was further supported by density functional theory (DFT) calculations, which show the complementary effects of ligand strain energy and metal-ligand binding energy that contribute to this conformational switch. This work demonstrates how novel ligand design strategies can be applied to tune the selectivity pattern for the Ln ions.
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http://dx.doi.org/10.1021/jacs.0c05217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084257PMC
August 2020

Exploring the In Vivo and In Vitro Anticancer Activity of Rhenium Isonitrile Complexes.

Inorg Chem 2020 Jul 7;59(14):10285-10303. Epub 2020 Jul 7.

Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, United States.

The established platinum-based drugs form covalent DNA adducts to elicit their cytotoxic response. Although they are widely employed, these agents cause toxic side-effects and are susceptible to cancer-resistance mechanisms. To overcome these limitations, alternative metal complexes containing the rhenium(I) tricarbonyl core have been explored as anticancer agents. Based on a previous study ( 2019, 25, 9206), a series of highly active tricarbonyl rhenium isonitrile polypyridyl (TRIP) complexes of the general formula -[Re(CO)(NN)(ICN)], where NN is a chelating diimine and ICN is an isonitrile ligand, that induce endoplasmic reticulum (ER) stress via activation of the unfolded protein response (UPR) pathway are investigated. A total of 11 of these TRIP complexes were synthesized, modifying both the equatorial polypyridyl and axial isonitrile ligands. Complexes with more electron-donating equatorial ligands were found to have greater anticancer activity, whereas the axial ICN ligands had a smaller effect on their overall potency. All 11 TRIP derivatives trigger a similar phenotype that is characterized by their abilities to induce ER stress and activate the UPR. Lastly, we explored the in vivo efficacy of one of the most potent complexes, -[Re(CO)(dmphen)(tolICN)] (), where dmphen = 2,9-dimethyl-1,10-phenanthroline and tolICN = -tolyl isonitrile, in mice. The Tc congener of was synthesized, and its biodistribution in BALB/c mice was investigated in comparison to the parent Re complex. The results illustrate that both complexes have similar biodistribution patterns, suggesting that Tc analogues of these TRIP complexes can be used as diagnostic partner agents. The in vivo antitumor activity of was then investigated in NSG mice bearing A2780 ovarian cancer xenografts. When administered at a dose of 20 mg/kg twice weekly, this complex was able to inhibit tumor growth and prolong mouse survival by 150% compared to the vehicle control cohort.
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http://dx.doi.org/10.1021/acs.inorgchem.0c01442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8114230PMC
July 2020

Endoplasmic reticulum stress: an arising target for metal-based anticancer agents.

Chem Soc Rev 2020 Nov 29;49(22):8113-8136. Epub 2020 Jun 29.

Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA.

The endoplasmic reticulum (ER) has recently emerged as a promising target for anticancer agents. Cytotoxic compounds that target the ER often exhibit selectivity for cancer cells over non-cancer cells. Furthermore, the induction of ER stress often leads to immunogenic cell death, providing another factor that contributes to the clinical efficacy of drugs that target this organelle. Among potential ER stress-inducing agents, metal complexes, which possess redox activity and modular structures, have arisen as promising candidates. In the last two decades, dozens of metal complexes have been reported that kill cancer cells via ER stress induction, and many of these complexes exhibit nanomolar activity in vitro as well as powerful tumor inhibition in vivo. In this review, we summarize the current state of investigations on the ER stress-inducing properties of metal complexes. This review starts with a description of the ER, its function, and its role in cancer progression and treatment. Following this discussion, a guide to experimental methods that can be used by researchers to detect ER stress is provided. The majority of this review summarizes previous studies on metal-based anticancer agents that cause ER stress. Finally, a discussion on the perspectives and significance of using metal complexes as ER stress-inducing agents for the treatment of cancer is provided, along with a summary of structural trends that contribute to this type of biological activity.
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http://dx.doi.org/10.1039/d0cs00259cDOI Listing
November 2020

X-Ray fluorescence microscopy reveals that rhenium(i) tricarbonyl isonitrile complexes remain intact in vitro.

Chem Commun (Camb) 2020 Jun;56(48):6515-6518

Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, USA.

The complex fac-[Re(CO)3(dmphen)(para-tolylisonitrile)]+ (TRIP), where dmphen = 2,9-dimethyl-1,10-phenanthroline, is an endoplasmic reticulum stress-inducing anticancer agent (A. P. King, S. C. Marker, R. V. Swanda, J. J. Woods, S.-B. Qian and J. J. Wilson, Chem. - Eur. J., 2019, 25, 9206-9210). A second-generation compound fac-[Re(CO)3(dmphen)(para-iodobenzeneisonitrile)]+ (I-TRIP) was synthesized, and its intracellular distribution was investigated using X-ray fluorescence microscopy to show that these complexes are highly stable in vitro.
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http://dx.doi.org/10.1039/d0cc02451aDOI Listing
June 2020

Exploring Ovarian Cancer Cell Resistance to Rhenium Anticancer Complexes.

Angew Chem Int Ed Engl 2020 08 27;59(32):13391-13400. Epub 2020 May 27.

Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY, 14853, USA.

Rhenium tricarbonyl complexes have been recently investigated as novel anticancer agents. However, little is understood about their mechanisms of action, as well as the means by which cancer cells respond to chronic exposure to these compounds. To gain a deeper mechanistic insight into these rhenium anticancer agents, we developed and characterized an ovarian cancer cell line that is resistant to a previously studied compound [Re(CO) (dmphen)(ptolICN)] , where dmphen=2,9-dimethyl-1,10-phenanthroline and ptolICN=para-tolyl isonitrile, called TRIP. This TRIP-resistant ovarian cancer cell line, A2780TR, was found to be 9 times less sensitive to TRIP compared to the wild-type A2780 ovarian cancer cell line. Furthermore, the cytotoxicities of established drugs and other rhenium anticancer agents in the TRIP-resistant cell line were determined. Notably, the drug taxol was found to exhibit a 184-fold decrease in activity in the A2780TR cell line, suggesting that mechanisms of resistance towards TRIP and this drug are similar. Accordingly, expression levels of the ATP-binding cassette transporter P-glycoprotein, an efflux transporter known to detoxify taxol, were found to be elevated in the A2780TR cell line. Additionally, a gene expression analysis using the National Cancer Institute 60 cell line panel identified the MT1E gene to be overexpressed in cells that are less sensitive to TRIP. Because this gene encodes for metallothioneins, this result suggests that detoxification by this class of proteins is another mechanism for resistance to TRIP. The importance of this gene in the A2780TR cell line was assessed, confirming that its expression is elevated in this cell line as well. As the first study to investigate and identify the cancer cell resistance pathways in response to a rhenium complex, this report highlights important similarities and differences in the resistance responses of ovarian cancer cells to TRIP and conventional drugs.
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http://dx.doi.org/10.1002/anie.202004883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7482417PMC
August 2020

Systematically altering the lipophilicity of rhenium(I) tricarbonyl anticancer agents to tune the rate at which they induce cell death.

Dalton Trans 2020 Nov;49(45):16062-16066

Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, USA.

Rhenium-based anticancer agents have arisen as promising alternatives to conventional platinum-based drugs. Based on previous studies demonstrating how increasing lipophilicity improves drug uptake within the cell, we sought to investigate the effects of lipophilicity on the anticancer activity of a series of six rhenium(i) tricarbonyl complexes. These six rhenium(i) tricarbonyl structures, called Re-Chains, bear pyridyl imine ligands with different alkyl chains ranging in length from two to twelve carbons. The cytotoxicities of these compounds were measured in HeLa cells. At long timepoints (48 h), all compounds are equally cytotoxic. At shorter time points, however, the compounds with longer alkyl chains are significantly more active than those with smaller chains. Cellular uptake studies of these compounds show that they are taken up via both passive and active pathways. Collectively, these studies show how lipophilicity affects the rate at which these Re compounds induce their biological activities.
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http://dx.doi.org/10.1039/d0dt01097aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108609PMC
November 2020

Oxyaapa: A Picolinate-Based Ligand with Five Oxygen Donors that Strongly Chelates Lanthanides.

Inorg Chem 2020 Apr 27;59(7):5116-5132. Epub 2020 Mar 27.

Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, United States.

Coordination compounds of the lanthanide ions (Ln) have important applications in medicine due to their photophysical, magnetic, and nuclear properties. To effectively use the Ln ions for these applications, chelators that stably bind them in vivo are required to prevent toxic side effects that arise from localization of these ions in off-target tissue. In this study, two new picolinate-containing chelators, a heptadentate ligand OxyMepa and a nonadentate ligand Oxyaapa, were prepared, and their coordination chemistries with Ln ions were thoroughly investigated to evaluate their suitability for use in medicine. Protonation constants of these chelators and stability constants for their Ln complexes were evaluated. Both ligands exhibit a thermodynamic preference for small Ln ions. The log = 12.21 and 21.49 for OxyMepa and Oxyaapa, respectively, indicating that the nonadentate Oxyaapa forms complexes of significantly higher stability than the heptadentate OxyMepa. X-ray crystal structures of the Lu complexes were obtained, revealing that Oxyaapa saturates the coordination sphere of Lu, whereas OxyMepa leaves an additional open coordination site for a bound water ligand. Solution structural studies carried out with NMR spectroscopy revealed the presence of two possible conformations for these ligands upon Ln binding. Density functional theory (DFT) calculations were applied to probe the geometries and energies of these conformations. Energy differences obtained by DFT are small but consistent with experimental data. The photophysical properties of the Eu and Tb complexes were characterized, revealing modest photoluminescent quantum yields of <2%. Luminescence lifetime measurements were carried out in HO and DO, showing that the Eu and Tb complexes of OxyMepa have two inner-sphere water ligands, whereas the Eu and Tb complexes of Oxyaapa have zero. Lastly, variable-temperature O NMR spectroscopy was performed for the Gd-OxyMepa complex to determine its water exchange rate constant of = (2.8 ± 0.1) × 10 s. Collectively, this comprehensive characterization of these Ln chelators provides valuable insight for their potential use in medicine and garners additional understanding of ligand design strategies.
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http://dx.doi.org/10.1021/acs.inorgchem.0c00372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111572PMC
April 2020

Metal complexes as a promising source for new antibiotics.

Chem Sci 2020 Mar 12;11(10):2627-2639. Epub 2020 Feb 12.

Centre for Superbug Solutions , Institute for Molecular Bioscience , The University of Queensland , St. Lucia , Queensland 4072 , Australia . Email: ; Email:

There is a dire need for new antimicrobial compounds to combat the growing threat of widespread antibiotic resistance. With a currently very scarce drug pipeline, consisting mostly of derivatives of known antibiotics, new classes of antibiotics are urgently required. Metal complexes are currently in clinical development for the treatment of cancer, malaria and neurodegenerative diseases. However, only little attention has been paid to their application as potential antimicrobial compounds. We report the evaluation of 906 metal-containing compounds that have been screened by the Community for Open Antimicrobial Drug Discovery (CO-ADD) for antimicrobial activity. Metal-bearing compounds display a significantly higher hit-rate (9.9%) when compared to the purely organic molecules (0.87%) in the CO-ADD database. Out of 906 compounds, 88 show activity against at least one of the tested strains, including fungi, while not displaying any cytotoxicity against mammalian cell lines or haemolytic properties. Herein, we highlight the structures of the 30 compounds with activity against Gram-positive and/or Gram-negative bacteria containing Mn, Co, Zn, Ru, Ag, Eu, Ir and Pt, with activities down to the nanomolar range against methicillin resistant (MRSA). 23 of these complexes have not been reported for their antimicrobial properties before. This work reveals the vast diversity that metal-containing compounds can bring to antimicrobial research. It is important to raise awareness of these types of compounds for the design of truly novel antibiotics with potential for combatting antimicrobial resistance.
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http://dx.doi.org/10.1039/c9sc06460eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069370PMC
March 2020

The cell-permeable mitochondrial calcium uniporter inhibitor Ru265 preserves cortical neuron respiration after lethal oxygen glucose deprivation and reduces hypoxic/ischemic brain injury.

J Cereb Blood Flow Metab 2020 06 3;40(6):1172-1181. Epub 2020 Mar 3.

Department of Pharmacology, Faculty of Medicine, Dalhousie University, Life Sciences Research Institute, Halifax, Canada.

The mitochondrial calcium (Ca) uniporter (MCU) mediates high-capacity mitochondrial Ca uptake implicated in ischemic/reperfusion cell death. We have recently shown that inducible MCU ablation in Thy1-expressing neurons renders mice resistant to sensorimotor deficits and forebrain neuron loss in a model of hypoxic/ischemic (HI) brain injury. These findings encouraged us to compare the neuroprotective effects of Ru360 and the recently identified cell permeable MCU inhibitor Ru265. Unlike Ru360, Ru265 (2-10 µM) reached intracellular concentrations in cultured cortical neurons that preserved cell viability, blocked the protease activity of Ca-dependent calpains and maintained mitochondrial respiration and glycolysis after a lethal period of oxygen-glucose deprivation (OGD). Intraperitoneal (i.p.) injection of adult male C57Bl/6 mice with Ru265 (3 mg/kg) also suppressed HI-induced sensorimotor deficits and brain injury. However, higher doses of Ru265 (10 and 30 mg/kg, i.p.) produced dose-dependent increases in the frequency and duration of seizure-like behaviours. Ru265 is proposed to promote convulsions by reducing Ca buffering and energy production in highly energetic interneurons that suppress brain seizure activity. These findings support the therapeutic potential of MCU inhibition in the treatment of ischemic stroke but also indicate that such clinical translation will require drug delivery strategies which mitigate the pro-convulsant effects of Ru265.
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http://dx.doi.org/10.1177/0271678X20908523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238378PMC
June 2020

Redox Stability Controls the Cellular Uptake and Activity of Ruthenium-Based Inhibitors of the Mitochondrial Calcium Uniporter (MCU).

Angew Chem Int Ed Engl 2020 04 28;59(16):6482-6491. Epub 2020 Feb 28.

Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY, 14853, USA.

The mitochondrial calcium uniporter (MCU) is the ion channel that mediates Ca uptake in mitochondria. Inhibitors of the MCU are valuable as potential therapeutic agents and tools to study mitochondrial Ca . The best-known inhibitor of the MCU is the ruthenium compound Ru360. Although this compound is effective in permeabilized cells, it does not work in intact biological systems. We have recently reported the synthesis and characterization of Ru265, a complex that selectively inhibits the MCU in intact cells. Here, the physical and biological properties of Ru265 and Ru360 are described in detail. Using atomic absorption spectroscopy and X-ray fluorescence imaging, we show that Ru265 is transported by organic cation transporter 3 (OCT3) and taken up more effectively than Ru360. As an explanation for the poor cell uptake of Ru360, we show that Ru360 is deactivated by biological reductants. These data highlight how structural modifications in metal complexes can have profound effects on their biological activities.
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http://dx.doi.org/10.1002/anie.202000247DOI Listing
April 2020

Inhibitors of the mitochondrial calcium uniporter for the treatment of disease.

Curr Opin Chem Biol 2020 04 20;55:9-18. Epub 2019 Dec 20.

Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY, 14583, USA. Electronic address:

The mitochondrial calcium uniporter (MCU) is a protein located in the inner mitochondrial membrane that is responsible for mitochondrial Ca uptake. Under certain pathological conditions, dysregulation of Ca uptake through the MCU results in cellular dysfunction and apoptotic cell death. Given the role of the MCU in human disease, researchers have developed compounds capable of inhibiting mitochondrial calcium uptake as tools for understanding the role of this protein in cell death. In this article, we describe recent findings on the role of the MCU in mediating pathological conditions and the search for small-molecule inhibitors of this protein for potential therapeutic applications.
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http://dx.doi.org/10.1016/j.cbpa.2019.11.006DOI Listing
April 2020

Establishing Radiolanthanum Chemistry for Targeted Nuclear Medicine Applications.

Chemistry 2020 Jan 9;26(6):1238-1242. Epub 2020 Jan 9.

Medical Physics Department, University of Wisconsin-Madison, 1111 Highland Avenue, Madison, Wisconsin, 53705, USA.

We report the first targeted nuclear medicine application of the lanthanum radionuclides La. These isotopes represent a matched pair for diagnosis via the positron emissions of La and therapy mediated by the Auger electron emissions of La. We identify two effective chelators, known as DO3Apic and macropa, for these radionuclides. The 18-membered macrocycle, macropa, bound La with better molar activity than DO3Apic under similar conditions. These chelators were conjugated to the prostate-specific membrane antigen (PSMA)-targeting agent DUPA to assess the use of radiolanthanum for in vivo imaging. The La-labeled targeted constructs showed high uptake in tumor xenografts expressing PSMA. This study validates the use of these radioactive lanthanum isotopes for imaging applications and motivates future work to assess the therapeutic effects of the Auger electron emissions of La.
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http://dx.doi.org/10.1002/chem.201905202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261199PMC
January 2020

Implementing f-Block Metal Ions in Medicine: Tuning the Size Selectivity of Expanded Macrocycles.

Inorg Chem 2019 Aug 27;58(16):10483-10500. Epub 2019 Jun 27.

The f-block elements, which comprise both the lanthanide and actinide series, possess interesting spectroscopic, magnetic, and nuclear properties that make them uniquely suited for a range of biomedical applications. In this Forum Article, we provide a concise overview on the different ways that these elements are employed in medicine, highlighting their dual implementation in both diagnostic and therapeutic applications. A key requirement for the use of these labile metal ions in medicine is a suitable chelating agent that controls their in vivo biodistribution. Toward this goal, we also report our research describing the synthesis and characterization of a rigid 18-membered macrocycle called CHX-macropa, an analogue of the previously reported nonrigid ligand macropa ( , , 3331). The lanthanide coordination chemistry of CHX-macropa is explored in detail by pH potentiometry and density functional theory (DFT) calculations. These studies reveal that CHX-macropa exhibits an enhanced thermodynamic selectivity for large over small lanthanides in comparison to its nonrigid analogue macropa. DFT calculations suggest that a key factor in the enhanced selectivity of this ligand for the large f-block ions is its rigid macrocyclic core, which cannot adequately distort to interact effectively with small ions. On the basis of its high affinity for large f-block ions, the design strategies implemented in CHX-macropa may be valuable for applying these elements in the diagnosis or treatment of disease.
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http://dx.doi.org/10.1021/acs.inorgchem.9b01277DOI Listing
August 2019

In Vivo Anticancer Activity of a Rhenium(I) Tricarbonyl Complex.

ACS Med Chem Lett 2019 May 23;10(5):822-827. Epub 2019 Apr 23.

Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, United States.

The rhenium(I) complex -[Re(CO)(2,9-dimethyl-1,10-phenanthroline)(OH)] () was previously shown to exhibit potent in vitro anticancer activity in a manner distinct from conventional platinum-based drugs ( , , 14302-14314). In this study, we report further efforts to explore its aqueous speciation and antitumor activity. The cellular uptake of was measured in A2780 and cisplatin-resistant A2780CP70 ovarian cancer cells by inductively coupled plasma mass spectrometry, revealing similar uptake efficiency in both cell lines. High accumulation in the mitochondria was observed, contradicting prior fluorescence microscopy studies. The luminescence of is highly dependent on pH and coordination environment, making fluorescence microscopy somewhat unreliable for determining compound localization. The in vivo anticancer activity of was evaluated in mice bearing patient-derived ovarian cancer tumor xenografts. These studies conclusively show that is capable of inhibiting tumor growth, providing further credibility for the use of these compounds as anticancer agents.
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http://dx.doi.org/10.1021/acsmedchemlett.9b00128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6512002PMC
May 2019

A Rhenium Isonitrile Complex Induces Unfolded Protein Response-Mediated Apoptosis in Cancer Cells.

Chemistry 2019 Jul 26;25(39):9206-9210. Epub 2019 Jun 26.

Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY, 14853, USA.

Complexes of the element Re have recently been shown to possess promising anticancer activity through mechanisms of action that are distinct from the conventional metal-based drug cisplatin. In this study, we report our investigations on the anticancer activity of the complex [Re(CO) (dmphen)(p-tol-ICN)] (TRIP) in which dmphen=2,9-dimethyl-1,10-phenanthroline and p-tol-ICN=para-tolyl isonitrile. TRIP was synthesized by literature methods and exhaustively characterized. This compound exhibited potent in vitro anticancer activity in a wide variety of cell lines. Flow cytometry and immunostaining experiments indicated that TRIP induces intrinsic apoptosis. Comprehensive biological mechanistic studies demonstrated that this compound triggers the accumulation of misfolded proteins, which causes endoplasmic reticulum (ER) stress, the unfolded protein response, and apoptotic cell death. Furthermore, TRIP induced hyperphosphorylation of eIF2α, translation inhibition, mitochondrial fission, and expression of proapoptotic ATF4 and CHOP. These results establish TRIP as a promising anticancer agent based on its potent cytotoxic activity and ability to induce ER stress.
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http://dx.doi.org/10.1002/chem.201902223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6625872PMC
July 2019

Combinatorial Synthesis to Identify a Potent, Necrosis-Inducing Rhenium Anticancer Agent.

Inorg Chem 2019 Mar 22;58(6):3895-3909. Epub 2019 Feb 22.

Department of Chemistry and Chemical Biology , Cornell University , Ithaca , New York 14853 , United States.

Combinatorial synthesis can be applied for developing a library of compounds that can be rapidly screened for biological activity. Here, we report the application of microwave-assisted combinatorial chemistry for the synthesis of 80 rhenium(I) tricarbonyl complexes bearing diimine ligands. This library was evaluated for anticancer activity in three different cancer cell lines, enabling the identification of three lead compounds with cancer cell growth-inhibitory activities of less than 10 μM. These three lead structures, Re-9B, Re-9C, and Re-9D, were synthesized independently and fully characterized by NMR spectroscopy, mass spectrometry, elemental analysis, and X-ray crystallography. The most potent of these three complexes, Re-9D, was further explored to understand its mechanism of action. Complex Re-9D is equally effective in both wild-type and cisplatin-resistant A2780 ovarian cancer cells, indicating that it circumvents cisplatin resistance. This compound was also shown to possess promising activity against ovarian cancer tumor spheroids. Additionally, flow cytometry showed that Re-9D does not induce cell cycle arrest or flipping of phosphatidylserine to the outer cell membrane. Analysis of the morphological changes of cancer cells treated with Re-9D revealed that this compound gives rise to rapid plasma membrane rupture. Collectively, these data suggest that Re-9D induces necrosis in cancer cells. To assess the in vivo biodistribution and stability of this compound, a radioactive Tc analogue of Re-9D, Tc-9D(HO), was synthesized and administered to naı̈ve BALB/c mice. Results of these studies indicate that Tc-9D(HO) exhibits high metabolic stability and a distinct biodistribution profile. This research demonstrates that combinatorial synthesis is an effective approach for the development of new rhenium anticancer agents with advantageous biological properties.
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http://dx.doi.org/10.1021/acs.inorgchem.8b03552DOI Listing
March 2019

A Selective and Cell-Permeable Mitochondrial Calcium Uniporter (MCU) Inhibitor Preserves Mitochondrial Bioenergetics after Hypoxia/Reoxygenation Injury.

ACS Cent Sci 2019 Jan 4;5(1):153-166. Epub 2019 Jan 4.

Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania 19140, United States.

Mitochondrial Ca (Ca) uptake mediated by the mitochondrial calcium uniporter (MCU) plays a critical role in signal transduction, bioenergetics, and cell death, and its dysregulation is linked to several human diseases. In this study, we report a new ruthenium complex Ru265 that is cell-permeable, minimally toxic, and highly potent with respect to MCU inhibition. Cells treated with Ru265 show inhibited MCU activity without any effect on cytosolic Ca dynamics and mitochondrial membrane potential (ΔΨ). Dose-dependent studies reveal that Ru265 is more potent than the currently employed MCU inhibitor Ru360. Site-directed mutagenesis of Cys97 in the N-terminal domain of human MCU ablates the inhibitory activity of Ru265, suggesting that this matrix-residing domain is its target site. Additionally, Ru265 prevented hypoxia/reoxygenation injury and subsequent mitochondrial dysfunction, demonstrating that this new inhibitor is a valuable tool for studying the functional role of the MCU in intact biological models.
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http://dx.doi.org/10.1021/acscentsci.8b00773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6346394PMC
January 2019

Physical properties, ligand substitution reactions, and biological activity of Co(iii)-Schiff base complexes.

Dalton Trans 2019 May;48(18):5987-6002

Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA.

Four cobalt(iii) complexes of the general formula [Co(Schiff base)(L)2]+, where L is ammonia (NH3) or 3-fluorobenzylamine (3F-BnNH2), were synthesized. The complexes were characterized by NMR spectroscopy, mass spectrometry, and X-ray crystallography. Their electrochemical properties, ligand substitution mechanisms, and ligand exchange rates in aqueous buffer were investigated. These physical properties were correlated to the cellular uptake and anticancer activities of the complexes. The complexes undergo sequential, dissociative ligand substitution, with the exchange rates depending heavily on the axial ligands. Eyring analyses revealed that the relative ligand exchange rates were largely impacted by differences in the entropy, rather than enthalpy, of activation for the complexes. Performing the substitution reactions in the presence of ascorbate led to a change in the reaction profile and kinetics, but no change in the final product. The cytotoxic activity of the complexes correlates with both the ligand exchange rate and reduction potential, with the more easily reduced and rapidly substituted complexes showing higher toxicity. These relationships may be valuable for the rational design of Co(iii) complexes as anticancer or antiviral prodrugs.
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http://dx.doi.org/10.1039/c8dt04606aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6504617PMC
May 2019

Rapid Dissolution of BaSO by Macropa, an 18-Membered Macrocycle with High Affinity for Ba.

J Am Chem Soc 2018 12 28;140(49):17071-17078. Epub 2018 Nov 28.

Department of Chemistry and Chemical Biology, Baker Laboratory , Cornell University , Ithaca , New York 14853 , United States.

Insoluble BaSO scale is a costly and time-consuming problem in the petroleum industry. Clearance of BaSO-impeded pipelines requires chelating agents that can efficiently bind Ba, the largest nonradioactive +2 metal ion. Due to the poor affinity of currently available chelating agents for Ba, however, the dissolution of BaSO remains inefficient, requiring very basic solutions of ligands. In this study, we investigated three diaza-18-crown-6 macrocycles bearing different pendent arms for the chelation of Ba and assessed their potential for dissolving BaSO scale. Remarkably, the bis-picolinate ligand macropa exhibits the highest affinity reported to date for Ba at pH 7.4 (log K' = 10.74), forming a complex of significant kinetic stability with this large metal ion. Furthermore, the BaSO dissolution properties of macropa dramatically surpass those of the state-of-the-art ligands DTPA and DOTA. Using macropa, complete dissolution of a molar equivalent of BaSO is reached within 30 min at room temperature in pH 8 buffer, conditions under which DTPA and DOTA only achieve 40% dissolution of BaSO. When further applied for the dissolution of natural barite, macropa also outperforms DTPA, showing that this ligand is potentially valuable for industrial processes. Collectively, this work demonstrates that macropa is a highly effective chelator for Ba that can be applied for the remediation of BaSO scale.
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http://dx.doi.org/10.1021/jacs.8b08704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6560633PMC
December 2018

A Single Dose of Ac-RPS-074 Induces a Complete Tumor Response in an LNCaP Xenograft Model.

J Nucl Med 2019 05 9;60(5):649-655. Epub 2018 Nov 9.

Division of Radiopharmaceutical Science, Department of Radiology, Weill Cornell Medicine, New York, New York

Promising biochemical responses to Ac-prostate-specific membrane antigen (PSMA) 617, even in patients who are refractory to β-particle radiation, illustrate the potential of targeted α-therapy for the treatment of metastatic castration-resistant prostate cancer. However, side effects such as xerostomia are severe and irreversible. To fully harness the potential of targeted α-therapy, it is necessary to increase the therapeutic index of the targeted radioligands. One emerging strategy is to increase clearance half-life through enhanced binding to serum albumin. We have evaluated the albumin-binding PSMA-targeting ligand RPS-074 in a LNCaP xenograft model to determine its potential value to the treatment of prostate cancer. Ac-RPS-074 was evaluated in male BALB/c mice bearing LNCaP xenograft tumors. A biodistribution study was performed over 21 d to determine the dosimetry in tumors and normal tissue. The dose response was measured in groups of 7 mice using 37, 74, and 148 kBq of Ac-RPS-074 and compared with positive and negative control groups. Mice were sacrificed when tumor volume exceeded 1,500 mm Ac-RPS-074 was labeled in greater than 98% radiochemical yield and showed high (>10% injected dose/g) and sustained accumulation in LNCaP tumors from 24 h to beyond 14 d. Signal in blood and highly vascularized tissues was evident over the first 24 h after injection and cleared by 7 d. The tumor-to-kidney ratio was 4.3 ± 0.7 at 24 h and 62.2 ± 9.5 at 14 d. A single injection of 148 kBq induced a complete response in 6 of 7 tumors, with no apparent toxic effects. Treatment with 74 kBq induced a partial response in 7 of 7 tumors, but from 42 d, 6 of 7 experienced significant regrowth. The 37-kBq group experienced a survival benefit relative to the negative control but not compared with the positive control group. A single dose of 148 kBq of Ac-RPS-074 induced a complete response in 86% of tumors, with tumor-to-normal-tissue ratios that predict an improved therapeutic index. The use of the macropa chelator enabled quantitative radiolabeling and may facilitate the clinical translation of this promising targeted α-therapeutic.
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http://dx.doi.org/10.2967/jnumed.118.219592DOI Listing
May 2019
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