Combination of Carriers with Complementary Intratumoral Microdistributions of Delivered α-Particles May Realize the Promise for ²²⁵Ac in Large, Solid Tumors

Abstract

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 ( 225 Ac), and we combine (1) a tumor-responsive liposome that upon tumor uptake releases in the interstitium a highlydiffusing form of its radioactive payload ( 225 Ac-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 225 Ac delivered (1) by the 225 Ac-DOTA-encapsulating liposomes, (2) by the 225 Ac-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 tumorresponsive liposomes may address partial tumor irradiation improving therapeutic effects.

Two diverse carriers are better than one: A case study in α‐particle therapy for prostate specific membrane antigen‐expressing prostate cancers

“…In addition, Figure 4 shows that on the same (intermediate) size spheroids (r = 200 μm) with increasing PSMA‐expression levels (left‐to‐right), the best inhibition of spheroid growth was exhibited when increasing fractions of the radioactivity were delivered by the liposomes. This is because the radiolabeled antibody delivers its therapeutic cargo mostly in the periphery of the spheroid (the so‐called binding site barrier effect) 12,21 : increasing PSMA‐expression levels by cells required a lower fraction of the antibody‐delivered radioactivity, since the same levels of delivered radioactivity per cell could be reached at lower antibody concentrations given the increased numbers of receptors per cell. In Figure 4a, on spheroids that do not express detectable PSMA levels, both the liposomes and the antibodies behaved as nontargeting particles with the latter being significantly smaller.…”

“…The extracellular pH e maps of PSMA‐expressing PC3‐PIP subcutaneous tumors confirmed the development of acidity in the interstitium, with regions reaching as low pH e values as 6.5 (Figure 6a); these pH e values were adequate to activate both the release and adhesion properties on the tumor‐responsive liposomes (Table 1). 12,16 …”

“…these pH e values were adequate to activate both the release and adhesion properties on the tumor-responsive liposomes (Table 1). 12,16 The α-camera images of tumor sections on the top panel in Histopathology analysis of H&E stained organ sections showed no noteworthy toxicities in the heart, lungs, liver, or kidneys across all constructs at the time of animal sacrifice (14 days post-treatment) (Figure S12). The spleen of mice treated with α-particles showed low levels of extramedullary hematopoiesis (EMH), which is to be expected as the spleen was observed as a major site of both liposome and antibody uptake.…”

“…We have recently discovered that we can improve the uniformity of distributions of α‐particles within established tumors when the same total radioactivity is equally split between two separate and diverse types of carriers, each preferentially killing a different region of the tumor 12 : (1) the tumor‐responsive liposomes that upon tumor uptake release in the interstitium a highly diffusing form of their radioactive payload ( 225 Ac‐DOTA), which then penetrates the deeper parts of tumors where antibodies do not reach, and (2) a separately administered, less‐penetrating radiolabeled‐antibody, irradiating the tumor perivascular regions from where the liposomes' contents clear too fast. Our tumor‐responsive liposomes are composed of membranes forming phase‐separated lipid domains (resembling lipid patches) with lowering pH 13 .…”

Pre-clinical investigation of astatine-211-parthanatine for high-risk neuroblastoma

“…Unlike radiometal alpha-emitter complexes, 211 At is a radiohalogen that can be covalently incorporated into small molecule drugs that provides a unique platform for alpha-therapeutics targeted to intracellular proteins. Furthermore, sufficient tumor diffusion of alpha-emitting therapeutics has been shown to be a critical component for optimal tumor response 16 , and organic small molecule PARPi exhibit large volume of distribution that suggests rapid transfer of drug from circulation to peripheral tissues. In this study we seek to deliver alpha-radiation directly to cancer cell nuclei by targeting PARP1.…”