A redox-responsive prodrug for tumor-targeted glutamine restriction.

Modulating the metabolism of cancer cells, immune cells, or both is a promising strategy to potentiate cancer immunotherapy in the nutrient-competitive tumor microenvironment. Glutamine has emerged as an ideal target as cancer cells highly rely on glutamine for replenishing the tricarboxylic acid cycle in the process of aerobic glycolysis. However, non-specific glutamine restriction may induce adverse effects in unconcerned tissues and therefore glutamine inhibitors have achieved limited success in the clinic so far. Here we report the synthesis and evaluation of a redox-responsive prodrug of 6-Diazo-5-oxo-L-norleucine (redox-DON) for tumor-targeted glutamine inhibition. When applied to treat mice bearing subcutaneous CT26 mouse colon carcinoma, redox-DON exhibited equivalent antitumor efficacy but a greatly improved safety profile, particularly, in spleen and gastrointestinal tract, as compared to the state-of-the-art DON prodrug, JHU083. Furthermore, redox-DON synergized with checkpoint blockade antibodies leading to durable cures in tumor-bearing mice. Our results suggest that redox-DON is a safe and effective therapeutic for tumor-targeted glutamine inhibition showing promise for enhanced metabolic modulatory immunotherapy. The approach of reversible chemical modification may be generalized to other metabolic modulatory drugs that suffer from overt toxicity.

Smart chemistry for traceless release of anticancer therapeutics.

In the design of delivery strategies for anticancer therapeutics, the controlled release of intact cargo at the destined tumor and metastasis locations is of particular importance. To this end, stimuli-responsive chemical linkers have been extensively investigated owing to their ability to respond to tumor-specific physiological stimuli, such as lowered pH, altered redox conditions, increased radical oxygen species and pathological enzymatic activities. To prevent premature action and off-target effects, anticancer therapeutics are chemically modified to be transiently inactivated, a strategy known as prodrug development. Prodrugs are reactivated upon stimuli-dependent release at the sites of interest. As most drugs and therapeutic proteins have the optimal activity when released from carriers in their native and original forms, traceless release mechanisms are increasingly investigated. In this review, we summarize the chemical toolkit for developing innovative traceless prodrug strategies for stimuli-responsive drug delivery and discuss the applications of these chemical modifications in anticancer treatment including cancer immunotherapy.