Thermo- and pH-dual responsive polymeric micelles with upper critical solution temperature behavior for photoacoustic imaging-guided synergistic chemo-photothermal therapy against subcutaneous and metastatic breast tumors.
Thermo- and pH-dual responsive polymeric micelles with upper critical solution temperature behavior for photoacoustic imaging-guided synergistic chemo-photothermal therapy against subcutaneous and metastatic breast tumors.
复制标题
具有上临界溶液温度行为的热和pH双重响应聚合物胶束，用于针对皮下和转移性乳腺肿瘤的光声成像引导的协同化学光热疗法
作者：
Yang Z;Cheng R;Zhao C;Sun N;Luo H;Chen Y;Liu Z;Li X;Liu J;Tian Z
化学光热疗法在抑制肿瘤生长方面显示出巨大的潜力。然而，实现最大的化学-光热协同功效是具有挑战性的，因为响应于外部或内部触发的可控化学药物释放的效率低。因此，需要一种纳米递送系统，其可以有效地实现光热治疗和双重刺激响应（热和pH）药物释放以抑制原发性乳腺肿瘤生长和转移。研究方法：本文中，合成了具有上临界溶解温度（UCST）的温度和pH响应性聚合物（mPEG-PAAV）以制备DOX和IR 780负载的胶束系统。系统研究了mPEG-PAAV胶束/IR 780 +DOX在不同pH值近红外照射下的光热性能和可控释药，并评价了其体外和体内的化学光热协同治疗效果。结果如下：由于mPEG-PAAV胶束/IR 780 +DOX（~200 nm，3.82 mV）的光热转换，在NIR激光照射下可在肿瘤部位诱导高局部温度。这种高温不仅产生增强的肿瘤坏死，而且在降低的pH环境下破坏胶束，导致在NIR激光照射后快速释放DOX和增强的细胞内药物积聚。此外，采用mPEG-PAAV/IR 780 +DOX胶束的光声成像（派）技术，可以监测肿瘤组织的形态和微血管分布，指导化疗光热治疗。最重要的是，全身施用mPEG-PAAV胶束/IR 780 +DOX联合NIR激光照射可以同时消除4 T1乳腺肿瘤并彻底抑制肺转移，没有任何明显的副作用。结论：本研究开发了一种pH和温度双重响应的UCST胶束系统，用于递送IR 780和DOX，该系统可实现NIR激光控制药物释放和PA成像指导，用于原发性乳腺肿瘤及其转移瘤的化学光热协同治疗。
Chemo-photothermal therapy shows great potential for inhibiting tumor growth. However, achieving maximal chemo-photothermal synergistic efficacy is challenging because of the low efficiency of controllable chemo-drug release in response to external or internal triggers. Thus, a nano-delivery system that could effectively achieve photothermal therapy and dual stimuli-responsive (heat and pH) drug release to inhibit both primary breast tumor growth and metastases is required. Methods: Herein, a thermo- and pH-responsive polymer (mPEG-PAAV) with an upper critical solution temperature (UCST) was synthesized to fabricate a DOX- and IR780-loaded micellar system. After systematic studies of the photothermal performance and controllable drug release of mPEG-PAAV micelles/IR780+DOX under NIR irradiation at different pH values, their chemo-photothermal synergetic therapy efficacies were also estimated both in in vitro and in vivo. Results: Because of the photothermal conversion of mPEG-PAAV micelle/IR780+DOX (~200 nm, 3.82 mV), high local temperature could be induced at the tumor site under NIR laser irradiation. This hyperthermia not only produced an enhanced tumor necrosis, but also broke down the micelles under the decreased pH environment, resulting in rapid DOX release and enhanced intracellular drug accumulation after NIR laser irradiation. In addition, photoacoustic imaging (PAI) of mPEG-PAAV/IR780+DOX micelle was adopted to monitor the morphology and micro-vascular distribution of the tumor tissue, which could also guide the chemo-photothermal therapy. Most importantly, the systemic administration of mPEG-PAAV micelles/IR780+DOX combined with NIR laser irradiation could simultaneously eliminate the 4T1 breast tumor and thoroughly suppress lung metastasis without any obvious adverse effects. Conclusion: Herein, a pH- and thermo-dual responsive UCST micelle system was developed for delivering IR780 and DOX, which could achieve NIR laser-controlled drug release and PA imaging guidance for chemo-photothermal synergistic therapy of both primary breast tumors and their metastases.