Schaal Jeffrey L, Li Xinghai, Mastria Eric, Bhattacharyya Jayanta, Zalutsky Michael R, Chilkoti Ashutosh, Liu Wenge
Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA.
Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA; Radiology, Duke University, Durham, NC 27708, USA.
J Control Release. 2016 Apr 28;228:58-66. doi: 10.1016/j.jconrel.2016.02.040. Epub 2016 Feb 27.
Intratumoral radiation therapy - 'brachytherapy' - is a highly effective treatment for solid tumors, particularly prostate cancer. Current titanium seed implants, however, are permanent and are limited in clinical application to indolent malignancies of low- to intermediate-risk. Attempts to develop polymeric alternatives, however, have been plagued by poor retention and off-target toxicity due to degradation. Herein, we report on a new approach whereby thermally sensitive micelles composed of an elastin-like polypeptide (ELP) are labeled with the radionuclide (131)I to form an in situ hydrogel that is stabilized by two independent mechanisms: first, body heat triggers the radioactive ELP micelles to rapidly phase transition into an insoluble, viscous coacervate in under 2 min; second, the high energy β-emissions of (131)I further stabilize the depot by introducing crosslinks within the ELP depot over 24h. These injectable brachytherapy hydrogels were used to treat two aggressive orthotopic tumor models in athymic nude mice: a human PC-3 M-luc-C6 prostate tumor and a human BxPc3-luc2 pancreatic tumor model. The ELP depots retained greater than 52% and 70% of their radioactivity through 60 days in the prostate and pancreatic tumors with no appreciable radioactive accumulation (≤ 0.1% ID) in off-target tissues after 72h. The (131)I-ELP depots achieved >95% tumor regression in the prostate tumors (n=8); with a median survival of more than 60 days compared to 12 days for control mice. For the pancreatic tumors, ELP brachytherapy (n=6) induced significant growth inhibition (p=0.001, ANOVA) and enhanced median survival to 27 days over controls.
瘤内放射治疗——“近距离放射疗法”——是治疗实体瘤，尤其是前列腺癌的一种高效疗法。然而，目前的钛籽植入物是永久性的，临床应用仅限于低至中风险的惰性恶性肿瘤。然而，开发聚合物替代物的尝试一直受到因降解导致的保留不佳和脱靶毒性的困扰。在此，我们报告一种新方法，即由类弹性蛋白多肽（ELP）组成的热敏胶束用放射性核素（131）I标记，形成一种原位水凝胶，该水凝胶通过两种独立机制得以稳定：第一，体温触发放射性ELP胶束在不到2分钟内迅速相转变为不溶性粘性凝聚层；第二，（131）I的高能β发射通过在24小时内在ELP储库内引入交联进一步稳定储库。这些可注射的近距离放射治疗水凝胶用于治疗无胸腺裸鼠的两种侵袭性原位肿瘤模型：人PC-3 M-luc-C6前列腺肿瘤和人BxPc3-luc2胰腺肿瘤模型。在前列腺和胰腺肿瘤中，ELP储库在60天内保留了超过52%和70%的放射性，72小时后在脱靶组织中没有明显的放射性积累（≤0.1%注射剂量）。（131）I-ELP储库在前列腺肿瘤（n = 8）中实现了>95%的肿瘤消退；与对照小鼠的12天相比，中位生存期超过60天。对于胰腺肿瘤，ELP近距离放射疗法（n = 6）诱导了显著的生长抑制（p = 0.001，方差分析），并将中位生存期延长至27天，超过对照组。
