Somasundaram Vijay Harish, Pillai Rashmi, Malarvizhi Giridharan, Ashokan Anusha, Gowd Siddaramana, Peethambaran Reshmi, Palaniswamy Shanmugasundaram, Unni Akk, Nair Shantikumar, Koyakutty Manzoor
Amrita Center for Nanosciences & Molecular Medicine, Amrita Institute of Medical Science & Research Centre, Amrita Vishwa Vidyapeetham, Ponekkara P.O. Kochi, Kerala 682041, India.
ACS Biomater Sci Eng. 2016 May 9;2(5):768-779. doi: 10.1021/acsbiomaterials.5b00511. Epub 2016 Apr 27.
Radiofrequency ablation (RFA) and doxorubicin (Dox) chemotherapy are separately approved for liver cancer therapy; however, both have limited success in the clinic due to suboptimal/nonuniform heating and systemic side effects, respectively. Here, we report a biodegradable nanoparticle (NP) system showing excellent RF hyperthermic response together with the ability to locally deliver Dox in the liver under RF trigger and control. The nanosystem was prepared by doping a clinically permissible dose (∼4.3 wt %, 0.03 ppm) of stannous ions in alginate nanoparticles (∼100 nm) coloaded with Dox at ∼13.4 wt % concentration and surface conjugated with galactose for targeting asialo-glycoprotein receptors in liver tumors. Targeted NP-uptake and increased cytotoxicity when combined with RF exposure was demonstrated in HEPG2 liver cancer cells. Following in vitro (chicken liver phantom) demonstration of locally augmented RF thermal response, in vivo scintigraphic imaging of Tc-labeled NPs was performed to optimize liver localization in Sprague-Dawley (SD) rats. RF ablation was performed in vivo using a cooled-tip probe, and uniformly enhanced (∼44%) thermal ablation was demonstrated with magnetic resonance imaging along with RF-controlled Dox release. In orthotopic rat liver tumor models, real-time infrared imaging revealed significantly higher (∼20 °C) RF thermal response at the tumor site, resulting in uniform augmented ablation (∼80%) even at a low RF power exposure of 15 W for just 1 min duration. Being a clinically acceptable, biodegradable material, alginate nanoparticles hold strong translational potential for augmented RF hyperthermia combined with triggered drug release.
射频消融（RFA）和阿霉素（Dox）化疗分别被批准用于肝癌治疗；然而，由于加热效果欠佳/不均匀以及全身副作用，两者在临床应用中效果均有限。在此，我们报道了一种可生物降解的纳米颗粒（NP）系统，该系统在射频触发和控制下，对射频具有出色的热疗响应，并能够在肝脏局部递送阿霉素。该纳米系统是通过在藻酸盐纳米颗粒（约100 nm）中掺杂临床允许剂量（约4.3 wt%，0.03 ppm）的亚锡离子制备而成，该纳米颗粒共负载了浓度约为13.4 wt%的阿霉素，并在表面偶联了半乳糖，用于靶向肝肿瘤中的去唾液酸糖蛋白受体。在HEPG2肝癌细胞中证实了与射频暴露相结合时靶向纳米颗粒的摄取增加以及细胞毒性增强。在体外（鸡肝模型）证明局部增强的射频热响应后，对锝标记的纳米颗粒进行了体内闪烁成像，以优化其在Sprague-Dawley（SD）大鼠肝脏中的定位。使用冷端探针在体内进行射频消融，磁共振成像显示热消融均匀增强（约44%），同时实现了射频控制的阿霉素释放。在原位大鼠肝肿瘤模型中，实时红外成像显示肿瘤部位的射频热响应显著更高（约20℃），即使在15 W的低射频功率下仅暴露1分钟，也能实现均匀增强的消融（约80%）。作为一种临床可接受的可生物降解材料，藻酸盐纳米颗粒在增强射频热疗与触发药物释放相结合方面具有很强的转化潜力。
