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ImmunoPET Imaging of Pancreatic Tumors with 89Zr-Labeled Gold Nanoparticle–Antibody Conjugates

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Abstract

Purpose

Targeted delivery in vivo remains an immense roadblock for the translation of nanomaterials into the clinic. The greatest obstacle is the mononuclear phagocyte system (MPS), which sequesters foreign substances from general circulation and causes accumulation in organs such as the liver and spleen. The purpose of this study was to determine whether attaching an active targeting antibody, 5B1, to the surface of gold nanoparticles and using clodronate liposomes to deplete liver and splenic macrophages could help to minimize uptake by MPS organs, increase targeted delivery to CA19.9-positive pancreatic tumors, and enhance pancreatic tumor delineation.

Procedures

To produce the antibody-gold nanoparticle conjugate (Ab-AuNP), the Ab was conjugated to p-isothiocyanatobenzyl-desferrioxamine (p-SCN-DFO) and subsequently conjugated to NHS-activated gold nanoparticles. The Ab-AuNP was characterized by transmission electron microscopy (TEM) and atomic force microscopy (AFM). Modified Lindmo assay was performed to assess binding affinity and internalization potential in vitro. The Ab-AuNP was radiolabeled with 89Zr and injected into CA19.9-positive BxPc-3 pancreatic orthotopic tumor-bearing mice pretreated with or without clodronate liposomes for PET imaging and biodistribution studies. Inductively coupled plasma-optical emission spectrometry (ICP-OES) analysis was used to confirm delivery of gold nanoparticles to BxPc-3 pancreatic subcutaneous xenografts.

Results

Mice pretreated with clodronate liposomes in an orthotopic setting demonstrated decreased liver uptake at early time points (12.2 ± 2.3 % ID/g vs. 22.8 ± 3.8 % ID/g at 24 h) and increased tumor uptake at 120 h (13.8 ± 8.0 % ID/g vs. 6.0 ± 1.2 % ID/g). This allowed for delineation of orthotopic pancreatic xenografts in significantly more mice treated with clodronate (6/6) than in mice not treated with clodronate (2/6) or mice injected with gold nanoparticles labeled with a nonspecific antibody (0/5).

Conclusions

The combination of clodronate liposomes and an active targeting antibody on the surface of gold nanoparticles allowed for PET/CT imaging of subcutaneous and orthotopic pancreatic xenografts in mice.

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Acknowledgments

The authors gratefully acknowledge the Radiochemistry and Molecular Imaging Probes Core Facility, the Small Animal Imaging Facility, and the Molecular Cytology Core Facility. The authors also gratefully acknowledge the Electron Microscopy Resource Center at The Rockefeller University. We gratefully acknowledge the Thompson Family Foundation, Inc., the Mr. William H. and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research, and the Center for Experimental Therapeutics of Memorial Sloan Kettering Cancer Center.

Funding

The Radiochemistry and Molecular Imaging Probes Core Facility, the Small Animal Imaging Facility, and the Molecular Cytology Core Facility were supported in part by NIH grant P30 CA08748. This study was also supported in part by NIH NCI R35 CA232130 (JSL).

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Authors and Affiliations

  1. Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Nicholas B. Sobol, Joshua A. Korsen, Kimberly J. Edwards & Jason S. Lewis

  2. Department of Pharmacology, Weill Cornell Medical College, New York, NY, USA

    Joshua A. Korsen & Jason S. Lewis

  3. Department of Chemistry, Hunter College, New York, NY, USA

    Ali Younes

  4. Program in Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Jason S. Lewis

  5. Department of Radiology, Weill Cornell Medical College, New York, NY, USA

    Jason S. Lewis

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  1. Nicholas B. Sobol
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Correspondence to Jason S. Lewis.

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Conflict of Interest

JSL received 5B1 antibody and research support for these studies from MabVax Therapeutics. All other authors have no other disclosures in relationship to this manuscript.

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Sobol, N.B., Korsen, J.A., Younes, A. et al. ImmunoPET Imaging of Pancreatic Tumors with 89Zr-Labeled Gold Nanoparticle–Antibody Conjugates. Mol Imaging Biol 23, 84–94 (2021). https://doi.org/10.1007/s11307-020-01535-3

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  • DOI: https://doi.org/10.1007/s11307-020-01535-3

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