The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China.
Department of Medical Oncology, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, Guangzhou 510060, China.
Theranostics. 2018 Jul 16;8(15):4097-4115. doi: 10.7150/thno.26195. eCollection 2018.
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. 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 and . 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. 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.
化学-光热疗法在抑制肿瘤生长方面具有巨大潜力。然而，由于对外界或内部刺激的可控化疗药物释放效率低，实现最大的化学-光热协同疗效具有挑战性。因此，需要一种纳米递药系统，能够有效实现光热治疗和双重刺激响应（热和 pH）药物释放，以抑制原发性乳腺癌肿瘤生长和转移。在此，合成了一种具有上临界溶液温度（UCST）的热和 pH 响应聚合物（mPEG-PAAV），以制备负载 DOX 和 IR780 的胶束系统。在不同 pH 值下，系统研究了 mPEG-PAAV 胶束/IR780+DOX 的光热性能和可控药物释放后，还评估了它们在体内和体内的化学-光热协同治疗效果。由于 mPEG-PAAV 胶束/IR780+DOX（~200nm，3.82mV）的光热转换，在近红外激光照射下，肿瘤部位可诱导产生较高的局部温度。这种热疗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，导致近红外激光照射后 DOX 快速释放和增强细胞内药物积累。此外，采用 mPEG-PAAV/IR780+DOX 胶束的光声成像（PAI）监测肿瘤组织的形态和微血管分布，也可以指导化学-光热治疗。最重要的是，mPEG-PAAV 胶束/IR780+DOX 联合近红外激光照射的全身给药可同时消除 4T1 乳腺癌并彻底抑制肺转移，而无明显不良反应。在此，开发了一种 pH 和热双重响应的 UCST 胶束系统，用于递送 IR780 和 DOX，可实现近红外激光控制药物释放和 PA 成像指导，用于原发性乳腺癌及其转移的化学-光热协同治疗。
