P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) is a principal obstacle for successful cancer chemotherapy. A novel P-gp inhibitor with a quinazoline scaffold, 12k, was considered to be the most promising for in-depth study. 12k possessed high potency (EC = 57.9 ± 3.5 nM), low cytotoxicity, and long duration of activity in reversing doxorubicin (DOX) resistance in K562/A02 cells. 12k also boosted the potency of other MDR-related cytotoxic agents with different structures, increased accumulation of DOX, blocked P-gp-mediated Rh123 efflux, and suppressed P-gp ATPase activity in K562/A02 MDR cells. However, 12k did not have any effects on CYP3A4 activity or P-gp expression. In particular, 12k had a good half-life and oral bioavailability and displayed no influence on DOX metabolism to obviate the side effects closely related to increased plasma concentrations of cytotoxic agents in vivo.

Closed-loop glucose-responsive insulin delivery with excellent biocompatibility has the potential to improve the health and quality of life of diabetic patients. Herein, we developed an excellent glucose-responsive insulin delivery system using a pH-sensitive peptide hydrogel loaded with insulin and a glucose-specific enzyme. The designed peptide can be used as a carrier that is loaded with insulin and enzyme via a self-assembly process under physiological conditions. When hyperglycemia is encountered, the enzymatic conversion of glucose into gluconic acid leads to a decrease in the local pH, and the hydrogel is disassembled because of the strong inter- and intramolecular electrostatic repulsions between ornithine (Orn) residues; this is followed by the release of insulin. The glucose-responsive hydrogel system was characterized by studying its structure, conformation, rheology, morphology, acid sensitivity and the amounts of consistent release of insulin in vitro and in vivo. In vivo experiments indicated that the closed-loop insulin glucose-responsive system could efficiently regulate blood glucose in streptozocin-induced (STZ-induced) type 1 diabetic rats for 8 days.

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