State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, P. R. China.
Frontiers Science Center for Materiobiology and Dynamic Chemistry, East China University of Science and Technology, Shanghai, 200237, P. R. China.
Small. 2021 May;17(18):e2007672. doi: 10.1002/smll.202007672. Epub 2021 Mar 24.
Multidrug resistance (MDR) is one of the biggest obstacles in cancer chemotherapy. Here, a remarkable reversal of MDR in breast cancer through the synergistic effects of bioactive hydroxyapatite nanoparticles (HAPNs) and doxorubicin (DOX) is shown. DOX loaded HAPNs (DHAPNs) exhibit a 150-fold reduction in IC compared with free DOX for human MDR breast cancer MCF-7/ADR cells, and lead to almost complete inhibition of tumor growth in vivo without obvious side effects of free DOX. This high efficacy and specificity could be attributed to multiple action mechanisms of HAPNs. In addition to acting as the conventional nanocarriers to facilitate the cellular uptake and retention of DOX in MCF-7/ADR cells, more importantly, drug-free HAPNs themselves are able to prevent drug being pumped out of MDR cells through targeting mitochondria to induce mitochondrial damage and inhibit ATP production and to trigger sustained mitochondrial calcium overload and apoptosis in MDR cancer cells while not affecting normal cells. The results demonstrate that this simple but versatile bioactive nanoparticle provides a practical approach to effectively overcome MDR.
多药耐药性（MDR）是癌症化疗的最大障碍之一。在这里，通过生物活性羟基磷灰石纳米粒子（HAPN）和阿霉素（DOX）的协同作用，显著逆转了乳腺癌的多药耐药性。负载 DOX 的 HAPN（DHAPN）对人 MDR 乳腺癌 MCF-7/ADR 细胞的 IC 与游离 DOX 相比降低了 150 倍，并且在体内几乎完全抑制了肿瘤生长，而没有游离 DOX 的明显副作用。这种高效性和特异性可归因于 HAPN 的多种作用机制。除了作为传统的纳米载体促进 MCF-7/ADR 细胞中 DOX 的细胞摄取和保留外，更重要的是，无药物的 HAPN 本身能够通过靶向线粒体来防止药物从 MDR 细胞中泵出，从而导致线粒体损伤和抑制 ATP 产生，并引发 MDR 癌细胞中的持续线粒体钙超载和细胞凋亡，而不影响正常细胞。结果表明，这种简单但多功能的生物活性纳米颗粒为有效克服 MDR 提供了一种实用方法。
