Enzyme‐Triggered Chemodynamic Therapy via a Peptide‐H₂S Donor Conjugate with Complexed Fe²⁺

Abstract

Inducing high levels of reactive oxygen species (ROS) inside tumor cells is a cancer therapy method termed chemodynamic therapy (CDT). Relying on delivery of Fenton reaction promoters such as Fe2+, CDT takes advantage of overproduced ROS in the tumor microenvironment. We developed a peptide‐H2S donor conjugate, complexed with Fe2+, termed AAN‐PTC–Fe2+. The AAN tripeptide was specifically cleaved by legumain, an enzyme overexpressed in glioma cells, to release carbonyl sulfide (COS). Hydrolysis of COS by carbonic anhydrase formed H2S, an inhibitor of catalase, an enzyme that detoxifies H2O2. Fe2+ and H2S together increased intracellular ROS levels and decreased viability in C6 glioma cells compared with controls lacking either Fe2+, the AAN sequence, or the ability to generate H2S. AAN‐PTC–Fe2+ performed better than temezolimide while exhibiting no cytotoxicity toward H9C2 cardiomyocytes. This study provides an H2S‐amplified, enzyme‐responsive platform for synergistic cancer treatment.

Constitutionally Isomeric Peptides: Subtle Changes Leading to Dramatic Differences in Properties

“…50,51 In this regard, an exogenous supply of gasotransmitters to the lesion site would be promising in disease treatment. 52,53 Because there is no literature on using constitutionally isomeric peptides to deliver NO or CO, to the best of our knowledge, in this section, we will focus on the delivery of H 2 S by peptidic isomers. In 2018, Matson and coworkers reported a set of isomeric tetrapeptide amphiphiles to deliver H 2 S (Figure 3).…”

“…Among them, gasotransmitter-based therapy attracts much attention because it is a green therapeutic modality with high efficacy and would not induce drug resistance. − The gasotransmitters so far recognized in the literature are nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H 2 S) . Although they were historically considered as poisonous toxic molecules, recent investigations proved that these gas molecules participate in many vital physiological/pathological processes. − In addition, the progression of disease such as diabetic wound is related to the lack of gasotransmitters. , In this regard, an exogenous supply of gasotransmitters to the lesion site would be promising in disease treatment. , Because there is no literature on using constitutionally isomeric peptides to deliver NO or CO, to the best of our knowledge, in this section, we will focus on the delivery of H 2 S by peptidic isomers. In 2018, Matson and co-workers reported a set of isomeric tetrapeptide amphiphiles to deliver H 2 S (Figure ).…”

Glutathione-Responsive and Hydrogen Sulfide Self-Generating Nanocages Based on Self-Weaving Technology To Optimize Cancer Immunotherapy

“…The induction of this cross-linker also guaranteed the simultaneous rapid release of BetP and αPD-L1 in the tumor site due to the glutathione (GSH)-responsive breaking of the trithiocarbonate of yne-BDATC. More importantly, the reaction product of GSH and trithiocarbonate was hydrogen sulfide (H 2 S), which was able to regulate oxygen metabolism by inhibiting cytochrome c oxidase activity, inducing mitochondrial dysfunction, and consequently inhibiting cellular respiration and oxygen consumption. − The accumulation of high levels of H 2 S can damage mitochondria and inevitably neutralize oxygen, − inducing immunogenic cell death (ICD) of tumor cells, , and can reverse protumor inflammation to remodel ITME. − In addition, in order to enhance the targeting ability of this SF nanocage toward the tumor site, we coated a layer of hyaluronic acid (HA) on the surface of the drug-loaded SF nanocage to recognize the overexpressed CD44 of tumor cells. In short, αPD-L1/BetP@HA-gNCs demonstrated positive targeting toward tumor sites and the generation of H 2 S and rapid release of loaded BetP and αPD-L1 in response to the GSH of ITME.…”

Smart Lipid Nanoparticle that Remodels Tumor Microenvironment for Activatable H2S Gas and Photodynamic Immunotherapy

“…Gas therapy using the gasotransmitters [e.g., carbon monoxide (CO), nitric oxide (NO)] has shown promise to improve the antitumor effect by regulating the TME, such as ameliorating tumor blood flow, − inducing vascular normalization, − and overcoming hypoxia . Besides NO and CO, H 2 S, the third gaseous signaling molecule, also contributes to maintain homeostasis in biology. − It is recognized that endogenous H 2 S exerts its physiological effects on vasodilation, , angiogenesis, cytoprotection, − and anti-inflammation, , and excessive H 2 S can suppress tumor growth. − Plenty of H 2 S donors have been reported to liberate H 2 S for H 2 S gas therapy; ,− however, it is challenging to precisely control the release of sufficient amount of H 2 S from the donors in tumors to exert the antitumor (not cytoprotection and anti-inflammation) effect. Furthermore, it is still controversial why the excess H 2 S could have an antitumor effect.…”