Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
Acta Biomater. 2017 Oct 15;62:144-156. doi: 10.1016/j.actbio.2017.08.027. Epub 2017 Aug 30.
To concurrently suppress multidrug resistance (MDR) and metastasis of breast cancer cells, paclitaxel (PTX) and honokiol (HNK) were coencapsulated into pH-sensitive polymeric micelles based on poly(2-ethyl-2-oxazoline)-poly(d,l-lactide) (PEOz-PLA). The physicochemical properties of dual drug-loaded PEOz-PLA micelles were characterized in size, drug loading and in vitro release. The efficiency of MDR reversal for the micelles was testified by synergetic enhancement of cytotoxicity and uptake by MCF-7/ADR cells. The flow cytometry and fluorescence polarization measurement results reinforced the conclusion that down-regulation of P-gp expression and increase of plasma membrane fluidity appeared to be possible mechanisms of MDR reversal by dual drug-loaded PEOz-PLA micelles. Further, the efficient inhibition of tumor metastasis by dual drug-loaded PEOz-PLA micelles was demonstrated by in vitro anti-invasion and anti-migration assessment in MDA-MB-231 cells and in vivo bioluminescence imaging in nude mice. The suppression of MDR and metastasis by the micelles was assigned to synergistic effects of pH-triggered drug release and HNK/PEOz-PLA-aroused P-gp inhibition, and pH-triggered drug release and PTX/HNK-aroused MMPs inhibition, respectively. In conclusion, our findings strengthen the usefulness of co-delivery of PTX and HNK by pH-responsive polymeric micelles for suppression of tumor MDR and metastasis.
Multidrug resistance (MDR) and metastasis are considered to be two of the major barriers for successful chemotherapy. The combination of a chemotherapeutic drug with a modulator has emerged as a promising strategy for efficiently treating MDR cancer and preventing tumor metastasis. Herein, a dual drug (paclitaxel and honokiol)-loaded pH-sensitive polymeric micelle system based on PEOz-PLA was successfully fabricated to ensure that tumor MDR and metastasis could be concurrently suppressed, therefore achieving distinguishing endo/lysosomal pH from physiological pH by accelerating drug release and then enhancing the cytotoxicity of paclitaxel to drug-resistant tumor cells MCF-7/ADR by increasing cellular uptake of paclitaxel, preventing in vitro invasion and migration for MDA-MB-231 cells and in vivo metastasis in nude mice. Further, the mechanism of MDR reversal by dual drug-loaded PEOz-PLA micelles was elucidated to be down-regulation of P-gp expression and increase of plasma membrane fluidity of MCF-7/ADR cells. The present findings strengthen the usefulness of co-delivery of PTX and HNK by pH-responsive polymeric micelles for suppression of tumor MDR and metastasis.
为了同时抑制乳腺癌细胞的多药耐药（MDR）和转移，将紫杉醇（PTX）和厚朴酚（HNK）共包封到基于聚（2-乙基-2-恶唑啉）-聚（DL-乳酸）（PEOz-PLA）的 pH 敏感聚合物胶束中。
通过测定载药胶束的粒径、载药量和体外释放，对双载药 PEOz-PLA 胶束的理化性质进行了表征。通过 MCF-7/ADR 细胞的协同细胞毒性增强和摄取，证明了胶束逆转 MDR 的效率。通过流式细胞术和荧光偏振测量结果，进一步证实了双载药 PEOz-PLA 胶束通过下调 P-糖蛋白（P-gp）表达和增加质膜流动性来逆转 MDR 的可能性机制。
进一步通过 MDA-MB-231 细胞的体外侵袭和迁移评估以及裸鼠体内生物发光成像，证明了双载药 PEOz-PLA 胶束对肿瘤转移的有效抑制。双载药 PEOz-PLA 胶束对 MDR 和转移的抑制作用归因于 pH 触发的药物释放与 HNK/PEOz-PLA 引起的 P-gp 抑制以及 pH 触发的药物释放与 PTX/HNK 引起的基质金属蛋白酶（MMPs）抑制的协同作用。
综上所述，本研究结果为通过 pH 响应性聚合物胶束共递紫杉醇和厚朴酚以抑制肿瘤 MDR 和转移提供了有力证据。
