ABSTRACT
Overproduction of reactive oxygen species (ROS) such as hydrogen peroxide (H2O2) leads to oxidative stress, causing inflammation and cellular damages and death. H2O2 is one of the most stable and abundant ROS and H2O2-mediated oxidative stress is considered as a key mediator of cellular and tissue damages during ischemia/reperfusion (I/R) injury. Therefore, H2O2 could hold tremendous potential as a diagnostic biomarker and therapeutic target for oxidative stress-associated inflammatory conditions such as I/R injury. Here, we report a novel nanotheranostic agent that can express ultrasound imaging and simultaneous therapeutic effects for hepatic I/R treatment, which is based on H2O2-triggered CO2-generating antioxidant poly(vanillin oxalate) (PVO). PVO nanoparticles generate CO2 through H2O2-triggered oxidation of peroxalate esters and release vanillin, which exerts antioxidant and anti-inflammatory activities. PVO nanoparticles intravenously administrated remarkably enhanced the ultrasound signal in the site of hepatic I/R injury and also effectively suppressed the liver damages by inhibiting inflammation and apoptosis. To our best understanding, H2O2-responsive PVO is the first platform which generates bubbles to serve as ultrasound contrast agents and also exerts therapeutic activities. We therefore anticipate that H2O2-triggered bubble-generating antioxidant PVO nanoparticles have great potential for ultrasound imaging and therapy of H2O2-associated diseases.
Subject(s)
Antioxidants/chemistry , Hydrogen Peroxide/chemistry , Nanoparticles/chemistry , Polymers/chemistry , Reperfusion Injury/drug therapy , Theranostic Nanomedicine , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Antioxidants/pharmacology , Apoptosis/drug effects , Dioxanes/chemistry , Dioxanes/pharmacology , Hydrogen Peroxide/pharmacology , Inflammation/drug therapy , Male , Mice , Mice, Inbred BALB C , Oxidative Stress/drug effects , Polyesters/chemistry , Polyesters/pharmacology , Reactive Oxygen Species/metabolism , UltrasonographyABSTRACT
Cancer cells, compared to normal cells, are under oxidative stress associated with an elevated level of reactive oxygen species (ROS) and are more vulnerable to oxidative stress induced by ROS generating agents. Thus, manipulation of the ROS level provides a logical approach to kill cancer cells preferentially, without significant toxicity to normal cells, and great efforts have been dedicated to the development of strategies to induce cytotoxic oxidative stress for cancer treatment. Fenton reaction is an important biological reaction in which irons convert hydrogen peroxide (H2O2) to highly toxic hydroxyl radicals that escalate ROS stress. Here, we report Fenton reaction-performing polymer (PolyCAFe) micelles as a new class of ROS-manipulating anticancer therapeutic agents. Amphiphilic PolyCAFe incorporates H2O2-generating benzoyloxycinnamaldehyde and iron-containing compounds in its backbone and self-assembles to form micelles that serve as Nano-Fenton reactors to generate cytotoxic hydroxyl radicals, killing cancer cells preferentially. When intravenously injected, PolyCAFe micelles could accumulate in tumors preferentially to remarkably suppress tumor growth, without toxicity to normal tissues. This study demonstrates the tremendous translatable potential of Nano-Fenton reactors as a new class of anticancer drugs.
Subject(s)
Hydrogen Peroxide/chemistry , Hydrogen Peroxide/pharmacology , Iron/chemistry , Iron/pharmacology , Oxidative Stress/drug effects , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Apoptosis/drug effects , Cell Line, Tumor , DNA Fragmentation/drug effects , Ferrous Compounds/chemistry , HEK293 Cells , Humans , Hydrogen Peroxide/metabolism , Hydrogen Peroxide/therapeutic use , Hydrogen-Ion Concentration , Hydroxyl Radical/chemistry , Hydroxyl Radical/pharmacology , Iron/therapeutic use , Metallocenes , Mice , Mice, Nude , Micelles , NIH 3T3 Cells , Neoplasms/drug therapy , Neoplasms/pathology , Polymers/chemical synthesis , Polymers/chemistry , Reactive Oxygen Species/metabolism , Transplantation, HeterologousABSTRACT
Cancer cells, compared with normal cells, are under oxidative stress associated with the increased generation of reactive oxygen species (ROS) including H2O2 and are also susceptible to further ROS insults. Cancer cells adapt to oxidative stress by upregulating antioxidant systems such as glutathione to counteract the damaging effects of ROS. Therefore, the elevation of oxidative stress preferentially in cancer cells by depleting glutathione or generating ROS is a logical therapeutic strategy for the development of anticancer drugs. Here we report a dual stimuli-responsive hybrid anticancer drug QCA, which can be activated by H2O2 and acidic pH to release glutathione-scavenging quinone methide and ROS-generating cinnamaldehyde, respectively, in cancer cells. Quinone methide and cinnamaldehyde act in a synergistic manner to amplify oxidative stress, leading to preferential killing of cancer cells in vitro and in vivo. We therefore anticipate that QCA has promising potential as an anticancer therapeutic agent.
