Mutually Synergistic Nanoparticles for Effective Thermo-Molecularly Targeted Therapy
Mutually Synergistic Nanoparticles for Effective Thermo-Molecularly Targeted Therapy
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用于有效热分子靶向治疗的相互协同纳米颗粒
DOI：
10.1002/adfm.201702834
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发表时间：
2017-10-19
影响因子：
19
通讯作者：
Chen, Huabing
中科院分区：
文献类型：
--
作者：
Luo, Huanhuan;Wang, Qiaoli;Chen, Huabing
光热疗法（PTT）作为一种高效的治疗方式在癌症治疗中尤为重要。然而，一个关键的挑战仍然是探索高效的策略，以最大限度地提高PTT效率，由于肿瘤的耐热性，从而导致肿瘤频繁复发。本文报道了一种合理制备的胶束，可以实现PTT和分子靶向治疗（MTT）在肿瘤消融中的相互协同作用。该胶束通过提高光热转化效率和ph依赖性药物释放产生明显的光热效应。在辐照下，通过活性氧介导的溶酶体破坏，胶束进一步表现出17-烯丙基氨基-17-去甲氧基格尔达霉素（17AAG）的有效细胞质易位。易位17AAG特异性结合热休克蛋白90 (HSP90)，从而抑制抗凋亡p-ERK1/2蛋白，通过早期凋亡产生较好的MTT效率。同时，易位的17AAG分子进一步阻断辐照下应激性过表达的HSP90，从而抑制p-Akt的过表达，从而降低肿瘤细胞的耐热性，从而通过促进Cypate的早期和晚期凋亡来提高PTT效率。此外，胶束具有增强的抗光漂白能力，更好的细胞摄取和有效的肿瘤积累，从而促进PTT/MTT治疗与肿瘤消融的相互协同。这些发现代表了有效癌症治疗的一般方法。
Photothermal therapy (PTT) is of particular importance as a highly potent therapeutic modality in cancer therapy. However, a critical challenge still remains in the exploration of highly effective strategy to maximize the PTT efficiency due to tumor thermoresistance and thus frequent tumor recurrence. Here, a rational fabrication of the micelles that can achieve mutual synergy of PTT and molecularly targeted therapy (MTT) for tumor ablation is reported. The micelles generate both distinct photothermal effect from Cypate through enhanced photothermal conversion efficiency and pH-dependent drug release. The micelles further exhibit effective cytoplasmic translocation of 17-allylamino-17-demethoxygeldanamycin (17AAG) through reactive oxygen species mediated lysosomal disruption caused by Cypate under irradiation. Translocated 17AAG specifically bind with heat shock protein 90 (HSP90), thereby inhibiting antiapoptotic p-ERK1/2 proteins for producing preferable MTT efficiency through early apoptosis. Meanwhile, translocated 17AAG molecules further block stressfully overexpressed HSP90 under irradiation and thus inhibit the overexpression of p-Akt for achieving the reduced thermoresistance of tumor cells, thus promoting the PTT efficiency through boosting both early and late apoptosis of Cypate. Moreover, the micelles possess enhanced resistance to photobleaching, preferable cellular uptake, and effective tumor accumulation, thus facilitating mutually synergistic PTT/MTT treatments with tumor ablation. These findings represent a general approach for potent cancer therapy.