Polyglutamic acid-coordinated assembly of hydroxyapatite nanoparticles for synergistic tumor-specific therapy

Nanotechnology offers exciting and innovative therapeutic strategies in the fight against cancer. Nano-scale hydroxyapatite, the inorganic constituent of the hard tissues of humans and animals, is not only an ideal carrier for the delivery of drugs but also exerts selective inhibitory effects on tumor cells. To perform the dual functions, we propose polyglutamic acid-coordinated hydroxyapatite nanoparticles (HA-PGA NP) as both DOX delivery vehicle and sustained calcium flow supplier to achieve a synergistic, tumor-specific therapy in this study. With PGA as the coordinator, the HA-PGA NPs were easily assembled into spherical nano-clusters with low crystallinity. The excellent dispersibility and solubility in the tumor environment endowed the HA-PGA NPs with an improved internalization into the tumor cells, thereby causing a dramatic elevation in the intracellular calcium influx by about 40%, which further induced a cascade of mitochondrial membrane damage, ATP content reduction, and reinforced sensitivity to chemotherapy. After the encapsulation of the model drug DOX, a pH-responsive release profile was achieved via the degradation of the nanoparticles and the deprotonation of PGA in the acidic tumor micro-environment. Consequently, the hybrid system, with the synergistic effects of sustained DOX and calcium overload, exhibited selectively intensified toxicity to tumor cells. The in vivo test further confirmed that the current system exhibited highly selective tumor inhibition and reduced heart toxicity, thus representing an effective anti-tumor platform.