Title: Alpha-particle radiotherapy: For large solid tumors diffusion trumps targeting
Authors: ZHU CharlesSEMPKOWSKI MichelleHOLLERAN TimothyLINZ ThomasBERTALAN ThomasJOSEFSSON AndersBRUCHERTSEIFER FrankMORGENSTERN AlfredSOFOU Stavroula
Citation: BIOMATERIALS vol. 130 p. 67-75
Publisher: ELSEVIER SCI LTD
Publication Year: 2017
JRC N°: JRC105343
ISSN: 0142-9612
URI: http://publications.jrc.ec.europa.eu/repository/handle/JRC105343
DOI: 10.1016/j.biomaterials.2017.03.035
Type: Articles in periodicals and books
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.
JRC Directorate:Nuclear Safety and Security

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