Sustained Release of Nitric Oxide and Cascade Generation of Reactive Nitrogen/Oxygen Species via an Injectable Hydrogel for Tumor Synergistic Therapy

Abstract

Reactive nitrogen species (RNS) generated via the reaction of nitric oxide (NO) with reactive oxygen species (ROS) are more lethal than ROS, and thus RNS‐mediated therapy has great potential in cancer treatment, yet it is still largely unexploited. Herein, a novel, injectable and NO‐releasing hydrogel (NO‐Gel) composed of α‐(nitrate ester) acetic acid‐modified amphiphilic copolymers is developed. To further convert released NO to RNS, glutathione (GSH)‐sensitive CuCys nanoparticles (NPs) and β‐lapachone (Lapa) are co‐loaded into the NO‐Gel. This hydrogel system possesses a temperature‐induced sol‐gel transition and can continuously liberate Lapa, CuCys NPs, and NO in vitro for up to 3 weeks. The sustained supply of Lapa can efficiently boost hydrogen peroxide (H2O2) concentration in cancer cells, and intracellular GSH can induce the rapid release of NO and the reduction of CuCys NPs. With elevating H2O2 levels and producing highly reactive Cu(I), the Cu(I)‐catalyzed Fenton‐like reaction is dramatically enhanced, resulting in the generation of abundant hydroxyl radicals (·OH), and the subsequent cascade reactions among ·OH, H2O2, and NO cause more lethal RNS pool. After a single peritumoral injection of the hydrogel system, the cascade generation of ROS and RNS plus the substantial depletion of GSH can significantly suppress tumor growth.

Reactive oxygen species-upregulating nanomedicines towards enhanced cancer therapy

“…In addition to enzymes that catalyze the production of H 2 O 2 , some anticancer drugs, such as camptothecin (CPT) 42,43 and doxorubicin (DOX), 44,45 and biological molecules including β-lapachone (Lapa) 46–48 and cinnamaldehyde (CA) 49,50 are capable of elevating intracellular ROS levels. DOX induces the upregulation of ROS through the activation of NADPH NOXs in the mitochondria, 51 while Lapa catalyzes the generation of H 2 O 2 in situ mainly through the catalysis of NAD(P)H:quinone oxidoreductase-1 (NQO1), which is overexpressed in many types of cancer.…”

Precision gas therapy by ultrasound‐triggered for anticancer therapeutics

“…Ji group 91 employed a similar approach to create a platform targeted to mitochondria and ultrasound‐responsive for delivery both of O 2 and NO, using human serum albumin as a carrier for the NO donor to incorporate IR780 sonosensitizer and perfluorodecalin (an ultrasound contrast agent) for theranostic applications. Amazingly, the in situ‐produced ROS can also be employed to initiate gas release 92,93 …”

“…As another significant gas transmitter, NO has been demonstrated to influence a variety of physiological processes such as apoptosis, angiogenesis, immune response, and neurotransmission 93,128,129 . And its' hindering tumor growth efficiency could be due to the “anti‐Warburg effect.” 130 Wang's group designed a nanocomplex, named T‐mTNPs@ l ‐Arg for synergistic NO gas therapy and SDT for breast cancer (Figure 8A(a)) 131 .…”

Injectable PTHF-based thermogelling polyurethane implants for long-term intraocular application

“…By changing the ratio of hydrophilic block and hydrophobic blocks, the phase transition between room temperature and body temperature can be achieved in block copolymer thermogels. These thermogels have been widely used in drug delivery [25][26][27][28], 3D cell culture [29], tissue engineering [30], and deep tissue imaging [31]. Thermogels have unique advantages for use as an ocular implant: (1) quick in situ gelation property response to temperature change (2) high water content mimicking natural eye tissue (3) benign gelation behavior without chemical trigger, (4) easy to inject via a small-bore needle, and (5) potential to encapsulate drugs or small molecules as a drug delivery system.…”