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Alpha-particle radiotherapy: For large solid tumors diffusion trumps targeting
- Zhu, Charles, Sempkowski, Michelle, Holleran, Timothy, Linz, Thomas, Bertalan, Thomas, Josefsson, Anders, Bruchertseifer, Frank, Morgenstern, Alfred, Sofou, Stavroula
- Biomaterials 2017 v.130 pp. 67-75
- animal models, antibodies, encapsulation, humans, irradiation, nanocarriers, neoplasms, radiolabeling, radiotherapy
- 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.