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Predicting response of micrometastases with MIRDcell V3: proof of principle with 225Ac-DOTA encapsulating liposomes that produce different activity distributions in tumor spheroids

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

Abstract

Purpose

The spatial distribution of radiopharmaceuticals within multicellular clusters is known to have a significant effect on their biological response. Most therapeutic radiopharmaceuticals distribute nonuniformly in tissues which makes predicting responses of micrometastases challenging. The work presented here analyzes published temporally dependent nonuniform activity distributions within tumor spheroids treated with actinium-225-DOTA encapsulating liposomes (225Ac-liposomes) and uses these data in MIRDcell V3.11 to calculate absorbed dose distributions and predict biological response. The predicted responses are compared with experimental responses.

Methods

Four types of liposomes were prepared having membranes with different combinations of release (R) and adhesion (A) properties. The combinations were R−A−, R−A+, R+A−, and R+A+. These afford different penetrating properties into tissue. The liposomes were loaded with either carboxyfluorescein diacetate succinimidyl ester (CFDA-SE) or 225Ac. MDA-MB-231 spheroids were treated with the CFDA-SE-liposomes, harvested at different times, and the time-integrated CFDA-SE concentration at each radial position within the spheroid was determined. This was translated into mean 225Ac decays/cell versus radial position, uploaded to MIRDcell, and the surviving fraction of cells in spherical multicellular clusters was simulated. The MIRDcell-predicted surviving fractions were compared with experimental fractional-outgrowths of the spheroids following treatment with 225Ac-liposomes.

Results

The biological responses of the multicellular clusters treated with 225Ac-liposomes with physicochemical properties R+A+, R−A+, and R−A− were predicted by MIRDcell with statistically significant accuracy. The prediction for R+A− was not predicted accurately.

Conclusion

In most instances, MIRDcell predicts responses of spheroids treated with 225Ac-liposomes that result in different tissue-penetrating profiles of the delivered radionuclides.

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Funding

This study was supported in part by grant 1R01CA245139 from NCI.

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Authors and Affiliations

  1. Division of Radiation Research, Department of Radiology and Center for Cell Signaling, New Jersey Medical School, Rutgers University, 205 S. Orange Avenue, Newark, NJ, 07103, USA

    Sumudu Katugampola, Jianchao Wang & Roger W. Howell

  2. Department of Chemical and Biomolecular Engineering, Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA

    Aprameya Prasad & Stavroula Sofou

Authors
  1. Sumudu Katugampola
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  2. Jianchao Wang
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  3. Aprameya Prasad
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  4. Stavroula Sofou
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  5. Roger W. Howell
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Contributions

SK analyzed data and drafted the manuscript. JW programmed MIRDcell V3.11 to facilitate the analysis. AP provided experimental data. SS conceived the liposome experiments, led the Hopkins team, and edited the manuscript. RWH conceived the collaborative project, led the Rutgers team, and edited the manuscript.

Corresponding author

Correspondence to Roger W. Howell.

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This article does not contain any studies with human participants or animals performed by any of the authors.

Conflict of interest

Sumudu Katugampola (SK), Jianchao Wang (JW), and Roger W. Howell (RWH) declare they have financial interests. RWH holds patent US 9,623,262 patent for MIRDcell V2. SK, JW, and RWH have petitioned Rutgers University to apply for a patent for MIRDcell V3.

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This article is part of the Topical Collection on Radiation biology.

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Katugampola, S., Wang, J., Prasad, A. et al. Predicting response of micrometastases with MIRDcell V3: proof of principle with 225Ac-DOTA encapsulating liposomes that produce different activity distributions in tumor spheroids. Eur J Nucl Med Mol Imaging 49, 3989–3999 (2022). https://doi.org/10.1007/s00259-022-05878-7

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  • DOI: https://doi.org/10.1007/s00259-022-05878-7

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