Mitochondria-Targeted Hydroxyapatite Nanoparticles for Selective Growth Inhibition of Lung Cancer in Vitro and in Vivo

Abstract

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 ([Ca]) 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 [Ca] in 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.

Hydroxyapatite as a Vehicle for the Selective Effect of Superparamagnetic Iron Oxide Nanoparticles against Human Glioblastoma Cells

“…49 Effects on lung cells challenged with HAP were similarly selective: toxic to alveolar adenocarcinoma A549 cells and harmless to normal bronchial epithelial 16HBE cells. 50 However, no cytotoxic effects of pure HAP on any glioblastoma cells have been reported previously.…”

Antimicrobial hydroxyapatite–gelatin–silica composite pastes with tunable setting properties

“…This could be the mechanism by which the combination of HAp as a carrier and vancomycin as the drug acts synergistically, endowing the antibiotic with a greater antibacterial efficacy than that typifying it alone. The increased apoptotic effects of chemotherapeutics following their delivery using CP nanoparticles were reported before 57,58,59,60 and were attributed to other possible causes, including the sustained drug release enabled by the CP carrier and the excessive calcium ion release 61,62 capable of triggering the caspase-dependent apoptotic pathway 63,64 by permeabilizing the mitochondrion 65 . However, if the release of ions, most critically Ca 2+ , is accepted as the mechanism for the augmentation of the toxic effect HAp particles have on microorganisms, it would be difficult to explain numerous cases where modifications of HAp particle properties affected the cell response even when their degradation rates did not significantly change.…”

6‐Triphenylphosphinehexanoic Acid Conjugated Near‐Infrared Persistent Luminescence Nanoprobe for Autofluorescence‐Free Targeted Imaging of Mitochondria in Cancer Cells

“…Co‐localization imaging in HepG2 cells was performed on CLSM to show whether the PLNP‐TPP could selectively locate in mitochondria. Mito‐tracker Green, a commercial mitochondrial‐specific dye, was chosen to stain mitochondria . The PLNP or PLNP‐TPP incubated HepG2 cells were stained with Mito‐Tracker Green to label mitochondria.…”

“…Mito-tracker Green, a commercial mitochondrialspecific dye, was chosen to stain mitochondria. [34][35][36] The PLNP or PLNP-TPP incubated HepG2 cells were stained with Mito-Tracker Green to label mitochondria. Figure 5 shows the CLSM images for the cells co-stained by the Mito-Tracker Green (green signal) and the nanoparticle (red signal).…”