Salivary Amylase-Responsive Buccal Tablets Wipe Out Chemotherapy-Rooted Refractory Oral Mucositis.

Oral mucositis (OM) is the most common and refractory complication of cancer chemotherapy and radiotherapy, severely affecting patients' life quality, lowering treatment tolerance, and discouraging patient compliance. Current OM delivery systems mostly affect the comfort of patient use and lead to poor compliance and unsatisfactory effects. Herein, salivary amylases (SAs)-responsive buccal tablets consisting of porous manganese-substituted Prussian blue (PMPB) nanocubes (NCs), anti-inflammatory apremilast (Apr) and starch controller have been engineered. PMPB NCs with large surface area can serve as carriers to load Apr, and their multienzyme-mimicking activity enables them to scavenge reactive oxygen species (ROS), which thus synergize with Apr to mitigate inflammation. More significantly, the starch controller can respond to abundant SAs in the oral cavity and realize the cascade, continuous, and complete drug release after enzymatic decomposition, which not only aids with high tissue affinity to prolong the resistance time but also improves the comfort of use. The preclinical study reveals that contributed by the above actions, such buccal tablets mitigate inflammation, promote endothelium proliferation and migration, and accelerate wound healing for repressing chemotherapy-originated intractable OM with positive oral microenvironment and shorter recovery time, thus holding high potentials in clinical translation.

Hydroxyapatite nanoparticles induced calcium overload-initiated cancer cell-specific apoptosis through inhibition of PMCA and activation of calpain.

Hydroxyapatite nanoparticles (HAPNs) have been reported to specifically induce apoptosis and sustained elevation of intracellular Ca2+ concentration ([Ca2+]i) in cancer cells. However, it remains unclear whether calcium overload, the abnormal intracellular accumulation of Ca2+, is the intrinsic cause of cell apoptosis, how HAPNs specifically evoke calcium overload in cancer cells, and which potential pathways were involved in apoptosis initiation in response to calcium overload. In this study, using various cancer and normal cells, we observed a positive correlation between the degree of increased [Ca2+]i and the specific toxicity of HAPNs. Moreover, chelating intracellular Ca2+ with BAPTA-AM inhibited HAPN-induced calcium overload and apoptosis, thus demonstrating that calcium overload was the main cause of HAPN-induced cytotoxicity in cancer cells. Notably, the dissolution of particles outside the cells did not affect cell viability or [Ca2+]i. In contrast, internalized HAPNs dissolved more readily in cancer cells than in normal cells and inhibited the activity of plasma membrane calcium-ATPase solely in cancer cells to prevent extrusion of excessive Ca2+, hence leading to calcium overload in tumor cells. Upon exposure to HAPNs, the Ca2+-sensitive cysteine protease calpain was activated and then cleaved the BH3-only protein Bid. Consequently, cytochrome c was released, and caspase-9 and -3 were activated, leading to mitochondrial apoptosis. However, these effects were alleviated by the calpain inhibitor calpeptin, confirming the involvement of calpain in HANP-induced apoptosis. Therefore, our results demonstrated that calcium overload induced by HAPNs caused cancer cell-specific apoptosis by inhibiting PMCA and activating calpain in tumor cells and thus may contribute to a more comprehensive understanding of biological effects of this nanomaterial and facilitate the development of calcium overload cancer therapy.

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

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.