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Combined, yet separate: cocktails of carriers (not drugs) for actinium-225 α-particle therapy of solid tumors expressing moderate-to-low levels of targetable markers

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Alpha-particle radionuclide-antibody conjugates are being clinically evaluated against solid tumors even when they moderately express the targeted markers. At this limit of lower tumor-absorbed doses, to maintain efficacy, the few(er) intratumorally delivered alpha-particles need to traverse/hit as many different cancer cells as possible. We complement antibody-radioconjugate therapies with a separate nanocarrier delivering a fraction of the same total injected radioactivity to tumor regions geographically different than those affected by targeting antibodies; these carrier-cocktails collectively distribute the alpha-particle emitters better.

Methods

The efficacy of actinium-225 delivered by our carrier-cocktails was assessed in vitro and on mice with orthotopic MDA-MB-436 and/or MDA-MB-231 triple-negative breast cancers and/or an ectopic BxPC3 pancreatic cancer. Cells/tumors were chosen to express low-to-moderate levels of HER1, as model antibody-targeted marker.

Results

Independent of cell line, antibody-radioconjugates were most lethal on cell monolayers. On spheroids, with radii greater than alpha-particles’ range, carrier-cocktails improved killing efficacy (p < 0.0500). Treatment with carrier-cocktails decreased the MDA-MB-436 and MDA-MB-231 orthotopic tumor volumes by 73.7% and 72.1%, respectively, relative to treatment with antibody-radioconjugates alone, at same total injected radioactivity; these carrier-cocktails completely eliminated formation of spontaneous metastases vs. 50% and 25% elimination in mice treated with antibody-radioconjugates alone. In BxPC3 tumor-bearing mice, carrier-cocktails increased the median survival to 25–26 days (in male–female animals) vs. 20–21 days of mice treated with antibody-radioconjugates alone (vs. 17 days for non-treated animals). Survival with carrier-cocktail radiotherapy was further prolonged by pre-injecting low-dose, standard-of-care, gemcitabine (p = 0.0390).

Conclusion

Tumor-agnostic carrier-cocktails significantly enhance the therapeutic efficacy of existing alpha-particle radionuclide-antibody treatments.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors thank Dr. George Sgouros at Johns Hopkins University for help with the dosimetry calculations, and Ms. Pooja Hariharan and Mr. Rohit Chaudhari for assistance with animal handling.

Funding

This work was partially supported by grants from the W.W. Smith Charitable Trust, the Allegheny Health Network-Johns Hopkins Cancer Research Fund, and the Elsa U. Pardee Foundation.

Author information

Author notes

  1. Rajiv Ranjit Nair and Aprameya Prasad equally contributed to this work.

Authors and Affiliations

  1. Chemical and Biomolecular Engineering (ChemBE), Institute for NanoBioTechnology (INBT), Johns Hopkins University, 3400 North Charles Street, Baltimore, MD, 21218, USA

    Rajiv Ranjit Nair, Aprameya Prasad, Omkar Bhatavdekar, Aira Sarkar & Stavroula Sofou

  2. Molecular and Comparative Pathobiology, Johns Hopkins University, Baltimore, MD, USA

    Kathleen L. Gabrielson

  3. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Cancer Invasion & Metastasis Program, Johns Hopkins University, Baltimore, MD, USA

    Stavroula Sofou

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  1. Rajiv Ranjit Nair
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Contributions

Material preparation and data collection were performed by Rajiv Nair, Aprameya Prasad, Omkar Bhatavdekar, and Aira Sarkar. Analysis was performed by Rajiv Nair, Aprameya Prasad, Kathleen Gabrielson, and Stavroula Sofou. The first draft of the manuscript was written by Stavroula Sofou, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Stavroula Sofou.

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Nair, R.R., Prasad, A., Bhatavdekar, O. et al. Combined, yet separate: cocktails of carriers (not drugs) for actinium-225 α-particle therapy of solid tumors expressing moderate-to-low levels of targetable markers. Eur J Nucl Med Mol Imaging (2024). https://doi.org/10.1007/s00259-024-06710-0

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