Enhanced cytotoxicity to lung cancer cells by mitochondrial delivery of camptothecin.

Delivering traditional DNA-damaging anticancer drugs into mitochondria to damage mitochondria is a promising chemotherapy strategy. The impermeability of this mitochondrial inner membrane, however, impedes the delivery of drug molecules that could impact other important biological roles of mitochondria. Herein, the prodrug camptothecin (CPT)-triphenylphosphine (TPP) modified with hyaluronic acid (HA) via electrostatic adsorption (HA/CPT-TPP, HCT) was used to mediate the mitochondrial accumulation of CPT. These nanoparticles (NPs) showed enhanced drug accumulation in cancer cells through tumor targeting. HCT entered acidic lysosomes through endosomal transport, HA was degraded by hyaluronidase (HAase) in acidic lysosomes, and the positively charged CPT-TPP was exposed and accumulated fully in the mitochondria. Subsequently, CPT-TPP significantly disrupted the mitochondrial structure and damaged mitochondrial function, leading to increased reactive oxygen species (ROS) levels and energy depletion. Finally, HCT enhanced lung cancer cell apoptosis via the activation of caspase-3 and caspase-9. Furthermore, greatly increased tumor growth inhibition was observed in nude mice bearing A549 xenograft tumors after the administration of HCT via tail injection. This study demonstrated that the mitochondria-targeted delivery of CPT may be a promising antitumor therapeutic strategy.

Effect of sex on the association between arterial partial pressure of oxygen and in-hospital mortality in ICU patients with cardiogenic shock: a retrospective cohort study.

Background: Maintaining tissue perfusion and oxygen supply are essential for cardiogenic shock (CS) treatment. Sex has been reported to be associated with mortality and oxygen use in patients with CS. Males and females respond differently to hypoxia. We designed this cohort study to evaluate the effects of sex on the association between the arterial partial pressure of oxygen (PaO2) and in-hospital mortality. Methods: We used the Medical Information Mart for Intensive Care (MIMIC) IV database for this cohort study. The outcome was in-hospital mortality. The relationship between the PaO2 and in-hospital mortality was compared with sex (via an interaction test) using multivariable Cox regression models. Presence of interaction between PaO2 and sex was tested by using inter interaction terms. Results: A total of 1,772 patients with CS were enrolled in this study. The association between PaO2 and in-hospital mortality appeared to differ between males and females [hazard ratio (HR): 0.997, 95% confidence interval (CI): 0.995-0.999 vs. HR: 1.002, 95% CI: 0.999-1.003, P for interaction =0.002]. We repeated the analyses, based on different PaO2 category (PaO2 <60 mmHg; PaO2 60-100 mmHg; PaO2 >100 mmHg) and the results remained stable, P for interaction =0.008. Conclusions: Sex affects the relationship between PaO2 and in-hospital mortality in CS patients. Our findings may lead to the development of individualized therapies that focus on the use of different target oxygen partial pressures in different sexes to treat patients with CS.