Alaina Howe1, Omkar Bhatavdekar1, Dominick Salerno1, Anders Josefsson2, Jesus Pacheco-Torres2, Zaver M Bhujwalla2, Kathleen L Gabrielson3, George Sgouros2, Stavroula Sofou4,5. 1. Chemical and Biomolecular Engineering, Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, Maryland. 2. Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, Maryland. 3. Molecular and Comparative Pathobiology, Johns Hopkins University, Baltimore, Maryland; and. 4. Chemical and Biomolecular Engineering, Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, Maryland; ssofou1@jhu.edu. 5. Sidney Kimmel Comprehensive Cancer Center, Cancer Invasion and Metastasis Program, Department of Oncology, Johns Hopkins University, Baltimore, Maryland.
Abstract
α-particle radiotherapy has already been shown to be impervious to most resistance mechanisms. However, in established (i.e., large, vascularized) soft-tissue lesions, the diffusion-limited penetration depths of radiolabeled antibodies or nanocarriers (≤50-80 μm) combined with the short range of α-particles (4-5 cell diameters) may result in only partial tumor irradiation, potentially limiting treatment efficacy. To address this challenge, we combined carriers with complementary intratumoral microdistributions of the delivered α-particles. We used the α-particle generator 225Ac, and we combined a tumor-responsive liposome (which, on tumor uptake, releases into the interstitium a highly diffusing form of its radioactive payload [225Ac-DOTA], potentially penetrating the deeper parts of tumors where antibodies do not reach) with a separately administered, less-penetrating radiolabeled antibody (irradiating the tumor perivascular regions where liposome contents clear too quickly). Methods: In a murine model with orthotopic human epidermal growth factor receptor 2-positive BT474 breast cancer xenografts, the biodistributions of each carrier were evaluated, and the control of tumor growth was monitored after administration of the same total radioactivity of 225Ac delivered by the 225Ac-DOTA-encapsulating liposomes, by the 225Ac-DOTA-SCN--labeled trastuzumab, and by both carriers at equally split radioactivities. Results: Tumor growth was significantly more inhibited when the same total injected radioactivity was divided between the 2 separate carriers than when delivered by either of the carriers alone. The combined carriers enabled more uniform intratumoral microdistributions of α-particles, at a tumor dose that was lower than the dose delivered by the antibody alone. Conclusion: This strategy demonstrates that more uniform microdistributions of the delivered α-particles within established solid tumors improve efficacy even at lower tumor doses. Augmentation of antibody-targeted α-particle therapies with tumor-responsive liposomes may address partial tumor irradiation, improving therapeutic effects.
α-particle radiotherapy has already been shown to be impervious to most resistance mechanisms. However, in established (i.e., large, vascularized) soft-tissue lesions, the diffusion-limited penetration depths of radiolabeled antibodies or nanocarriers (≤50-80 μm) combined with the short range of α-particles (4-5 cell diameters) may result in only partial tumor irradiation, potentially limiting treatment efficacy. To address this challenge, we combined carriers with complementary intratumoral microdistributions of the delivered α-particles. We used the α-particle generator 225Ac, and we combined a tumor-responsive liposome (which, on tumor uptake, releases into the interstitium a highly diffusing form of its radioactive payload [225Ac-DOTA], potentially penetrating the deeper parts of tumors where antibodies do not reach) with a separately administered, less-penetrating radiolabeled antibody (irradiating the tumor perivascular regions where liposome contents clear too quickly). Methods: In a murine model with orthotopic human epidermal growth factor receptor 2-positive BT474 breast cancer xenografts, the biodistributions of each carrier were evaluated, and the control of tumor growth was monitored after administration of the same total radioactivity of 225Ac delivered by the 225Ac-DOTA-encapsulating liposomes, by the 225Ac-DOTA-SCN--labeled trastuzumab, and by both carriers at equally split radioactivities. Results: Tumor growth was significantly more inhibited when the same total injected radioactivity was divided between the 2 separate carriers than when delivered by either of the carriers alone. The combined carriers enabled more uniform intratumoral microdistributions of α-particles, at a tumor dose that was lower than the dose delivered by the antibody alone. Conclusion: This strategy demonstrates that more uniform microdistributions of the delivered α-particles within established solid tumors improve efficacy even at lower tumor doses. Augmentation of antibody-targeted α-particle therapies with tumor-responsive liposomes may address partial tumor irradiation, improving therapeutic effects.
Authors: Clemens Kratochwil; Frank Bruchertseifer; Frederik L Giesel; Mirjam Weis; Frederik A Verburg; Felix Mottaghy; Klaus Kopka; Christos Apostolidis; Uwe Haberkorn; Alfred Morgenstern Journal: J Nucl Med Date: 2016-07-07 Impact factor: 10.057
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Authors: George Sgouros; John C Roeske; Michael R McDevitt; Stig Palm; Barry J Allen; Darrell R Fisher; A Bertrand Brill; Hong Song; Roger W Howell; Gamal Akabani; Wesley E Bolch; A Bertrand Brill; Darrell R Fisher; Roger W Howell; Ruby F Meredith; George Sgouros; Barry W Wessels; Pat B Zanzonico Journal: J Nucl Med Date: 2010-01-15 Impact factor: 10.057
Authors: Dominick Salerno; Alaina Howe; Omkar Bhatavdekar; Anders Josefsson; Jesus Pacheco-Torres; Zaver M Bhujwalla; Kathleen L Gabrielson; Stavroula Sofou Journal: Bioeng Transl Med Date: 2021-11-17