Coburn Jeannine, Harris Jamie, Zakharov Alexander D, Poirier Jennifer, Ikegaki Naohiko, Kajdacsy-Balla Andre, Pilichowska Monika, Lyubimov Alexander V, Shimada Hiroyuki, Kaplan David L, Chiu Bill
Department of Biomedical Engineering, Tufts University, 4 Colby Street, Medford, MA.
Department of Surgery, University of Illinois at Chicago, 840 S. Wood Street, Chicago, IL.
Int J Cancer. 2017 Feb 1;140(3):726-735. doi: 10.1002/ijc.30479. Epub 2016 Nov 3.
Neuroblastoma is the most common extracranial childhood solid tumor. Treatment of high risk tumors require intense multicycle chemotherapies, resulting in short- and long-term toxicities. Here, we present treatment of an orthotopic neuroblastoma mouse model, with silk fibroin materials loaded with vincristine, doxorubicin or the combination as a intratumoral, sustained release system. The materials, loaded with vincristine with or without doxorubicin, significantly decreased neuroblastoma tumor growth compared to materials loaded without drug or doxorubicin only as well as intravenous (IV) drug treatment. The intratumoral drug concentration was significantly higher with intratumoral delivery versus IV. Furthermore, intratumor delivery decreased the maximum plasma concentration compared to IV delivery, reducing systemic exposure and possibly reduing long-term side effects of chemotherapy exposure. Histopathologically, tumors with remission periods >25 days before recurrence transformed from a "small-round-blue cell" (SBRC) to predominantly "large cell" neuroblastoma (LCN) histopathology, a more aggressive tumor subtype with unfavorable clinical outcomes. These results show that intratumoral chemotherapy delivery may be a treatment strategy for pediatric neuroblastoma, potentially translatable to other focal tumors types. Furthermore, this treatment modality allows for a clinically relevant mouse model of tumor transformation that may be used for studying the phenotypical tumor recurrence and developing more effective treatment strategies for recurrent tumors.
神经母细胞瘤是儿童最常见的颅外实体瘤。高危肿瘤的治疗需要多周期强化化疗，会导致短期和长期毒性。在此，我们展示了一种原位神经母细胞瘤小鼠模型的治疗方法，使用负载长春新碱、阿霉素或两者组合的丝素蛋白材料作为瘤内缓释系统。与未载药、仅载阿霉素的材料以及静脉给药相比，负载长春新碱（无论有无阿霉素）的材料显著降低了神经母细胞瘤的肿瘤生长。瘤内给药时瘤内药物浓度显著高于静脉给药。此外，与静脉给药相比，瘤内给药降低了最大血浆浓度，减少了全身暴露，并可能降低化疗暴露的长期副作用。组织病理学上，复发前缓解期>25天的肿瘤从“小圆蓝细胞”（SBRC）组织病理学转变为主要为“大细胞”神经母细胞瘤（LCN）组织病理学，后者是一种临床预后不良的侵袭性更强的肿瘤亚型。这些结果表明，瘤内化疗给药可能是小儿神经母细胞瘤的一种治疗策略，有可能推广到其他局部肿瘤类型。此外，这种治疗方式允许建立一种与临床相关的肿瘤转化小鼠模型，可用于研究肿瘤复发的表型并制定更有效的复发性肿瘤治疗策略。
