Oxygen-releasing nanodroplets relieve intratumoral hypoxia in head and neck cancer spheroids.

Hypoxia in solid tumors, including head and neck cancer (HNC), contributes to treatment resistance, aggressive phenotypes, and poor clinical outcomes. Perfluorocarbon nanodroplets have emerged as promising oxygen carriers to alleviate tumor hypoxia. However, a thorough characterization of the hypoxia alleviation effects in terms of sustenance of oxygenated environments have not been thoroughly studied. In this study, we developed and characterized perfluoropentane nanodroplets (PFP NDs) for co-delivery of oxygen and the photoactivatable drug or photosensitizer benzoporphyrin derivative (BPD) to hypoxic HNC spheroids. The PFP NDs exhibited excellent stability, efficient oxygen loading/release, and biocompatibility. Using 3D multicellular tumor spheroids of FaDu and SCC9 HNC cells, we demonstrated the ability of oxygenated PFP NDs to penetrate the hypoxic core and alleviate hypoxia, as evidenced by reduced fluorescence of a hypoxia-sensing reagent and downregulation of hypoxia-inducible factors HIF-1α and HIF-2α. BPD-loaded PFP NDs successfully delivered the photosensitizer into the spheroid core in a time-dependent manner. These findings highlight the potential of PFP NDs as a co-delivery platform to overcome hypoxia-mediated treatment resistance and improve therapy outcomes in HNC.

Polygodial, a Sesquiterpene Dialdehyde, Activates Apoptotic Signaling in Castration-Resistant Prostate Cancer Cell Lines by Inducing Oxidative Stress.

Prostate cancer (PCa) is the second leading cause of cancer death among men in the United States. Surgery, radiation therapy, chemotherapy, and androgen deprivation therapy are currently the standard treatment options for PCa. These have poor outcomes and result in the development of castration-resistant prostate cancer (CRPC), which is the foremost underlying cause of mortality associated with PCa. Taxanes, diterpene compounds approved to treat hormonal refractory PCa, show poor outcomes in CRPC. Polygodial (PG) is a natural sesquiterpene isolated from water pepper (Persicaria hydropiper), Dorrigo pepper (Tasmannia stipitata), and mountain pepper (Tasmannia lanceolata). Previous reports show that PG has an anticancer effect. Our results show that PG robustly inhibits the cell viability, colony formation, and migration of taxane-resistant CRPC cell lines and induces cell cycle arrest at the G0 phase. A toxicity investigation shows that PG is not toxic to primary human hepatocytes, 3T3-J2 fibroblast co-cultures, and non-cancerous BPH-1 cells, implicating that PG is innocuous to healthy cells. In addition, PG induces oxidative stress and activates apoptosis in drug-resistant PCa cell lines. Our mechanistic evaluation by a proteome profiler-human apoptotic array in PC3-TXR cells shows that PG induces upregulation of cytochrome c and caspase-3 and downregulation of antiapoptotic markers. Western blot analysis reveals that PG activates apoptotic and DNA damage markers in PCa cells. Our results suggest that PG exhibits its anticancer effect by promoting reactive oxygen species generation and induction of apoptosis in CRPC cells.