title: Alpha-particle radiotherapy: For large solid tumors diffusion trumps targeting.
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-releasing225Ac-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.
authors.affiliation: Departments of Biomedical Engineering, Rutgers University, 599 Taylor Road, Piscataway, NJ 08854, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Zhu
authors.affiliation: Departments of Biomedical Engineering, Rutgers University, 599 Taylor Road, Piscataway, NJ 08854, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Sempkowski
authors.affiliation: Departments of Biomedical Engineering, Rutgers University, 599 Taylor Road, Piscataway, NJ 08854, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Holleran
authors.affiliation: Chemical and Biochemical Engineering, Rutgers University, 599 Taylor Road, Piscataway, NJ 08854, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Linz
authors.affiliation: Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ 08544, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bertalan
authors.affiliation: Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Anders
authors.initials: A
authors.lastname: Josefsson
authors.affiliation: European Commission, Joint Research Centre, Directorate for Nuclear Safety and Security, P.O. Box 2340, D-76125 Karlsruhe, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Bruchertseifer
authors.affiliation: European Commission, Joint Research Centre, Directorate for Nuclear Safety and Security, P.O. Box 2340, D-76125 Karlsruhe, Germany.
authors.forename: Alfred
authors.initials: A
authors.lastname: Morgenstern
authors.affiliation: Departments of Biomedical Engineering, Rutgers University, 599 Taylor Road, Piscataway, NJ 08854, USA; Chemical and Biochemical Engineering, Rutgers University, 599 Taylor Road, Piscataway, NJ 08854, USA; The Rutgers Center for Lipid Research, Rutgers University, 599 Taylor Road, Piscataway, NJ 08854, USA. Electronic address: ss1763@soe.rutgers.edu.
authors.forename: Stavroula
authors.initials: S
authors.lastname: Sofou
mesh_terms: D000186:Actinium; D000512:Alpha Particles / Q000627:therapeutic use*; D000818:Animals; D000906:Antibodies / Q000378:metabolism; D016923:Cell Death; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004058:Diffusion; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008081:Liposomes / Q000737:chemistry; D008819:Mice, Nude; D009369:Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D010766:Phosphorylation; D018874:Spheroids, Cellular / Q000378:metabolism; D016019:Survival Analysis
chemical_list: C000615155:Actinium-225; D000906:Antibodies; C468783:H2AX protein, human; D006657:Histones; D008081:Liposomes; D000186:Actinium
keywords: Actinium-225; Interstitial transport; Solid tumors; Tumor penetration; pH-responsive liposomes; α-particle therapy