Synergistic Combination of Bioactive Hydroxyapatite Nanoparticles and the Chemotherapeutic Doxorubicin to Overcome Tumor Multidrug Resistance

• Published in: Small (Weinheim an der Bergstrasse, Germany) Vol. 17; no. 18; pp. e2007672 - n/a
• Main Authors: Dong, Xiulin, Sun, Yi, Li, Yuanyuan, Ma, Xiaoyu, Zhang, Shuiquan, Yuan, Yuan, Kohn, Joachim, Liu, Changsheng, Qian, Jiangchao
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 01.05.2021
• Subjects: anti‐tumor activity; Apoptosis; bioactivity; Biological activity; Breast cancer; Doxorubicin; Hydroxyapatite; hydroxyapatite nanoparticles; Mitochondria; mitochondrial Ca 2+ overload; multidrug resistance reversal; Nanoparticles; Nanotechnology; Side effects; Synergistic effect; Tumors; multidrug resistance reversal; hydroxyapatite nanoparticles; anti-tumor activity; bioactivity; mitochondrial Ca 2+ overload
• ISSN: 1613-6810; 1613-6829
• DOI: 10.1002/smll.202007672

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 IC50 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. The major components of bone, hydroxyapatite nanoparticles, are able to kill multidrug resistant (MDR) MCF‐7/ADR cells. They can facilitate drug delivery into and prevent doxorubicin (DOX) efflux from MDR cells, thus act synergistically with DOX to overcome MDR, leading to a 150‐fold decrease in the IC50 of DOX and almost complete inhibition of tumor growth in vivo.