Synergistic targeting and stimuli-responsive drug delivery from a dual-network injectable hydrogel for enhanced breast cancer treatment.

Injectable hydrogels show great potential in treating breast cancer due to their precise treatment, stimulation response and slow release characteristics. By crosslinking reaction of N-carboxyethyl chitosan (CEC) and oxidized chondroitin sulfate (OXCS), we developed a novel hydrogel (denoted as ODPDC) loaded doxorubicin (DOX) and a nano drug delivery system (DMO-PTX-FA). DMO-PTX-FA was based on an ethane-bridged double-shelled mesoporous organosilica nanosphere (DMO) which was loaded with paclitaxel (PTX) and then covered by bovine serum albumin (BSA) and folic acid (FA). In an acidic tumor environment (pH 5.5), the hydrogel tended to collapse, leading to faster DOX release (56.04% cumulative release amount) compared to weak alkaline medium, while DMO-PTX-FA in ODPDC was concurrently released with a 35.10% cumulative release percentage. FA, as a navigation molecule, significantly enhanced the accuracy of targeted delivery systems by binding to folate receptors overexpressed on the surface of cancer cells. Meanwhile, the disulfide bond in BSA can be biodegraded when exposed to a large amount of glutathione (GSH) at the tumor site, releasing PTX (cumulative release percentage 39.63%) and realizing the "redox triggered release", which manifested pH/redox responsive drug release. The results of cell experiments demonstrated that ODPDC induced 32.2% apoptosis rate of 4T1 cells and had high levels of IL-6 (62.474 ± 1.323) and TNF-α (514.000 ± 32.417) jointly facilitating the regression of tumors. After 14 days of administration to the mice, no observable pathological alterations or necrotic changes in cardiac, hepatic, splenic, pulmonary, or renal tissues. The above results fully showed that ODPDC had excellent biocompatibility, high biodegradability and strong ability to kill breast cancer cells.