State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
Department of Nuclear Medicine, Fudan University Shanghai Cancer Center , Shanghai 200032, China.
ACS Nano. 2016 Mar 22;10(3):3496-508. doi: 10.1021/acsnano.5b07706. Epub 2016 Feb 15.
The intrinsic or acquired drug resistance is the main challenge for cancer chemotherapy today. So far, many nanosized drug delivery systems (NDDS) have been exploited to combat cancer drug resistance. However, the therapy efficacy of current NDDS is severely impaired by the limited tumor penetration of the nanoparticles due to the existence of physiological and pathological barriers in the solid tumor. In this study, we report on the design and fabrication of intracellularly acid-switchable multifunctional micelles for combinational photo- and chemotherapy of the drug-resistant tumor. The micelles were composed of a pH-responsive diblock copolymer, a photosensitizer, and a polymeric prodrug of doxorubicin. The micelle displayed silenced fluorescence and photoactivity during the blood circulation and switched to an active state in weakly acid conditions (i.e., pH ≤ 6.2) in the endocytic vesicles to dramatically induce a 7.5-fold increase of the fluorescence signal for fluorescence imaging. Upon near-infrared (NIR) laser irradiation, the micelle induced notable reactive oxygen species generation to trigger cytosol release of the chemotherapeutics and perform photodynamic therapy (PDT). Moreover, the micelle efficiently converted the NIR light to local heat for enhancing tumor penetration of the anticancer drug, tumor specific photothermal therapy, and photoacoustic (PA) imaging. Furthermore, the micelles could generate amplified magnetic resonance (MR) signal in an acidic microenvironment to perform MR imaging. Collectively, this study presents a robust nanoplatform for multimodal imaging and combinational therapy of the drug-resistant tumor, which might provide an insight for developing polymer-based NDDS for cancer therapy.
内在或获得性药物耐药性是当今癌症化疗的主要挑战。迄今为止，已经开发了许多纳米药物递送系统（NDDS）来对抗癌症耐药性。然而，由于实体瘤中存在生理和病理屏障，纳米颗粒的肿瘤穿透性有限，目前 NDDS 的治疗效果受到严重影响。在本研究中，我们报告了用于耐药肿瘤联合光化疗的细胞内酸响应多功能胶束的设计和制备。胶束由 pH 响应的两亲嵌段共聚物、光敏剂和阿霉素的聚合物前药组成。胶束在血液循环过程中显示出沉默的荧光和光活性，并在内涵体中弱酸性条件（即 pH≤6.2）下转变为活性状态，从而使荧光信号显著增加 7.5 倍，用于荧光成像。近红外（NIR）激光照射后，胶束诱导显著的活性氧生成，引发化疗药物的细胞质释放，并进行光动力治疗（PDT）。此外，胶束有效地将 NIR 光转换为局部热量，以增强抗癌药物在肿瘤中的穿透性、肿瘤特异性光热治疗和光声（PA）成像。此外，胶束可以在酸性微环境中产生放大的磁共振（MR）信号，以进行 MR 成像。总之，本研究提出了一种用于耐药肿瘤的多模态成像和联合治疗的强大纳米平台，为开发用于癌症治疗的基于聚合物的 NDDS 提供了新的思路。
