Local Reactive Oxygen Species Research Articles

Reactive Oxygen Species Responsive Theranostic Nanoplatform for Two-Photon Aggregation-Induced Emission Imaging and Therapy of Acute and Chronic Inflammation.

Inflammation is a protective response to stimuli trauma, which can also lead to severe tissue injury. The existing anti-inflammatory drugs, such as corticosteroids and glucocorticoids, generally exhibit side effects and poor accumulation in inflammatory tissue. Hence, a theranostic nanoplatform with serial reactive oxygen species (ROS) responsiveness and two-photon AIE bioimaging has been constructed for dimensional diagnosis and accurate therapy of inflammation. Prednisolone (Pred) is bridged to a two-photon fluorophore (TP) developed by us via a ROS sensitive bond to form a diagnosis-therapy compound TPP, which is then loaded by the amphipathic polymer PMPC-PMEMA (PMM) through self-assembling into the core-shell structured micelles (TPP@PMM). With a particle size of 57.5 nm, TPP@PMM can realize the accumulation in the inflammatory site via the oedematous tissue and the accurate release of anti-inflammatory drug Pred through the serial response to the local overexpressed ROS. The micellar structure is first interrupted by the ROS triggered hydrophobic-to-hydrophilic conversion of PMEMA, which allows the release of TPP. Then the ROS responsive bond in TPP is subsequently broken, resulting in the accurate delivery of Pred and the inflammation therapy. Furthermore, TPP@PMM can be traced in vivo with a distinct two-photon imaging due to the AIE active fluorophore TP. The theranostic TPP@PMM reveals high-resolution inflammation diagnosis and efficient anti-inflammatory activity owing to the two-photon fluorophore and the serial ROS responsiveness and has been proven to achieve the efficient treatment of acute lung injury, arthritis, and atherosclerosis. Therefore, TPP@PMM holds considerable promise as a potential strategy for acute and chronic inflammation theranostics.

Proteomic and metabolomic basis for improved textural quality in crisp grass carp (Ctenopharyngodon idellus C.et V) fed with a natural dietary pro-oxidant

Reactive oxygen species (ROS) regulate metabolism and chemical composition of various tissues. To understand how ROS affect the textural quality of fish muscle, we performed a multi-omics analysis on an established crisp grass carp model fed with a natural pro-oxidant faba bean. ROS levels were systemically and significantly increased up to three-fold in crisp grass carp, improving the muscle texture. Lipid metabolism was significantly enhanced up to five-fold in muscle and liver possibly to compensate the impaired carbohydrate metabolism of these tissues, but this caused further local ROS production. Mitochondrial damage associated with autophagy was evident in crisp grass carp. Proteomics revealed that elevated ROS likely disturbed the actin-myosin interaction and collagen turnover inducing fragmentation of myofibrillar proteins, all of which could have positively impacted the textural quality. The systemic metabolic changes that lead to the partial collapse of redox regulation likely underlie the ROS-induced improvement of textural quality.

Bioactivatable reactive oxygen species-sensitive nanoparticulate system for chemo-photodynamic therapy

Bioactivatable polymer nanoparticles (NPs) have attracted considerable attention as a prospective cancer therapy. Herein, we describe bioactivatable reactive oxygen species (ROS)-sensitive prodrug NPs designed to elicit spatiotemporally controlled, phototriggered chemo-photodynamic therapy. First, an effective anticancer agent, doxorubicin (DOX), was conjugated to poly(ethylene glycol) (PEG) via an ROS-responsive degradable thioketal (TK) linker. The resulting amphiphilic PEG-DOX conjugate (PEG-TK-DOX) self-assembled into a bioactivatable ROS-responsive NP system could efficiently encapsulate a hydrophobic photodynamic therapy (PDT) agent, pheophorbide A (PhA), with good colloidal stability and unimodal size distribution. Second, after the selective retention of NPs in the tumor, the site-specific release of DOX and PhA was spatiotemporally controlled, initially by endogenous ROS and subsequently by exogenous ROS produced during PDT. The locoregional treatment not only photoactivates PhA molecules to generate cytotoxic ROS but also triggers an ROS cascade, which accelerates the release of DOX and PhA via the ROS-mediated structural destruction of NPs, resulting in an enhanced anticancer therapeutic effect. This prodrug-NP system may function as an effective nanomedicine platform, working synergistically to maximize the efficacy of the combination of chemotherapy and photodynamic therapy with a remote-controlled release mechanism. Statement of significancePhotodynamic therapy (PDT) is a noninvasive therapy involving local ROS generation through the activation of photosensitizer (PS) molecules induced via external irradiation with near-infrared (NIR) light. Combinational therapies with PDT could synergistically enhance the therapeutic efficacy and overcome the limitations of monotherapy. In this study, we describe bioactivatable reactive oxygen species (ROS)-sensitive prodrug nanoparticles designed to elicit spatiotemporally controlled, photo triggered chemo-photodynamic therapy. Upon accumulation in tumor by enhanced permeation and retention (EPR) effect, the nanoparticles exhibited target-specific release of chemo-drug and photosensitizer in a spatiotemporally controlled cascade manner by endogenous ROS in the initial stage and the excessive production of exogenous ROS during PDT, leading to a further ROS cascade that accelerates the release of therapeutic cargo.

SCHENGEN receptor module drives localized ROS production and lignification in plant roots

Production of reactive oxygen species (ROS) by NADPH oxidases (NOXs) impacts many processes in animals and plants, and many plant receptor pathways involve rapid, NOX‐dependent increases of ROS. Yet, their general reactivity has made it challenging to pinpoint the precise role and immediate molecular action of ROS. A well‐understood ROS action in plants is to provide the co‐substrate for lignin peroxidases in the cell wall. Lignin can be deposited with exquisite spatial control, but the underlying mechanisms have remained elusive. Here, we establish a kinase signaling relay that exerts direct, spatial control over ROS production and lignification within the cell wall. We show that polar localization of a single kinase component is crucial for pathway function. Our data indicate that an intersection of more broadly localized components allows for micrometer‐scale precision of lignification and that this system is triggered through initiation of ROS production as a critical peroxidase co‐substrate.

In vivo assessment of silver nanoparticle induced reactive oxygen species reveals tissue specific effects on cellular redox status in the nematode Caenorhabditis elegans

The current study provides an in vivo analysis of the production of reactive oxygen species (ROS) and oxidative stress in the nematode Caenorhabditis elegans following exposure to EU reference silver nanoparticles NM300K and AgNO3. Induction of antioxidant defenses was measured through the application of a SOD-1 reporter, and the HyPer and GRX biosensor strains to monitor changes in the cellular redox state. Both forms of Ag resulted in an increase in sod-1 expression, elevated H2O2 levels and an imbalance in the cellular GSSG/GSH redox status. Microscopy analysis of the strains revealed that AgNO3 induced ROS-related effects in multiple tissues, including the pharynx, intestinal cells and muscle tissues. In contrast, NM300K resulted in localized ROS production and oxidative stress, specifically in tissues surrounding the intestinal lumen. This indicates that Ag from AgNO3 exposure was readily transported across the whole body, while Ag or ROS from NM300K exposure was predominantly confined within the luminal tissues. Concentrations resulting in an increase in ROS production and changes in GSSG/GSH ratio were in line with the levels associated with observed physiological toxic effects. However, sod-1 was not induced at the lowest Ag concentrations, although reprotoxicity was seen at these levels. While both forms of Ag caused oxidative stress, impaired development, and reprotoxicity, the results suggest different involvement of ROS production to the toxic effects of AgNO3versus NM300K.

Photosynthesis-inspired H2 generation using a chlorophyll-loaded liposomal nanoplatform to detect and scavenge excess ROS

A disturbance of reactive oxygen species (ROS) homeostasis may cause the pathogenesis of many diseases. Inspired by natural photosynthesis, this work proposes a photo-driven H2-evolving liposomal nanoplatform (Lip NP) that comprises an upconversion nanoparticle (UCNP) that is conjugated with gold nanoparticles (AuNPs) via a ROS-responsive linker, which is encapsulated inside the liposomal system in which the lipid bilayer embeds chlorophyll a (Chla). The UCNP functions as a transducer, converting NIR light into upconversion luminescence for simultaneous imaging and therapy in situ. Functioning as light-harvesting antennas, AuNPs are used to detect the local concentration of ROS for FRET biosensing, while the Chla activates the photosynthesis of H2 gas to scavenge local excess ROS. The results thus obtained indicate the potential of using the Lip NPs in the analysis of biological tissues, restoring their ROS homeostasis, possibly preventing the initiation and progression of diseases.

Determining the ROS and the Antioxidant Status of Leaves During Cold Acclimation.

Cold slows down Calvin cycle activity stronger than photosynthetic electron transport, which supports production of reactive oxygen species (ROS). Even under extreme temperature conditions, most ROS are detoxified by the combined action of low-molecular weight antioxidants and antioxidant enzymes. Subsequent regeneration of the low-molecular weight antioxidants by NAD(P)H and thioredoxin/thiol-dependent pathways relaxes the electron pressure in the photosynthetic electron transport chain. In general, the chloroplast antioxidant system protects plants from severe damage of enzymes, metabolites, and cellular structures by both ROS detoxification and antioxidant recycling. Various methods have been developed to quantify ROS and antioxidant levels in photosynthetic tissues. Here, we summarize a series of exceptionally fast and easily applicable methods that show local ROS accumulation and provide information on the overall availability of reducing sugars, mainly ascorbate, and of thiols.

Long circulating photoactivable nanomicelles with tumor localized activation and ROS triggered self-accelerating drug release for enhanced locoregional chemo-photodynamic therapy

Although chemo-photodynamic therapy demonstrates promising synergetic therapeutic effect in malignant cancers, the currently available nanocarriers offer the limited capabilities for selective toxicity, drug release and tumor penetration. Herein, we developed photoactivatable nanomicelles, which are constructed by self-assembling of poly (ethylene glycol) (PEG)-stearamine (C18) conjugate (PTS) with a ROS-sensitive thioketal linker (TL) and co-loaded with doxorubicin (DOX) and photosensitizer pheophorbide A (PhA), for enhanced locoregional chemo-photodynamic therapy. Upon accumulation in tumor region, the resulting PTS nanomicelles loaded with Dox and PhA (PTS-DP) demonstrated reactive oxygen species (ROS) cascade responsive release of the DOX and PhA loaded inside. Initial intracellular release of DOX and PhA from the PTS-DP was triggered by the intrinsic presence of endogenous ROS within cancer cells. Furthermore, upon laser irradiation on the tumor region, enhanced singlet oxygen (1O2) was generated by PhA released initially in cancer cells, which in turns accelerated the cytoplasmic release of DOX through rapid dissociation of nanomicelles. The gradual elevation of local ROS level generated by light-activated PhA subsequent ROS-triggered release of DOX synergistically inhibited tumor growth and enhances the anti-tumor immunity. Findings of our study suggested that ROS-sensitive PTS nanomicelles could be a promising and innovative nanocarrier for locoregional chemo-photodynamic therapy.

Curved corannulene dually targets mitochondria and endoplasmic reticulum, and initiates apoptosis via localized ROS induction upon light triggering.

Organelle-targeting agents are promising in both fundamental and applied biomedicine research, but such materials are very limited. As a curved 2D carbon material, corannulene (Cor) displays an uneven intramolecular electron distribution, producing a large dipole moment that can favor the electrostatic interaction. Based on the large negative mitochondrial membrane potential and the presence of a connection structure between mitochondria and endoplasmic reticulum (ER), we hypothesized that Cor could simultaneously target both mitochondria and ER. Such hypothesis was well validated by using the fluorescence tag-labelled Cor. The co-localization analysis in a model cell line (PC3) revealed a preferred accumulation of Cor in both organelles, as evidenced by a large Pearson correlation coefficient. The large dipole also empowered Cor the ability of controlled production of reactive oxygen species (ROS) upon light irradiation. This feature plus mitochondria targeting of Cor induced depletion of adenosine triphosphate (ATP) and caspase 9/3 activation. The triggered ROS generation in ER caused the calcium dumping in the cytosol, as revealed by a calcium-specific fluorescence probe. A significant degree of apoptosis was induced by Cor as a result of the interplay of dual mitochondria/ER targeting and triggered organelle-specific ROS delivery. This study demonstrated the subcellular targeting ability of Cor for potential ROS-based therapy, and implied that the dipole could be a valuable parameter for efficient design and tailored screening of organelle-targeting materials for various biomedical applications.

Radical Stress Is More Cytotoxic in the Nucleus than in Other Organelles.

Cells are exposed to reactive oxygen species (ROS) as a by-product of mitochondrial metabolism, especially under hypoxia. ROS are also enzymatically generated at the plasma membrane during inflammation. Radicals cause cellular damage leading to cell death, as they react indiscriminately with surrounding lipids, proteins, and nucleotides. However, ROS are also important for many physiological processes, including signaling, pathogen killing and chemotaxis. The sensitivity of cells to ROS therefore likely depends on the subcellular location of ROS production, but how this affects cell viability is poorly understood. As ROS generation consumes oxygen, and hypoxia-mediated signaling upregulates expression of antioxidant transcription factor Nrf2, it is difficult to discern hypoxic from radical stress. In this study, we developed an optogenetic toolbox for organelle-specific generation of ROS using the photosensitizer protein SuperNova which produces superoxide anion upon excitation with 590 nm light. We fused SuperNova to organelle specific localization signals to induce ROS with high precision. Selective ROS production did not affect cell viability in most organelles except for the nucleus. SuperNova is a promising tool to induce locally targeted ROS production, opening up new possibilities to investigate processes and organelles that are affected by localized ROS production.

Effects of bioenergetics, temperature and cadmium on liver mitochondria reactive oxygen species production and consumption

A by-product of mitochondrial substrate oxidation and electron transfer to generate cellular energy (ATP) is reactive oxygen species (ROS). Superoxide anion radical and hydrogen peroxide (H2O2) are the proximal ROS produced by the mitochondria. Because low levels of ROS serve critical regulatory roles in cell physiology while excessive levels or inappropriately localized ROS result in aberrant physiological states, mitochondrial ROS need to be tightly regulated. While it is known that regulation of mitochondrial ROS involves balancing the rates of production and removal, the effects of stressors on these processes remain largely unknown. To illuminate how stressors modulate mitochondrial ROS homeostasis, we investigated the effects of temperature and cadmium (Cd) on H2O2 emission and consumption in rainbow trout liver mitochondria. We show that H2O2 emission rates increase with temperature and Cd exposure. Energizing mitochondria with malate-glutamate or succinate increased the rate of H2O2 emission; however, Cd exposure imposed different patterns of H2O2 emission depending on the concentration and substrate. Specifically, mitochondria respiring on malate-glutamate exhibited a saturable graded concentration-response curve that plateaued at 5 μM while mitochondria respiring on succinate had a biphasic concentration-response curve characterized by a spike in the emission rate at 1 μM Cd followed by gradual diminution at higher Cd concentrations. To explain the observed substrate- and concentration-dependent effects of Cd, we sequestered specific mitochondrial ROS-emitting sites using blockers of electron transfer and then tested the effect of the metal. The results indicate that the biphasic H2O2 emission response imposed by succinate is due to site IIF but is further modified at sites IQ and IIIQo. Moreover, the saturable graded H2O2 emission response in mitochondria energized with malate-glutamate is consistent with effect of Cd on site IF. Additionally, Cd and temperature acted cooperatively to increase mitochondrial H2O2 emission suggesting that increased toxicity of Cd at high temperature may be due to increased oxidative insult. Surprisingly, despite their clear stimulatory effect on H2O2 emission, Cd, temperature and bioenergetic status did not affect the kinetics of mitochondrial H2O2 consumption; the rate constants and half-lives for all the conditions tested were similar. Overall, our study indicates that the production processes of rainbow trout liver mitochondrial H2O2 metabolism are highly responsive to stressors and bioenergetics while the consumption processes are recalcitrant. The latter denotes the presence of a robust H2O2 scavenging system in liver mitochondria that would maintain H2O2 homeostasis in the face of increased production and reduced scavenging capacity.

Whole-Plant Live Imaging of Reactive Oxygen Species

Reactive oxygen species (ROS) are key regulators of numerous subcellular, cellular, and systemic signals. They function in plants as an integral part of many different hormonal, physiological, and developmental pathways, as well as play a critical role in defense and acclimation responses to different biotic and abiotic conditions. Although many ROS imaging techniques have been developed and utilized in plants, a whole-plant imaging platform for the dynamic detection of ROS in mature plants is lacking. Here we report a robust and straightforward method for the whole-plant live imaging of ROS in mature plants grown in soil. This new method could be used to study local and systemic ROS signals in different genetic variants, conduct phenotyping studies to identify new pathways for ROS signaling, monitor the stress level of different plants and mutants, and unravel novel routes of ROS integration into stress, growth regulation, and development in plants. We demonstrate the utility of this new method for studying systemic ROS signals in different Arabidopsis mutants and wound responses in cereals such as wheat and corn.

Local supply of reactive oxygen species into a tissue model by atmospheric-pressure plasma-jet exposure

The supply of reactive oxygen species (ROSs) into a tissue by plasmas must be controlled for the safe and effective use of plasma technologies in biomedical applications. In this study, the two-dimensional distributions of ROSs after passing through an agarose tissue model by the plasma-jet exposures were visualized using a KI-starch gel reagent to evaluate the local ROS supply. Partial ROS supply on the tissue model surface induced the local ROS supply in a pointlike shape just under the plasma-exposed spot. The O3-containing gas exposure without direct plasma contact could not induce the local ROS supply. Therefore, the local ROS supply was assumed to be induced by plasma-specific effects. However, the results also indicated that the plasma jet coming in direct contact with the tissue model surface did not necessarily induce the local ROS supply. The effects of the tissue model thickness on the local ROS supply were also studied; the local ROS supply could penetrate to a depth of 2 mm in the tissue model under the given experimental conditions.

Self-Assembled Responsive Bilayered Vesicles with Adjustable Oxidative Stress for Enhanced Cancer Imaging and Therapy.

In the present study, we report the development of magnetic-plasmonic bilayer vesicles assembled from iron oxide-gold Janus nanoparticles (Fe3O4-Au JNPs) for reactive oxygen species (ROS) enhanced chemotherapy. The amphiphilic Fe3O4-Au JNPs were grafted with poly(ethylene glycol) (PEG) on the Au surface and ROS-generating poly(lipid hydroperoxide) (PLHP) on the Fe3O4 surface, respectively, which were then assembled into vesicles containing two closely attached Fe3O4-Au NPs layers in opposite directions. The self-assembly mechanism of the bilayered vesicles was elucidated by performing a series of numerical simulations. The enhanced optical properties of the bilayered vesicles were verified by the calculated results and experimental data. The vesicles exhibited enhanced T2 relaxivity and photoacoustic properties over single JNPs due to the interparticle magnetic dipole interaction and plasmonic coupling. In particular, the vesicles are pH responsive and disassemble into single JNPs in the acidic tumor environment, activating an intracellular biochemical reaction between the grafted PLHP and released ferrous ions (Fe2+) from Fe3O4 NPs, resulting in highly efficient local ROS generation and increased intracellular oxidative stress. In combination with the release of doxorubicin (DOX), the vesicles combine ROS-mediated cytotoxicity and DOX-induced chemotherapy, leading to greatly improved therapeutic efficacy than monotherapies. High tumor accumulation efficiency and fast vesicle clearance from the body were also confirmed by positron emission tomography (PET) imaging of radioisotope 64Cu-labeled vesicles.

RBOH-Dependent ROS Synthesis and ROS Scavenging by Plant Specialized Metabolites To Modulate Plant Development and Stress Responses.

Reactive oxygen species (ROS) regulate plant growth and development. ROS are kept at low levels in cells to prevent oxidative damage, allowing them to be effective signaling molecules upon increased synthesis. In plants and animals, NADPH oxidase/respiratory burst oxidase homolog (RBOH) proteins provide localized ROS bursts to regulate growth, developmental processes, and stress responses. This review details ROS production via RBOH enzymes in the context of plant development and stress responses and defines the locations and tissues in which members of this family function in the model plant Arabidopsis thaliana. To ensure that these ROS signals do not reach damaging levels, plants use an array of antioxidant strategies. In addition to antioxidant machineries similar to those found in animals, plants also have a variety of specialized metabolites that scavenge ROS. These plant specialized metabolites exhibit immense structural diversity and have highly localized accumulation. This makes them important players in plant developmental processes and stress responses that use ROS-dependent signaling mechanisms. This review summarizes the unique properties of plant specialized metabolites, including carotenoids, ascorbate, tocochromanols (vitamin E), and flavonoids, in modulating ROS homeostasis. Flavonols, a subclass of flavonoids with potent antioxidant activity, are induced during stress and development, suggesting that they have a role in maintaining ROS homeostasis. Recent results using genetic approaches have shown how flavonols regulate development and stress responses through their action as antioxidants.

Oxidative stress levels and dynamic changes in mitochondrial gene expression in a radiation-induced lung injury model.

The purpose of this study was to set up a beagle dog model, for radiation-induced lung injury, that would be able to supply fresh lung tissues in the different injury phases for research into oxidative stress levels and mitochondrial gene expression. Blood serum and tissues were collected via CT-guided core needle biopsies from dogs in the various phases of the radiation response over a 40-week period. Levels of reactive oxygen species (ROS) and manganese superoxide dismutase 2 (MnSOD) protein expression in radiation-induced lung injury were determined by in situ immunocytochemistry; malondialdehyde (MDA) content and reductase activity in the peripheral blood were also tested; in addition, the copy number of the mitochondrial DNA and the level of function of the respiratory chain in the lung tissues were assessed. ROS showed dynamic changes and peaked at 4 weeks; MnSOD was mainly expressed in the Type II alveolar epithelium at 8 weeks; the MDA content and reductase activity in the peripheral blood presented no changes; the copy numbers of most mitochondrial genes peaked at 8 weeks, similarly to the level of function of the corresponding respiratory chain complexes; the level of function of the respiratory chain complex III did not peak until 24 weeks, similarly to the level of function of the corresponding gene Cytb. Radiation-induced lung injury was found to be a dynamically changing process, mainly related to interactions between local ROS, and it was not associated with the levels of oxidative stress in the peripheral blood. Mitochondrial genes and their corresponding respiratory chain complexes were found to be involved in the overall process.

ROS-sensitive thioketal-linked polyphosphoester-doxorubicin conjugate for precise phototriggered locoregional chemotherapy

Minimizing drug leakage at off-target sites and triggering sufficient drug release in tumor tissue are major objectives for effective nanoparticle (NP)-based cancer therapy. The current covalent and cleavable drug-NP conjugation strategy is promising but lacks high controllability to realize tumor-specific release. As a proof-of-concept, the reactive oxygen species (ROS)-activatable thioketal (TK) bond was explored as the linkage between doxorubicin (DOX) and polyphosphoester (PPE-TK-DOX). The Ce6@PPE-TK-DOX NPs constructed by co-self-coassembly of PPE-TK-DOX and the photosensitizer Ce6 efficiently prevented premature drug leakage in the off-target tissue and cells because of the high stability of the TK bond under physiological conditions. Once circulating into the tumor site, the 660-nm red light was precisely employed to irradiate the tumor area under the guidance of fluorescence/magnetic resonance (MR) dual-model imaging, which can induce localized ROS generation, resulting in rapid cleavage of the TK bond. Consequently, the DOX prodrug was locoregionally released and activated, achieving tumor-specific drug delivery with high controllability by light. Such phototriggered prodrug release and activation at the desired site significantly enhanced the therapeutic efficacy and minimized the side effect, providing new avenues to develop drug delivery systems for remote on-demand drug delivery in vivo.

Injectable Bioresponsive Gel Depot for Enhanced Immune Checkpoint Blockade.

Although cancer immunotherapy based on immune checkpoint inhibitors holds great promise toward many types of cancers, several challenges still remain, associated with low objective response of patient rate as well as systemic side effects. Here, a combination immunotherapy strategy is developed based on a thermogelling reactive oxygen species (ROS)-responsive polypeptide gel for sustained release of anti-programmed cell death-ligand 1 antibody and dextro-1-methyl tryptophan, inhibitor of indoleamine-2,3-dioxygenase with leveraging the ROS level in the tumor microenvironment. This bioresponsive gel depot can effectively reduce the local ROS level and facilitate release of immunotherapeutics, which leads to enhanced anti-melanoma efficacy in vivo.

Ultrasound induced phase-transition and invisible nanobomb for imaging-guided tumor sonodynamic therapy.

Sonodynamic therapy (SDT) kills tumor cells by converting molecular oxygen (O2) into reactive oxygen species (ROS) using sonosensitizers and appropriate ultrasound (US) stimulation. However, pre-existing tumorous hypoxia severely limits SDT efficacy. Worse is that O2 consumption during SDT will aggravate local hypoxia. In this study, we developed an O2 self-supplied and lossless US-responsive detonation strategy to overcome the above limitation. This explores a perfluorohexane (PFH) bubbling-based "stealth camouflage" and a US-controlled on-demand system (RBC-HPBs/HMME/PFH) to realize US imaging-guided precise drug delivery and locally positioning tumor therapy. Compared with HPBs/HMME/PFH, the results showed that RBC encapsulation can promote cell phagocytosis. After US stimulation, the PFH phase change induced RBC instantaneous blasting. Simultaneous release of HMME and O2 resulted in plenty of ROS production and the intracellular redox system imbalance, significantly enhancing their cytotoxicity. Following US imaging guidance, the greatly improved local ROS level and the anti-tumor effect were proved in 4T1 tumor-bearing mice for HMME and the O2 synchronous co-transport system. Immunohistochemistry results proved that RBC-HPBs/HMME/PFH + US could significantly relieve tumorous hypoxia and reduce the microvessel density as an O2 reservoir, which would block nutritional sources to starve tumor cells and inhibit their metastasis, achieving a cancer multi-mechanism treatment.

Theranostic Prodrug Vesicles for Reactive Oxygen Species‐Triggered Ultrafast Drug Release and Local‐Regional Therapy of Metastatic Triple‐Negative Breast Cancer

AbstractA reactive oxygen species (ROS)‐activatable doxorubicin (Dox) prodrug vesicle (RADV) is presented for image‐guided ultrafast drug release and local‐regional therapy of the metastatic triple‐negative breast cancer (TNBC). RADV is prepared by integrating a ROS‐activatable Dox prodrug, a poly(ethylene glycol) (PEG)‐modified photosensitizer pyropheophorbide‐a, an unsaturated phospholipid 1,2‐dioleoyl‐sn‐glycero‐3‐phosphocholine, and cholesterol into one single nanoplatform. RADV is of extremely high drug loading ratio (27.5 wt%) by self‐assembly of the phospholipid‐mimic Dox prodrug into the liposomal bilayer membrane. RADV displays good colloidal stability to prevent premature drug leakage during the blood circulation and inert photochemotoxicity to avoid nonspecific side effect. RADV passively accumulates at tumor site through the enhanced permeability and retention effect when administrated systemically. Once deposited at the tumor site, RADV generates fluorescent and photoacoustic signals to guide near‐infrared (NIR) laser irradiation, which can induce localized ROS generation, not only to trigger prodrug activation and ultrafast drug release but also conduct photodynamic therapy in a spatiotemporally controlled manner. In combination with NIR laser irradiation, RADV efficiently inhibits the tumor growth and distant metastasis of TNBC. Local‐regional tumor therapy using intelligent theranostic nanomedicine might provide an alternative option for highly efficient treatment of the metastatic TNBC.