About

Michael Rod Zalutsky is a distinguished professor whose laboratory focuses on the development of novel radioactive compounds to improve cancer diagnosis and treatment. His work primarily involves radiohalogenation of biomolecules through site-specific approaches, often utilizing demetallation reactions. He employs radionuclides such as I-123, I-124, and F-18 for imaging purposes, with particular interest in F-18 for quantifying biochemical and physiological processes via positron emission tomography. For therapeutic applications, he works with astatine-211, which emits alpha-particles that are highly cytotoxic and have a very short range, enabling extremely focal irradiation of malignant cells while sparing neighboring healthy tissue. His recent contributions include developing reagents for protein and peptide radioiodination that significantly reduce deiodination in vivo, demonstrating the efficacy of At-211 labeled monoclonal antibodies in treating rat models of neoplastic meningitis, synthesizing thymidine analogues labeled with At-211 that are incorporated into cellular DNA with high cytotoxicity, and creating radiohalobenzylguanidines specifically cytotoxic to human neuroblastoma cells. His research aims to advance targeted radiopharmaceuticals for cancer therapy, emphasizing precision and efficacy in treatment modalities.

Research topics

• Biochemistry
• Biology
• Genetics
• Cancer research
• Natural resource economics
• Biochemical engineering
• Business
• Economics
• Chemistry
• Environmental science
• Physics
• Molecular biology
• Internal medicine
• Engineering
• Medicine

Selected publications

• 191Pt-labeled trithiol-Hoechst-PSMA: preliminary evaluation of conjugates designed for delivery to genomic DNA of PSMA-positive cancers

  EJNMMI Radiopharmacy and Chemistry · 2026-01-09

  articleOpen accessSenior author

  Several platinum radionuclides, including 191Pt, are promising candidates for DNA-targeted Auger electron radiotherapy; however, effective compound designs are needed for this application. In this study, we developed six novel 191Pt-labeled compounds and evaluated their DNA-targeting properties in PSMA-positive tumors. Six trithiol-Hoechst-PSMA (THP) conjugates that consist of a trithiol ligand for 191Pt labeling, Hoechst33258 for DNA binding, and a PSMA-targeted moiety were synthesized and labeled with 191Pt, achieving radiochemical yields of 60–80%. The six [191Pt]Pt-THP compounds were evaluated for DNA-binding ability and PSMA targeting specificity in vitro, and biodistribution experiments were performed with five of the compounds in mice bearing subcutaneous PSMA-positive and PSMA-negative xenografts. Among them, [191Pt]Pt-THP3–4 and [191Pt]Pt-THP3–8, in which Hoechst33258 is linked on one side of the trithiol ligand via a linear PEG linker and the PSMA-targeting moiety is linked on the other side via a C4 linker, had the best properties. These compounds maintained higher PSMA targeting specificity and DNA-binding ability both in vitro and in vivo than the other [191Pt]Pt-THP compounds, exhibiting similar DNA binding in PSMA-positive PC3 PIP tumors in vivo as in the cultured cells from which the xenograft was derived. This study highlighted the importance of the linkers between the three components (trithiol-Hoechst-PSMA) and demonstrated binding of intravenously administered [191Pt]Pt-THP3–4 and [191Pt]Pt-THP3–8 to DNA in PSMA-positive tumors. Our compound designs and findings could be a useful foundation for DNA-targeted Auger electron cancer therapy, especially with Pt radionuclides.

  PublisherDOI

• Effective treatment of human prostate carcinoma xenografts with Single-Dose PSMA-targeted [211At]YF2

  European Journal of Nuclear Medicine and Molecular Imaging · 2025-10-30 · 2 citations

  articleSenior author
  PublisherDOI

• Structural analysis of nanobody interactions with their prostate-specific membrane antigen binding epitopes

  International Journal of Biological Macromolecules · 2025-07-01 · 3 citations

  articleOpen access

  Prostate-specific membrane antigen (PSMA), overexpressed in prostate cancer, is a promising target for diagnostics and therapy. However, the monoclonal antibodies in current use for PSMA targeting and inhibition have suboptimal activities due to their poor tissue and cell penetration and slow normal tissue clearance. Potentially superior alternatives are nanobodies (NBs), the single-chain variable domains of heavy-chain antibodies derived from camelids. The advantages of NBs include small size (~15 kDa), ability to bind hidden epitopes, and rapid clearance. In contrast to most known PSMA inhibitors, which bind to the same catalytic site in PMSA, NBs can bind to different PSMA epitopes, facilitating heterovalent binding strategies that could enhance their therapeutic and diagnostic potential. The objective of this study was to map these binding epitopes and hence to acquire an atomic-resolution understanding of NB-PMSA binding by investigating the structural interactions between PSMA and three NBs (NB7, NB8, and NB37). Using cryo-electron microscopy to generate high-resolution structures of NB-PSMA complexes, we found that NB7 had the highest affinity for PSMA due to a larger interface and to stabilizing interactions, including salt bridges and π-π stacking. Notably, we also found that NB7 and NB8 can bind simultaneously to different PSMA epitopes without interfering with the function of PSMA (which is still not completely known), opening the way for the development of theranostic applications for prostate cancer treatment and imaging. Importantly, NB7 binds specifically to human PSMA but not to murine PSMA, due to key amino acid differences responsible for its species specificity.

  PublisherDOI

• Enhancing the therapeutic index of [211At]YF2 with iodo pseudo carrier: A simple strategy for reducing accumulation in kidneys, salivary and lacrimal glands

  Nuclear Medicine and Biology · 2025-05-11 · 2 citations

  articleOpen accessSenior authorCorresponding
  PublisherOA PDFDOI

• Trithiol ligand provides tumor-targeting 191Pt-complexes with high molar activity and promising in vivo properties

  ChemRxiv · 2025-06-13

  preprintOpen accessSenior author

  Purpose: The Auger electron-emitting radionuclide 191Pt is a promising candidate for radiopharmaceutical therapy. Herein, we explored novel labeling methods for 191Pt using thiol-containing ligands to improve the in vivo stability and targeting ability of 191Pt-labeled complexes. Methods: We synthesized dithiol-containing N2S2 and NS2 ligands, and a trithiol ligand, and then compared their radiochemical reactivity with 191Pt. [191Pt]Pt-trithiol was synthesized and its biodistribution was evaluated in mice and compared with free 191Pt. Finally, a 191Pt-trithiol complex targeting prostate-specific membrane antigen (PSMA): [191Pt]Pt-trithiol-PSMA was developed and evaluated in mice bearing tumor xenografts and compared with a 191Pt-complex labeled via monothiol-containing Cys ([191Pt]Pt-Cys-PSMA). Results: A comparison of N2S2, NS2, and trithiol showed that the trithiol ligand is the best for producing 191Pt-labeled compounds in high yield and as a single peak in preparative HPLC. Notably, the trithiol ligand made 191Pt-labeled compounds and precursors separatable, achieving 191Pt-labeled products with a high molar activity: 200–400 mCi/µmol (7.4–14.8 GBq/µmol) at EOS. Additionally, [191Pt]Pt-trithiol and [191Pt]Pt-trithiol-PSMA were stable in vivo with rapid clearance compared with free 191Pt and [191Pt]Pt-Cys-PSMA. [191Pt]Pt-trithiol-PSMA resulted in a low uptake in most normal organs and a high uptake in the kidneys and prostate cancer with PSMA expression. Conclusions: This study demonstrated that a labeling method with trithiol for Pt radionuclides achieves 191Pt-labeled products with high molar activity. 191Pt-trithiol-PSMA showed promising in vivo stability and tumor-targeting specificity, which should facilitate the pharmaceutical development of Pt radionuclides for radiopharmaceutical therapy, especially Auger electron cancer therapy.

  PublisherOA PDFDOI

• Longitudinal Imaging Reveals Tumor Uptake and Prolonged Retention of Bispecific T Cell–Engaging Antibody in GBM via Passive and Active Mechanisms

  Clinical Cancer Research · 2025-06-13 · 2 citations

  articleOpen access

  PURPOSE: This study aimed to assess the dynamics of tumor-specific uptake, retention, and blood-tumor barrier penetration of our unique IL-13 receptor α-2 × CD3 bispecific T-cell engager (BTE) following systemic administration in mice with intracranial glioblastoma (GBM) xenografts. EXPERIMENTAL DESIGN: In vitro, BTE binding and accumulation were evaluated in glioma neurospheres. In in vivo studies, the BTEs labeled with either iodine-124 using residualizing chemistry or conjugated to Cy5 were used for longitudinal tracking in patient-derived xenograft models of GBM using PET/CT and confocal microscopy. The survival analysis in mice bearing intracranial GBM tumors was conducted to validate the findings from imaging studies. RESULTS: In vitro, the BTE demonstrated target-specific binding and accumulation in IL-13 receptor α-2-expressing glioma spheres. In vivo, PET/CT imaging revealed that the BTE reached the tumor site within 3 hours after injection, achieving up to 4.8% ID/g, with sustained tumor retention for up to 24 hours, significantly higher than background levels in surrounding normal brain tissue. Confocal microscopy confirmed BTE presence in the tumor bed extravascular space with evidence of T cell-mediated BTE transport across the blood-tumor barrier. Despite its short plasma half-life, the BTE remained in the tumor microenvironment for at least 24 hours. Mice bearing GBM6 brain tumors treated with BTE for 3 to 4 days apart via the intravenous route showed a significant survival advantage over the control group. CONCLUSIONS: Our findings provide critical insights into the pharmacokinetics of BTE molecules in GBM. They demonstrate effective penetration and prolonged intratumoral retention following a single systemic dose, supporting further exploration of BTE treatment regimens for translation to clinical settings.

  PublisherOA PDFDOI

• Trithiol ligand provides tumor-targeting 191Pt-complexes with high molar activity and promising in vivo properties

  Nuclear Medicine and Biology · 2025-06-10 · 2 citations

  articleSenior authorCorresponding
  PublisherDOI

• PSMA-reactive NB7 single domain antibody fragment: A potential scaffold for developing prostate cancer theranostics

  Nuclear Medicine and Biology · 2024-04-25 · 9 citations

  articleSenior authorCorresponding
  PublisherDOI

• A third generation PSMA-targeted agent [211At]YF2: Synthesis and in vivo evaluation

  Nuclear Medicine and Biology · 2024-05-01 · 15 citations

  articleOpen accessSenior authorCorresponding
  PublisherOA PDFDOI

• Supplemental Materials and Methods from <sup>131</sup>I-labeled Anti-HER2 Camelid sdAb as a Theranostic Tool in Cancer Treatment

  2023-03-31

  preprintOpen access

  <p>A detailed description of the materials and methods used for the HER2-2Rs15d structure determination, the radioiodination of sdAbs, and all flow cytometry experiments.</p>

  PublisherOA PDFDOI

Recent grants

• Astatine And Iodine Radiolabeled Monoclonal Antibodies

  NIH · $8.1M · 1985–2021

• Small Molecule PSMA-Targeted Alpha Therapy

  NIH · $3.6M · 2014–2026

• NIH Grant P01CA154291

  NIH · $20.4M · 2017

• NIH Grant R37CA042324

  NIH · $4.2M · 2010

• A novel cellular tumor vaccine strategy for mutant IDH1 glioma

  NIH · $33.0M · 2014–2025

Frequent coauthors

• Ganesan Vaidyanathan

  Duke University Hospital

  414 shared

• Darell D. Bigner

  Duke University

  295 shared

• Roger E. McLendon

  Duke University

  155 shared

• Henry S. Friedman

  Duke Medical Center

  153 shared

• Gamal Akabani

  Texas A&M University

  133 shared

• Donna J. Affleck

  Duke University

  106 shared

• James E. Herndon

  Duke University

  99 shared

• David A. Reardon

  Dana-Farber Cancer Institute

  91 shared

Labs

• Michael Zalutsky LaboratoryPI

Education

• BA, Chemistry

  Clark University

• PhD, Chemistry

  washington university

Awards & honors

• Aebersold Award. Society of Nuclear Medicine. 2007
• MERIT Award. National Institutes of Health. 2005