About

Professor Marvin W. Makinen is a faculty member in the Department of Biochemistry and Molecular Biology at The University of Chicago. His research focuses on the synthesis and characterization of vanadium-based compounds, particularly vanadyl chelates, for applications in cancer imaging and therapy. His work includes developing novel radiotracers such as Vanadium-48-labeled vanadyl acetylacetonate for PET imaging and investigating the structural and functional mechanisms of vanadyl chelates in cellular contexts. Professor Makinen has contributed to understanding the biochemical interactions of vanadyl chelates, including their inhibition of protein tyrosine phosphatase-1B and their role in increasing glucose uptake in cancer cells. His research also explores the potential of vanadium compounds as magnetic resonance imaging probes for early cancer detection. With a background that integrates inorganic chemistry, biochemistry, and molecular biology, he has advanced the development of vanadium-based agents for medical imaging and cancer research.

Research topics

• Organic chemistry
• Chemistry
• Radiochemistry
• Nuclear chemistry
• Materials science
• Nuclear medicine
• Condensed matter physics
• Chromatography
• Chemical physics
• Mathematics
• Inorganic chemistry
• Metallurgy
• Nuclear magnetic resonance
• Physics
• Nanotechnology
• Medicine

Selected publications

• Application of EPR Saturation Methods to Paramagnetic Metal Ions in Proteins

  CRC Press eBooks · 2024 · 2 citations

  1st authorCorresponding
  • Materials science
  • Nuclear magnetic resonance
  • Chemistry

  Saturation of a paramagnetic spin system with incident microwave power has been widely applied in electron paramagnetic resonance (EPR) studies to evaluate both electronic and structural properties of spin systems. The method essentially consists of irradiating the spin system with high levels of microwave power and observing the response of the system to reestablish thermal equilibrium of the spins with the lattice, and can be employed with both continuous wave (cw) and pulse saturation and recovery techniques. In the former, the spin system is progressively irradiated with increasingly higher levels of incident microwave power during which time the spectrum is collected to monitor the change in signal intensity; in the latter, the system is subjected to an intense pulse of microwave power of short duration after which the kinetic response of the system to reestablish thermal equilibrium is followed. Application of either method requires thorough familiarity with the physical principles and theory underlying relaxation processes as well as with the limitations of the technique with respect to instrumentation. Therefore, in this chapter we first discuss the salient features of magnetic relaxation theory that are necessary to describe and interpret results from experiments using saturation techniques in EPR studies, and we briefly outline the basic requirements for instrumentation, particularly with a view on limitations in data collection. Because this chapter is directed to structural analysis of paramagnetic metal ion sites in proteins, the discussion is restricted to relaxation theory of transition metal ions in ionic solids. Furthermore, for all of the transition metal ions discussed in this review, we need concern ourselves only with magnetic resonance theory applied to Kramers ions. Readers are directed to reviews and monographs on EPR spectroscopy and relaxation phenomena [1–6] for more detailed or specialized discussions of the concepts outlined here.

  PublisherDOI

• Efficient Synthesis and HPLC-Based Characterization for Developing Vanadium-48-Labeled Vanadyl Acetylacetonate as a Novel Cancer Radiotracer for PET Imaging

  Molecules · 2024 · 2 citations

  • Chemistry
  • Radiochemistry
  • Nuclear chemistry

  . Preliminary results of preclinical, small-animal PET studies are presented.

  PublisherOA PDFDOI

• Preliminary investigation of 48V-labeled VO(acac)2 for cancer imaging: An initial proof-of-concept study

  Applied Radiation and Isotopes · 2022 · 8 citations

  • Radiochemistry
  • Chemistry
  • Nuclear chemistry

  . In vitro cellular studies demonstrated radiotracer uptake and saturation around 0.48 nM. These studies pave the way for improving methodologies and in vivo experiments, including imaging studies, in future investigations.

  PublisherDOI

• V-48 labeled VO(acac)2for hybrid PET/MR imaging of cancer

  2019-05-01

  article

  1176 Objectives: We previously demonstrated the use of vanadyl (VO2+) chelate bis(acetylacetonato) oxovanadium(IV) [VO(acac)2] as an effective contrast agent in magnetic resonance imaging (MRI) for potential early detection and staging of cancer, such as in mouse models of colorectal cancer (CRC) [1,2]. Previous studies showed increased tumor uptake of 48V-VO(acac)2 in PET (positron emission tomography) imaging in CRC [3]. Our current research is extended to development of dual-modality PET/MR imaging using 48V labeled VO(acac)2 for improved imaging in cancer detection and staging. We report our progress on improving the cyclotron production of 48V, optimizing the synthesis of 48V-VO(acac)2, decreasing radiotracer impurities, and validating the utility of this new radiotracer in PET/MR studies of CRC in mouse models. Methods: Two thin natural titanium foils were irradiated via the 48Ti(p,n)48V reaction at 40 µA until an optimal activity was obtained. The foil was left to decay overnight to mitigate short-lived isotopes. The target was dissolved in HF and H2SO4 (4:1) and 48V was isolated in a series of radiochemical steps before being complexed with acetyl acetone under reflux to form 48V-VO(acac)2. The solution was passed through an OnGuard II M cartridge (Thermo Fisher Scientific), used to concentrate free transition metals, to separate 48V-VO(acac)2 from free vanadium, which does not target the same metabolic pathways and decreases image quality. The purity of the resulting radiotracer was assessed using aluminum-backed thin layer chromatography (TLC). Two drops of the sample were placed 1 cm from the plate edge. The plate was developed in MeOH and H2O (99:1) and evaluated using a TLC imaging scanner (Mini-Scan, Eckert & Ziegler): chelated and free vanadium were expected to separate due to their chemical state. Once purity was established, the radiotracer was validated in PET/MR studies by demonstrating uptake in a xenograph mouse model of CRC. Mice were imaged over 30 minutes in an MRI scanner with a PET-insert. The results were confirmed with separate PET and MR imaging studies. In-vivo biodistribution studies were performed 48 hours post injection. Results: Two thin 12 µm natural titanium foils (13 mg together) were irradiated for 33 hours amounting to 1323µA[asterisk]h, yielding 17.8 mCi which decayed to 11.65 mCi by the beginning of isolation. Both foils were dissolved in 400 µL HF and 100 µL H2SO4. After heating under argon flow, 10.6 mCi were transferred to a platinum crucible, neutralized, and oxidized at 790°C with a mixture of Na2CO3 and NaNO3 (43:1). Once cooled, 7.5 mCi were centrifuged for 10 minutes at 5000 rpm. The 7 mCi supernatant was pH adjusted to 3-4 with HCl. The solution was passed through a Chelex-100 column which was then eluted with NH3, yielding 3.8 mCi as NH4VO3. The solvent was dried at 300°C before 1.3 mCi was combined with acetyl acetonate and heated under reflux. The resulting 182 µCi of 48V-VO(acac)2 was passed through an OnGuard II M filter, which trapped free vanadium and passed 48V-VO(acac)2, yielding 85 µCi. The composition of the eluent was assessed twice with TLC, showing high counts of 48V-VO(acac)2. Uptake of 48V-VO(acac)2 was validated in PET/MR imaging experiments. The biodistribution was followed two days post injection and confirmed the uptake of the radiotracer in respective organs and tumor. Conclusion: This experiment yielded a workable geometry for foil irradiation given the activity produced. Despite low synthesis yields, several steps were identified for improvement. Further investigation found that additional steps should be taken when chelated compounds are present using the OnGuard II M cartridge; forgoing these steps results in a smearing of yellow iron in the cartridge, which was observed. The counts of free vanadium indicate the filtration was not completely successful; the additional procedure could produce higher yields. PET/MR imaging validated the increased uptake of this novel radiotracer for potentially improving early cancer detection.

  Publisher

• The Wallenberg Affair and the Onset of the Cold War

  Journal of Cold War Studies · 2017-08-01

  article1st authorCorresponding

  The tragic fate of the courageous Swedish diplomat Raoul Wallenberg after he was seized by Soviet forces at the end of World War II has never been adequately explained. For more than four decades afterward, Soviet officials refused to explain why Wallenberg was detained or what happened to him afterward. Even after the Soviet Union broke apart, officials in Moscow were averse to divulging much information about Wallenberg. The book Auf den Spuren Wallenbergs, edited by Stefan Karner, brings together contributors from several countries who draw on the latest releases from Moscow archives and produce up-to-date essays about what is known at this stage about Wallenberg's mysterious disappearance.

  PublisherDOI

• Inhibition of protein tyrosine phosphatase-1B in vitro and in vivo

  Journal of Biotechnology & Biomaterials · 2017-03-31

  article1st authorCorresponding
  Publisher

• Kinetic characterization of the inhibition of protein tyrosine phosphatase-1B by Vanadyl (VO2+) chelates

  JBIC Journal of Biological Inorganic Chemistry · 2017-10-25 · 6 citations

  articleOpen accessSenior author
  PublisherOA PDFDOI

• Electron microscope study of the kinetics of the fiber-to-crystal transition of sickle cell hemoglobin (mutant hemoglobins/nucleation kinetics/optical diffraction/protein self-assembly/sickle cell anemia)

  2016-01-01

  articleSenior author

  The intermediates and the rate-limiting step in the crystallization of deoxygenated sickle hemoglobin have been determined by a kinetic study with the use of electron microscopy. In slowly stirred solutions of deoxygenated hemo- globin S (Pumphrey, J. & Steinhardt, J. (1977) J. Mol. Biol. 112, 359-375), the sequential appearance of fibers having a diameter of ;210 i, bundles of aligned fibers in well-ordered arrays, thick fibers of t470 A diameter, and microcrystals is ob- served. Only the fibers having a diameter of z210 A and bundles of aligned fibers are assigned as kinetically important inter- mediates of the fiber-to-crystal transition. Addition of micro- scopic seed crystals obtained from slowly stirred solutions of deoxyhemoglobin S to a solution composed of only fibers and hemoglobin monomers results in more rapid crystallization than in control solutions. Addition of seed crystals after the formation of bundles of aligned fibers does not alter the overall kinetics of crystallization. The results demonstrate that alignment of fibers is the rate-limiting step in the crystallization process and results in formation of nucleation sites for crystal growth. The aggregation of hemoglobin S (Hb S) in deoxygenated so- lutions is accompanied by changes in several physical properties of the solution. The most important with respect to physiological consequences is the large increase in viscosity attendant with gelation and associated with the formation of helical fibers (1-4). Because the kinetics of gelation exhibit a concentration dependence similar to that observed for condensation processes, the phase transition to a gel has been assumed to require the crystallization of fibers by their alignment (5-8). However, conditions of gentle agitation or stirring inhibit gelation and promote the crystallization of Hb S (9). These observations imply that two physically distinct processes govern the aggre- gation of Hb S. Because the kinetics of gelation may be a major determinant of the clinical severity of sickle cell anemia (8, 10), it is important to define the molecular packing of Hb S in gels and crystals and to characterize those factors that govern its aggregation and polymerization tendencies. In this communication we report the results of an electron microscopic study of the kinetics of crystallization of Hb S in gently agitated solutions. The results demonstrate that fiber formation is part of this crystallization process and that the rate-limiting step in crystal formation is the alignment of helical fibers. Designation of the rate-limiting step in crystal formation as the alignment of fibers requires that gelation is governed by a different rate-determining step and results simply in the en- tanglement of fibers in highly viscous media. Differentiation of the two rate-governing processes, when correlated with the results of other structural and physiological studies, suggests that gelation and fiber alignment have different roles in the pathophysiology of sickle cell anemia.

  Publisher

• Neutral metal-bound water is the b alcohol dehydrogenase (electron paramagnetic resonance/oxygen-17/pH dependence of kin(

  2016-01-01

  article1st authorCorresponding

  The catalytic role of the active site metal-water complex in horse liver alcohol dehydrogenase (alcohol:NAD+ ox- idoreductase, EC 1.1.1.1) is investigated on the basis of a com- parative analysis of the pH dependence of steady-state kinetic pa- rameters of the native and active-site-specific Co +-reconstituted enzyme and on the basis of assignment of the coordination en- vironment of the Co2+ by electron paramagnetic resonance meth- ods. The pH dependence of the kinetic parameters for the oxi- dation of benzyl alcohol reveals two ionizations (pK 6.7; pK2 - 10.6) that govern kcat and belong to the ternary enzyme-NAD+- alcohol complex and two ionizations (pKl' = 7.5; pK2' 8.9) that govern kecat/Km and belong to the binary enzyme-NAD, complex. The ionizations pK2 and pK2' decrease by 0.5-1 pKa unit upon replacement of the active site Zn2+ by Co2+. A similar metal ion dependence of pK2 and pK2' is observed for the oxidation of 2- propanol. We attribute these ionizations to a metal-bound water molecule. The zero-field splitting energy of the Co2+ in the bi- nary enzyme-NADH complex and the ternary enzyme-NADH- CF3CH2OH complex is =22 cm- 1, indicative of a pentacoordinate species. Binding of a water molecule to the metal ion as the fifth' ligand in the ternary enzyme-NADH-CF3CH20OH complex is confirmed on the basis of magnetic interactions of H2170 with Co2+. The results indicate that the active site metal ion in catalytically competent ternary enzyme-coenzyme-substrate complexes is pentacoordinate and is ligated by a neutral water molecule in the physiological pH range. We suggest that the neutral metal-bound water molecule serves as the base catalyst for proton abstraction in alcohol oxidation.

  Publisher

• Preferential sequestration of a vanadyl chelate by cancer tissue facilitates 2-(fluorine-18)-2- deoxyglucose (FDG) uptake for positron emission tomography (PET) imaging

  Journal of Postgenomics Drug & Biomarker Development · 2015-05-20

  article1st authorCorresponding
  Publisher

Recent grants

• NIH Grant R01AA006374

  NIH · $958k · 1993

• NIH Grant R21DK057599

  NIH · $305k · 2005

• NIH Grant T32GM008720

  NIH · $4.0M · 2021

• NIH Grant R01GM021900

  NIH · $3.0M · 2000

Frequent coauthors

• Devkumar Mustafi

  62 shared

• Lawrence C. Kuo

  Janssen (United States)

  17 shared

• Gregg B. Wells

  Bryan College

  12 shared

• J. Krzystek

  National High Magnetic Field Laboratory

  9 shared

• E. V. Gal'tseva

  Florida State University

  9 shared

• Moon B. Yim

  9 shared

• William A. Eaton

  National Institute of Diabetes and Digestive and Kidney Diseases

  9 shared

• Louis‐Claude Brunel

  9 shared

Labs

• Marvin W. Makinen's LabPI

  1-2 sentence research focus

Education

• D. Phil., Laboratory of Molecular Biophysics

  Oxford University

  1974

• M. D., School of Medicine

  University of Pennsylvania

  1968

• B. A., Chemistry

  University of Pennsylvania

  1961