Preirradiation of Spheroids with Ac-Trastuzumab Improves Penetration of Ac-Liposomes and MIRDcell Predictions of Responses to Drug Cocktails.

Journal: Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Published Date: Jun 12, 2025

Abstract

This investigation examined the factors involved in predicting the responses of micrometastases to targeted Ac-based therapies and in optimizing these therapies through the use of cocktails of radiopharmaceuticals (RPTs). MIRDcell version 4 was used to model the surviving fraction (SF) of cells in multicellular spheroids that were treated with cocktails of Ac RPTs as previously reported by Howe et al. in this journal. Spheroids were treated with varying activity concentrations of [Ac]Ac-DOTA-SCN-trastuzumab (Ac-trastuzumab) and Ac-DOTA-encapsulating liposomes (Ac-liposomes). With the total activity concentration kept constant at 13.75 kBq/mL, 5 different activity distributions among the liposomes and antibodies were evaluated: 0%, 30%, 50%, 70%, and 100% of the total activity on each carrier. Penetration of the Ac-trastuzumab and Ac-liposomes into the spheroids was obtained with fluorescent surrogates in the previous work and remeasured here to determine whether preirradiating the spheroids with Ac-trastuzumab affected the spatiotemporal distribution of the liposomes. These data were used to compare MIRDcell-predicted SFs with experimental spheroid outgrowths. In addition, the artificial intelligence tool in MIRDcell was used to optimize the best cocktail formulation of Ac-antibodies and Ac-liposomes to achieve SFs of less than 0.0001 while minimizing the number of total decays necessary. The penetration profiles of spheroids with 200-µm radii show a 42% increase in the total number of decays attributed to Ac-liposomes between 0 and 100 µm from the centers of spheroids when first pretreated with 6.5 kBq/mL Ac-trastuzumab. The MIRDcell predictions based on liposome penetration data obtained after preirradiation with Ac-trastuzumab also provided a better match to the experimental data. Artificial intelligence optimization found that although Ac-liposomes alone are able to sterilize all the cancer cells in the spheroid, 44% more total decays are required than when using a cocktail of Ac-trastuzumab and Ac-liposomes. Penetration of Ac-liposomes was enhanced by pretreatment with Ac-trastuzumab, and strategies to optimize penetration into micrometastases are important for RPT therapy with carrier cocktails. RPT cocktails, as opposed to single agents, may be required to eliminate circulating tumor cells, disseminated tumor cells, and micrometastases.

Authors

  • Hima Tallam
    From the Department of Radiology and Imaging Sciences (H.T., D.C.E., S.L., R.M.S.) and Department of Biostatistics and Clinical Epidemiology Service (P.W.), Clinical Center, National Institutes of Health, 10 Center Dr, Bldg 10, Room 1C224D, MSC 1182, Bethesda, MD 20892-1182; and Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, Wis (P.J.P.).
  • Rajiv Nair
    Department of Chemical and Biomolecular Engineering, Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, Maryland; and.
  • Aira Sarkar
    Department of Chemical and Biomolecular Engineering, Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, Maryland; and.
  • Sumudu Katugampola
    Division of Radiation Research, Department of Radiology, New Jersey Medical School, Rutgers University, Newark, New Jersey.
  • Stavroula Sofou
    Department of Chemical and Biomolecular Engineering, Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, Maryland; and rhowell@rutgers.edu ssofou1@jhu.edu.
  • Roger W Howell
    Division of Radiation Research, Department of Radiology, New Jersey Medical School, Rutgers University, Newark, New Jersey rhowell@rutgers.edu.

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