Engineered liposomes for potential α-particle therapy of metastatic cancer

Stavroula Sofou, James L. Thomas, Hung Yin Lin, Michael R. McDevitt, David A. Scheinberg, George Sgouros

Research output: Contribution to journalArticle

Abstract

Disseminated, metastatic cancer is frequently incurable. Targeted α-particle emitters hold great promise as therapeutic agents for disseminated disease. 225Ac is a radionuclide generator that has a 10-d half-life and results in α-emitting daughter elements ( 221Fr, 217At, 213Bi) that lead to the emission of a total of 4 α-particles. The aim of this study was to develop approaches for stable and controlled targeting of 225Ac to sites of disseminated tumor metastases. Liposomes with encapsulated 225Ac were developed to retain the potentially toxic daughters at the tumor site. Methods: 225Ac was passively entrapped in liposomes. To experimentally test the retention of actinium and its daughters by the liposomes, the γ-emissions of 213Bi were measured in liposome fractions, which were separated from the parent liposome population and the free radionuclides, at different times. Under equilibrium conditions the decay rate of 213Bi was used to determine the concentration of 225Ac. Measurements of the kinetics of 213Bi activity were performed to estimate the entrapment of 213Bi, the last α-emitting daughter in the decay chain. Results: Stable pegylated phosphatidylcholine-cholesterol liposomes of different sizes and charge were prepared. Multiple (more than 2) 225Ac atoms were successfully entrapped per liposome. 225Ac retention by zwitterionic liposomes was more than 88% over 30 d. Retention by cationic liposomes was lower. A theoretical calculation showed that for satisfactory 213Bi retention (>50%), liposomes of relatively large sizes (>650 nm in diameter) are required. 213Bi retention was experimentally verified to be liposome-size dependent. For large liposomes, the measured 213Bi retention was lower than theoretically predicted (less than 10%). Conclusion: This work supports the hypothesis that it may be possible to develop 225Ac-based therapies by delivering multiple 225Ac atoms in liposomes. Improvements in the retention of 225Ac daughters will likely be necessary to fulfill this potential. Because of the size of the liposomal structures required to contain the daughters, the approach is ideally suited for locoregional therapy (e.g., intraperitoneal, intrahepatic artery, or intrathecal).

Original languageEnglish (US)
Pages (from-to)253-260
Number of pages8
JournalJournal of Nuclear Medicine
Volume45
Issue number2
StatePublished - Feb 1 2004

Keywords

  • Ac
  • Ac membrane binding
  • Liposomes
  • α-particle therapy

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging

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  • Cite this

    Sofou, S., Thomas, J. L., Lin, H. Y., McDevitt, M. R., Scheinberg, D. A., & Sgouros, G. (2004). Engineered liposomes for potential α-particle therapy of metastatic cancer. Journal of Nuclear Medicine, 45(2), 253-260.