Dual Chemodrug-Loaded Single-Walled Carbon Nanohorns for Multimodal Imaging-Guided Chemo-Photothermal Therapy of Tumors and Lung Metastases
Dual Chemodrug-Loaded Single-Walled Carbon Nanohorns for Multimodal Imaging-Guided Chemo-Photothermal Therapy of Tumors and Lung Metastases
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双化疗药物负载单壁碳纳米角用于肿瘤和肺转移瘤多模态成像引导化疗光热治疗
DOI：
10.7150/thno.23848
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发表时间：
2018-01-01
期刊：
影响因子：
12.4
通讯作者：
Zhang, Chunfu
中科院分区：
文献类型：
--
作者：
Yang, Jingxing;Su, Huilan;Zhang, Chunfu
使用具有多模式协同治疗作用的纳米制剂的肿瘤联合治疗显示出完全消融肿瘤的巨大潜力。然而，利用纳米结构靶向肿瘤转移是治疗的主要障碍。因此，开发一种能够通过协同治疗同时靶向原发性肿瘤及其远处转移灶的联合治疗系统对于彻底根除肿瘤是可取的。为此，开发了一种基于单壁碳纳米角（SWNH）的双化疗药物治疗诊断系统，用于靶向原发性乳腺肿瘤及其肺转移瘤。方法：首先通过疏水-疏水相互作用和 π-π 堆积，同时对 SWNH 进行修饰，同时使用聚（马来酸酐-alt-1-十八碳烯）（C18PMH）和甲氧基聚乙二醇-b-聚-D，L-丙交酯（mPEG-PLA）进行修饰。然后顺铂和阿霉素（DOX）（2.9:1摩尔比）以非干扰方式依次负载到修饰的纳米角上。在仔细检查负载药物的释放曲线和双化疗药物负载SWNH（称为SWNHs/C18PMH/mPEG-PLA-DOX-Pt）的光热性能后，评估了双药物化疗和化疗光热协同治疗对肿瘤细胞的作用。随后，通过光声成像（PAI）研究了载药 SWNH 的体内行为和肿瘤积累。对于肿瘤的化学光热治疗，4T1荷瘤小鼠以10mg/kg体重的剂量静脉注射SWNHs/C18PMH/mPEG-PLA-DOX-Pt。 （在 SWNH 中），注射后 24 小时用 808 nm 激光（1W/cm2，5 分钟）照射肿瘤。结果：DOX 和顺铂以高效率（分别为 44 wt% 和 66 wt%）负载到修饰的 SWNH 上，并以 pH 敏感、串联和可持续的方式释放。 SWNHs/C18PMH/mPEG-PLA-DOX-Pt的流体动力学直径为182±3.2 nm，在生理环境中高度稳定，在体外同时具有双药物化疗（CI = 0.439）和化疗光热协同抗肿瘤作用（CI = 0.396）。此外，双载药SWNH具有较长的血液半衰期（10.9小时），静脉注射后可以治疗原发性乳腺肿瘤及其肺转移瘤。因此，化学光热联合疗法消融了原发肿瘤，同时根除了转移性肺结节。结论：我们的研究表明，SWNHs/C18PMH/mPEG-PLA-DOX-Pt 对于原发性肿瘤的化学光热联合治疗和远处转移灶的鸡尾酒化疗非常有效。
Tumor combination therapy using nano formulations with multimodal synergistic therapeutic effects shows great potential for complete ablation of tumors. However, targeting tumor metastases with nano structures is a major obstacle for therapy. Therefore, developing a combination therapy system able to target both primary tumors and their metastases at distant sites with synergistic therapy is desirable for the complete eradication of tumors. To this end, a dual chemodrug-loaded theranostic system based on single walled carbon nanohorns (SWNHs) is developed for targeting both primary breast tumors and their lung metastases. Methods: SWNHs were first modified simultaneously with poly (maleic anhydride-alt-1-octadecene) (C18PMH) and methoxypolyethyleneglycol-b-poly-D, L-lactide (mPEG-PLA) via hydrophobic-hydrophobic interactions and π-π stacking. Then cisplatin and doxorubicin (DOX) (2.9:1 molar ratio) were sequentially loaded onto the modified nanohorns in a noninterfering way. After careful examinations of the release profiles of the loaded drugs and the photothermal performance of the dual chemodrug-loaded SWNHs, termed SWNHs/C18PMH/mPEG-PLA-DOX-Pt, the dual drug chemotherapeutic and chemo-photothermal synergetic therapeutic effects on tumor cells were evaluated. Subsequently, the in vivo behavior and tumor accumulation of the drug-loaded SWNHs were studied by photoacoustic imaging (PAI). For chemo-photothermal therapy of tumors, 4T1 tumor bearing mice were intravenously injected with SWNHs/C18PMH/mPEG-PLA-DOX-Pt at a dose of 10 mg/kg b.w. (in SWNHs) and tumors were illuminated by an 808 nm laser (1W/cm2 for 5 min) 24 h post-injection. Results: DOX and cisplatin were loaded onto the modified SWNHs with high efficiency (44 wt% and 66 wt%, respectively) and released in a pH-sensitive, tandem and sustainable manner. The SWNHs/C18PMH/mPEG-PLA-DOX-Pt had a hydrodynamic diameter of 182 ± 3.2 nm, were highly stable in physiological environment, and had both dual drug chemotherapeutic (CI = 0.439) and chemo-photothermal synergistic antitumor effects (CI = 0.396) in vitro. Moreover, the dual drug-loaded SWNHs had a long blood half-life (10.9 h) and could address both the primary breast tumors and their lung metastases after intravenous administration. Consequently, chemo-photothermal combination therapy ablated the primary tumors and simultaneously eradicated the metastatic lung nodules. Conclusion: Our study demonstrates that SWNHs/C18PMH/mPEG-PLA-DOX-Pt is highly potent for chemo-photothermal combination therapy of primary tumors and cocktail chemotherapy of their metastases at a distant site.