Mitochondria-Targeted Hydroxyapatite Nanoparticles for Selective Growth Inhibition of Lung Cancer in Vitro and in Vivo.
Lung cancer is the leading cause of cancer-related mortality worldwide. Most patients have metastases at the time of diagnosis, thus demanding development of more effective and specific agents. In this study, the specific anticancer effect of hydroxyapatite nanoparticles (HAPNs) to human lung cancer cells (A549) and the underlying mechanisms were investigated, using normal bronchial epithelial cells (16HBE) as the control. Rod-shaped HAPNs (∼10 nm in width and 50 nm in length) were prepared by aqueous precipitation method. Without any further functionalization and drug loading, HAPNs selectively inhibited cancer-cell proliferation. Their efficient mitochondrial targeting correlated strongly with decreased mitochondrial membrane potential and induction of mitochondria-dependent apoptosis in A549 cells. Caveolae-mediated endocytosis via lysosome trafficking was observed to be a prominent internalization pathway for HAPNs in both A549 and 16HBE cells. However, more nanoparticles were taken up into A549 cells. HAPNs triggered a sustained elevation of intracellular calcium concentration ([Ca2+]i) in cancer cells but only a transitory increase in normal control cells. In a nude mouse lung cancer model with xenotransplanted A549 cells, HAPN treatment demonstrated nearly 40% tumor growth inhibition without apparent side effect. These results demonstrated that the enhanced cellular uptake and mitochondrial targeting of HAPNs, together with the prolonged elevation of [Ca2+]iin A549 cells, could result in the cancer-specific cytotoxicity of HAPNs. Thus, HAPNs might be a promising agent or mitochondria-targeted delivery system for effective lung cancer therapy.
Yi
Y
Sun
Yaying
Y
Chen
Xiaoyu
X
Ma
Yuan
Y
Yuan
Changsheng
C
Liu
New Jersey Center for Biomaterials, Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey , New Brunswick, New Jersey 08855, United States.
Joachim
J
Kohn
Jiangchao
J
Qian
D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D017886:Durapatite; D006801:Humans; D008175:Lung Neoplasms; D051379:Mice; D008928:Mitochondria; D053758:Nanoparticles
D017886:Durapatite
cytotoxicity; hydroxyapatite nanoparticles; lung cancer; mitochondrion-targeted; uptake