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-粒子放疗已被证明不受大多数​​耐药机制的影响。然而，在已建立的（即大的、血管化的）软组织病变中，放射性标记的抗体或纳米载体（≤50-80 μm）的扩散限制穿透深度与短程 α 粒子（4-5 个细胞直径）相结合可能导致仅部分肿瘤照射，可能会限制治疗效果。为了应对这一挑战，我们将载体与递送的 α 粒子的互补瘤内微分布相结合。我们使用了 α 粒子发生器²²⁵ Ac，并结合了肿瘤响应脂质体（在肿瘤摄取时，其放射性有效载荷的高度扩散形式释放到间质中 [ ²²⁵Ac-DOTA]，可能穿透抗体无法到达的肿瘤的较深部分）用单独施用的、穿透性较低的放射性标记抗体（照射脂质体内容物清除过快的肿瘤血管周围区域）。方法：在具有原位人表皮生长因子受体 2 阳性 BT474 乳腺癌异种移植物的小鼠模型中，评估每种载体的生物分布，并在施用相同的总放射性²²⁵ Ac后监测肿瘤生长的控制。 ²²⁵ Ac-DOTA 封装的脂质体，由²²⁵ Ac-DOTA-SCN 标记的曲妥珠单抗，以及两种具有同等放射性的载体。结果：当相同的总注入放射性在两个单独的载体之间分配时，肿瘤生长明显比单独由任一载体递送时受到抑制。联合载体使 α 粒子的瘤内微分布更加均匀，其肿瘤剂量低于单独使用抗体递送的剂量。结论：该策略表明，即使在较低的肿瘤剂量下，在已建立的实体瘤内更均匀地递送的 α 粒子的微分布也能提高疗效。用肿瘤反应性脂质体增强抗体靶向 α 粒子疗法可以解决部分肿瘤照射，提高治疗效果。