RT Journal Article
SR Electronic
T1 Combination of Carriers with Complementary Intratumoral Microdistributions of Delivered <strong>α</strong>-Particles May Realize the Promise for <sup>225</sup>Ac in Large, Solid Tumors
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 1223
OP 1230
DO 10.2967/jnumed.121.262992
VO 63
IS 8
A1 Alaina Howe
A1 Omkar Bhatavdekar
A1 Dominick Salerno
A1 Anders Josefsson
A1 Jesus Pacheco-Torres
A1 Zaver M. Bhujwalla
A1 Kathleen L. Gabrielson
A1 George Sgouros
A1 Stavroula Sofou
YR 2022
UL http://jnm.snmjournals.org/content/63/8/1223.abstract
AB 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.