Linoleic Acid-Glucosamine Hybrid for Endogenous Iron-Activated Ferroptosis Therapy in High-Grade Serous Ovarian Cancer.

As the most common subtype in ovarian malignancies, high-grade serous ovarian cancer (HGSOC) made less therapeutic progress in past decades due to the lack of effective drug-able targets. Herein, an effective linoleic acid (LA) and glucosamine (GlcN) hybrid (LA-GlcN) was synthesized for the treatment of HGSOC. The GlcN was introduced to recognize the glucose transporter 1 (GLUT 1) overexpressed in tumor cells to enhance the uptake of LA-GlcN, and the unsaturated LA was employed to trigger ferroptosis by iron-dependent lipid peroxidation. Since the iron content of HGSOC was ∼5 and 2 times, respectively, higher than that of the normal ovarian cells and low-grade serous ovarian cancer cells, these excess irons make them a good target to enhance the ferroptosis of LA-GlcN. The in vitro study demonstrated that LA-GlcN could selectively kill HGSOC cells without affecting normal cells; the in vivo study revealed that LA-GlcN at the dose of 50 mg kg-1 achieved a comparable tumor inhibition as doxorubicin hydrochloride (4 mg kg-1) while the overall survival of mice was extended largely due to the low toxicity, and when the dose was increased to 100 mg kg-1, the therapeutic outcomes could be improved further. This dietary hybrid which targets the excess endogenous iron to activate ferroptosis represents a promising drug for HGSOC treatment.

Nitroreductase-induced bioorthogonal ligation for prodrug activation: A traceless strategy for cancer-specific imaging and therapy.

Prodrug development is of great interest in cancer therapy. From bio-friendly standpoints, traceless prodrug activation would be an ideal approach for cancer treatment owning to the avoidance of byproduct which might induce side effects in living system. Here, we report a fully traceless strategy for cancer imaging and therapy via a metal-free bioorthogonal ligation triggered by nitroreductase (NTR) overexpressed in solid tumors. The reduction of nitro substrates to amines by NTR and further condensation of amines with aldehydes can be seamlessly combined to yield imine-based resveratrol (RSV) with water as the only byproduct. In comparison with RSV, this precursor exhibited not only the same level of anticancer efficiency both in vitro and in vivo under hypoxia, but also a high sensitivity to hypoxia and much lower perturbation towards normal cells, which holds a great potential of theranostic prodrug for cancer therapy.

A whole-course-repair system based on ROS/glucose stimuli-responsive EGCG release and tunable mechanical property for efficient treatment of chronic periodontitis in diabetic rats.

Elevated glucose levels, multiple pro-inflammatory cytokines and the generation of excessive reactive oxygen species (ROS) are pivotal characteristics within the microenvironments of chronic periodontitis with diabetes mellitus (CPDM). Control of inflammation and modulation of immune system are required in the initial phase of CPDM treatment, while late severe periodontitis requires a suitable scaffold to promote osteogenesis, rebuild periodontal tissue and reduce alveolar bone resorption. Herein, a whole-course-repair system is introduced by an injectable hydrogel using phenylboronic acid functionalized oxidized sodium alginate (OSA-PBA) and carboxymethyl chitosan (CMC). Epigallocatechin-3-gallate (EGCG) was loaded to simultaneously adjust the mechanical property of the OSA-PBA/CMC + EGCG hydrogel (OPCE). This hydrogel has distinctive adaptability, injectability, and ROS/glucose-triggered release of EGCG, making it an ideal drug delivery carrier. As expected, OPCE hydrogel shows favourable antioxidant and anti-inflammatory properties, along with a regulatory influence on the phenotypic transition of macrophages, providing a favourable immune microenvironment. Apart from that, it provides a favourable mechanical support for osteoblast/osteoclast differentiation regulation at the late proliferation stage of periodontal regeneration. The practical therapeutic effects of OPCE hydrogels were also confirmed when applied for treating periodontitis in diabetic rats. In summary, OPCE hydrogel may be a promising whole-course-repair system for the treatment of CPDM.