Alpha-particle radiotherapy: For large solid tumors diffusion trumps targeting

Charles Zhu, Michelle Sempkowski, Timothy Holleran, Thomas Linz, Thomas Bertalan, Anders Josefsson, Frank Bruchertseifer, Alfred Morgenstern, Stavroula Sofou

Research output: Contribution to journalArticlepeer-review

Abstract

Diffusion limitations on the penetration of nanocarriers in solid tumors hamper their therapeutic use when labeled with α-particle emitters. This is mostly due to the α-particles’ relatively short range (≤100 μm) resulting in partial tumor irradiation and limited killing. To utilize the high therapeutic potential of α-particles against solid tumors, we designed non-targeted, non-internalizing nanometer-sized tunable carriers (pH-tunable liposomes) that are triggered to release, within the slightly acidic tumor interstitium, highly-diffusive forms of the encapsulated α-particle generator Actinium-225 (225Ac) resulting in more homogeneous distributions of the α-particle emitters, improving uniformity in tumor irradiation and increasing killing efficacies. On large multicellular spheroids (400 μm-in-diameter), used as surrogates of the avascular areas of solid tumors, interstitially-releasing liposomes resulted in best growth control independent of HER2 expression followed in performance by (a) the HER2-targeting radiolabeled antibody or (b) the non-responsive liposomes. In an orthotopic human HER2-negative mouse model, interstitially-releasing 225Ac-loaded liposomes resulted in the longest overall and median survival. This study demonstrates the therapeutic potential of a general strategy to bypass the diffusion-limited transport of radionuclide carriers in solid tumors enabling interstitial release from non-internalizing nanocarriers of highly-diffusing and deeper tumor-penetrating molecular forms of α-particle emitters, independent of cell-targeting.

Original languageEnglish (US)
Pages (from-to)67-75
Number of pages9
JournalBiomaterials
Volume130
DOIs
StatePublished - Jun 1 2017

Keywords

  • Actinium-225
  • Interstitial transport
  • Solid tumors
  • Tumor penetration
  • pH-responsive liposomes
  • α-particle therapy

ASJC Scopus subject areas

  • Bioengineering
  • Ceramics and Composites
  • Biophysics
  • Biomaterials
  • Mechanics of Materials

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