Departments of Biomedical Engineering, Rutgers University, 599 Taylor Road, Piscataway, NJ 08854, USA.
Chemical and Biochemical Engineering, Rutgers University, 599 Taylor Road, Piscataway, NJ 08854, USA.
Biomaterials. 2017 Jun;130:67-75. doi: 10.1016/j.biomaterials.2017.03.035. Epub 2017 Mar 25.
Diffusion limitations on the penetration of nanocarriers in solid tumors hamper their therapeutic use when labeled with α-particle emitters. This is mostly due to the α-particles' relatively short range (≤100 μm) resulting in partial tumor irradiation and limited killing. To utilize the high therapeutic potential of α-particles against solid tumors, we designed non-targeted, non-internalizing nanometer-sized tunable carriers (pH-tunable liposomes) that are triggered to release, within the slightly acidic tumor interstitium, highly-diffusive forms of the encapsulated α-particle generator Actinium-225 (Ac) resulting in more homogeneous distributions of the α-particle emitters, improving uniformity in tumor irradiation and increasing killing efficacies. On large multicellular spheroids (400 μm-in-diameter), used as surrogates of the avascular areas of solid tumors, interstitially-releasing liposomes resulted in best growth control independent of HER2 expression followed in performance by (a) the HER2-targeting radiolabeled antibody or (b) the non-responsive liposomes. In an orthotopic human HER2-negative mouse model, interstitially-releasing Ac-loaded liposomes resulted in the longest overall and median survival. This study demonstrates the therapeutic potential of a general strategy to bypass the diffusion-limited transport of radionuclide carriers in solid tumors enabling interstitial release from non-internalizing nanocarriers of highly-diffusing and deeper tumor-penetrating molecular forms of α-particle emitters, independent of cell-targeting.
纳米载体在固体肿瘤中的渗透受到扩散限制，当用α粒子发射体标记时，会妨碍其治疗用途。这主要是由于α粒子的射程相对较短（≤100μm），导致肿瘤部分照射和杀伤有限。为了利用α粒子对固体肿瘤的高治疗潜力，我们设计了非靶向、非内化的纳米尺寸可调载体（pH 可调脂质体），这些载体在微酸性肿瘤间质内被触发释放，封装的α粒子发生器锕-225（Ac）的高扩散形式，从而导致α粒子发射体更均匀的分布，提高肿瘤照射的均匀性，并提高杀伤效果。在用作实体瘤无血管区域替代物的大（400μm 直径）多细胞球体上，间质释放的脂质体表现出最佳的生长控制，而与 HER2 表达无关，其次是（a）针对 HER2 的放射性标记抗体或（b）无反应性脂质体。在原位人 HER2 阴性小鼠模型中，间质释放的 Ac 负载脂质体导致最长的总生存期和中位生存期。这项研究证明了一种绕过固体肿瘤中放射性核素载体扩散限制的运输的一般策略的治疗潜力，该策略能够从非内化的纳米载体中释放具有高扩散性和更深肿瘤穿透力的α粒子发射体的分子形式，而无需细胞靶向。
