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

Rajiv Ranjit Nair; Aprameya Prasad; Omkar Bhatavdekar; Aira Sarkar; Kathleen L Gabrielson; Stavroula Sofou

doi:10.1007/s00259-024-06710-0

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 Apr 20. doi: 10.1007/s00259-024-06710-0. Online ahead of print.

Authors

Rajiv Ranjit Nair^#¹, Aprameya Prasad^#¹, Omkar Bhatavdekar¹, Aira Sarkar¹, Kathleen L Gabrielson², Stavroula Sofou^{3

4}

Affiliations

¹ Chemical and Biomolecular Engineering (ChemBE), Institute for NanoBioTechnology (INBT), Johns Hopkins University, 3400 North Charles Street, Baltimore, MD, 21218, USA.
² Molecular and Comparative Pathobiology, Johns Hopkins University, Baltimore, MD, USA.
³ Chemical and Biomolecular Engineering (ChemBE), Institute for NanoBioTechnology (INBT), Johns Hopkins University, 3400 North Charles Street, Baltimore, MD, 21218, USA. ssofou1@jhu.edu.
⁴ Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Cancer Invasion & Metastasis Program, Johns Hopkins University, Baltimore, MD, USA. ssofou1@jhu.edu.

^# Contributed equally.

PMID: 38641714
DOI: 10.1007/s00259-024-06710-0

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.

Keywords: Actinium-225; Alpha-particle radiotherapy; Antibody-targeted radiotherapy; Intratumor distributions; Low targeted markers; Spheroids.