Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin Key Laboratory of Biomedical Materials, Tianjin 300192, China.
Department of Anesthesiology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China.
Acta Biomater. 2018 Jul 15;75:386-397. doi: 10.1016/j.actbio.2018.05.033. Epub 2018 May 21.
The combination of chemotherapy and photothermaltherapy (PTT) via stimuli-responsive nanovesicles has great potential in tumor treatment. In the present study, bubble-generating polymersomes, which can generate bubbles in response to low pH or hyperthermia, were fabricated to simultaneously encapsulate chemotherapeutic drug and photosensitizing agent for the synergistic chemo-photothermal tumor therapy. Photosensitizer indocyanine green (ICG) was encapsulated into the bilayer of polymersomes formed by amphiphilic triblock copolymer PCL-PEG-PCL through thin film re-hydration method, while chemotherapeutic doxorubicin (DOX) was loaded into the hydrophilic lumen using a transmembrane ammonium bicarbonate gradient loading procedure. Under acidic condition or laser irradiation, the ammonium bicarbonate (NHHCO) encapsulated in the bubble-generating DOX-ICG-co-delivery polymersomes (BG-DIPS) would decompose to produce CO bubbles, resulting in destruction of vesicle structure and rapid drug release. In vitro drug release study confirmed that acidic environment and NIR laser irradiation could accelerate DOX release from the BG-DIPS. Cellular uptake study indicated that laser-induced hyperthermia highly enhanced endocytosis of BG-DIPS into 4T1-Luc cancer cells. In vitro cytotoxicity study demonstrated that BG-DIPS exhibited much higher cytotoxicity than free drugs under laser irradiation. In vivo biodistribution study indicated that BG-DIPS could accumulate in the tumor region, prolong drug retention, and increase photothermal conversion efficiency. Furthermore, in vivo antitumor study showed that BG-DIPS with laser irradiation efficiently inhibited 4T1-Luc tumor growth with reduced systemic toxicity. Hence, the formulated bubble-generating polymersomes system was a superior multifunctional nanocarrier for stimuli-response controlled drug delivery and combination chemo-photothermal tumor therapy.
The combination of chemotherapy and photothermaltherapy via stimuli-responsive nanovesicles has great potential in tumor treatment. Herein, bubble-generating polymersomes, which can generate bubbles in response to low pH or hyperthermia, were fabricated to simultaneously encapsulate chemotherapeutic drug (DOX) and photosensitizing agent (ICG) for the synergistic chemo-photothermal tumor therapy. The results in vitro and in vivo demonstrated that bubble-generating DOX-ICG-co-delivery polymersomes (BG-DIPS) would accelerate DOX release from the BG-DIPS and accumulate in the tumor region, prolong drug retention, and increase photothermal conversion efficiency. BG-DIPS with laser irradiation could efficiently inhibited 4T1-Luc tumor growth with reduced systemic toxicity. Hence, the formulated bubble-generating polymersomes system was a superior multifunctional nanocarrier for stimuli-response controlled drug delivery and combination chemo-photothermal tumor therapy.
通过刺激响应纳米囊泡的化疗和光热疗法（PTT）在肿瘤治疗中有很大的潜力。在本研究中，制备了能够响应低 pH 值或热疗产生气泡的气泡生成聚合物囊泡，以同时包封化疗药物和光敏剂，用于协同化疗-光热肿瘤治疗。亲脂性三嵌段共聚物 PCL-PEG-PCL 通过薄膜再水合方法将光敏剂吲哚菁绿（ICG）包封在聚合物囊泡的双层中，而通过跨膜碳酸氢铵梯度加载程序将化疗药物阿霉素（DOX）载入亲水性内腔中。在酸性条件或激光照射下，封装在产生气泡的 DOX-ICG-共递药聚合物囊泡（BG-DIPS）中的碳酸氢铵（NHHCO）会分解产生 CO 气泡，导致囊泡结构破坏和药物快速释放。体外药物释放研究证实，酸性环境和近红外激光照射可以加速 BG-DIPS 中 DOX 的释放。细胞摄取研究表明，激光诱导的热疗会极大地促进 BG-DIPS 进入 4T1-Luc 癌细胞的内吞作用。体外细胞毒性研究表明，在激光照射下，BG-DIPS 表现出比游离药物更高的细胞毒性。体内生物分布研究表明，BG-DIPS 可以在肿瘤区域积聚，延长药物保留时间，并增加光热转换效率。此外，体内抗肿瘤研究表明，激光照射的 BG-DIPS 能够有效抑制 4T1-Luc 肿瘤生长，同时降低全身毒性。因此，所构建的产生气泡的聚合物囊泡系统是一种用于刺激响应控制药物输送和联合化疗-光热肿瘤治疗的优异多功能纳米载体。
通过刺激响应纳米囊泡的化疗和光热疗法在肿瘤治疗中有很大的潜力。本文制备了能够响应低 pH 值或热疗产生气泡的气泡生成聚合物囊泡，以同时包封化疗药物（DOX）和光敏剂（ICG），用于协同化疗-光热肿瘤治疗。体外和体内结果表明，产生气泡的 DOX-ICG-共递药聚合物囊泡（BG-DIPS）会加速 BG-DIPS 中 DOX 的释放并在肿瘤区域积聚，延长药物保留时间，并增加光热转换效率。激光照射的 BG-DIPS 可有效抑制 4T1-Luc 肿瘤生长，同时降低全身毒性。因此，所构建的产生气泡的聚合物囊泡系统是一种用于刺激响应控制药物输送和联合化疗-光热肿瘤治疗的优异多功能纳米载体。
