ROS-responsive dexamethasone micelles normalize the tumor microenvironment enhancing hypericin in cancer photodynamic therapy

The efficacy of photodynamic therapy (PDT) for cancer is limited owing to the abnormality of the tumor microenvironment (TME), such as the dysfunctional tumor vascular system leading to restricted drug distribution in tumor lesions, and hypoxia resulting in hampering the application of the photosensitizer because of the shortage of oxygen. Therefore, normalizing the TME is a novel strategy for enhancing the therapeutic efficacy of PDT. Herein, we designed and fabricated reactive oxygen species (ROS)-responsive micelles with a self-circulating release manner to co-deliver a glucocorticoid steroid dexamethasone (DXM) and a photosensitizer hypericin (HYP) (denoted as HDTM). The current drug delivery system showed the following advantageous properties: (1) The DXM inhibited the migration, invasion and angiogenesis of vein endothelial cells by suppressing the function of vascular endothelial growth factor, thus promoting the delivery of oxygen and HDTM into the tumor site. (2) When the HDTM arrived at the tumor site, the endogenous ROS partially cleaved the outer shell of the micelle to release the HYP and DXM. With the use of an external light source with a wavelength of 590 nm, the in situ released HYP was excited, enabling ROS production, which resulted in effective cell apoptosis. Moreover, the upregulated ROS further cleaved the micelles, thus achieving the subsequent self-circulating burst release of HYP and DXM for PDT. Notably, real-time accumulation and elimination of drugs can be monitored owing to the red fluorescence property of HYP. This facile design not only provides a platform for cancer theranostics, but also offers a feasible strategy to combat cancer in an integral way.