Combination of carriers, with complementary intratumoral microdistributions of delivered α-particles, may realize the promise for Actinium-225 in large solid tumors.

Alpha-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 and/or nanocarriers (up to 50-80µm) 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 use the α-particle generator Actinium-225 (225Ac), and we combine (1) a tumor-responsive liposome that upon tumor uptake releases in the interstitium a highly-diffusing form of its radioactive payload (225Ac-DOTA), which may penetrate the deeper parts of tumors where antibodies do not reach, with (2) a separately administered, less-penetrating radiolabeled-antibody irradiating the tumor perivascular regions from where liposome contents clear too fast. Methods: On a murine model with orthotopic HER2-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 (1) by the 225Ac-DOTA-encapsulating liposomes, (2) by the 225Ac-DOTA-SCN-labeled-trastuzumab, and (3) by both carriers at equally split radioactivities. Results: Tumor growth inhibition was significantly more pronounced when the same total injected radioactivity was divided between the two separate carriers, as compared to the growth delay by the same total injected radioactivity when delivered by either of the carriers alone. The combined carriers enabled more uniform intratumoral microdistributions of α-particles, at a tumor delivered dose that was lower than the dose delivered by the antibody alone. Significance: This strategy demonstrates that more uniform microdistributions of the delivered α-particles within established solid tumors improve efficacy even at lower tumor delivered doses. Augmentation of antibody-targeted α-particle therapies with tumor-responsive liposomes may address partial tumor irradiation improving therapeutic effects.