Intracellular Redox Environment Research Articles

Intracellular Redox Environment Determines Cancer-normal Cell Selectivity of Selenium Nanoclusters.

Elucidating the chemical structure and intracellular action mechanisms is still the critical limit for the clinical translation of nanomedicines. Intracellular redox environments originating from cell metabolism are key factors affecting internalized drug efficacy. Herein, we engineer Se-Se/Se-S bond to assemble selenium nanoclusters with intracellular redox environment-driven selective structure. Chemical structure analysis reveals that, the bonding of sulfur atom in intermediates to the two neighboring or interposition selenium atoms in selenium rings is the key internal driving force for nanoparticle cluster formation. This nanocluster can be predominantly transformed to selenocysteine to facilitate selenoproteins synthesis in normal cells, while metabolize to cytotoxic SeO32- based on the oxidative intracellular redox environment of cancer cells. Resultantly, selenium nanoclusters exhibit significant cell proliferation inhibition ability to cancer cells and impressive safety to normal cells. Taken together, this study not only clarifies the chemical nature of the atom engineering of selenium nanocluster, but also elucidates its intracellular redox environment-oriented anticancer mechanism.

Intracellular Redox Environment Determines Cancer‐normal Cell Selectivity of Selenium Nanoclusters

Elucidating the chemical structure and intracellular action mechanisms is still the critical limit for the clinical translation of nanomedicines. Intracellular redox environments originating from cell metabolism are key factors affecting internalized drug efficacy. Herein, we engineer Se‐Se/Se‐S bond to assemble selenium nanoclusters with intracellular redox environment‐driven selective structure. Chemical structure analysis reveals that, the bonding of sulfur atom in intermediates to the two neighboring or interposition selenium atoms in selenium rings is the key internal driving force for nanoparticle cluster formation. This nanocluster can be predominantly transformed to selenocysteine to facilitate selenoproteins synthesis in normal cells, while metabolize to cytotoxic SeO32‐ based on the oxidative intracellular redox environment of cancer cells. Resultantly, selenium nanoclusters exhibit significant cell proliferation inhibition ability to cancer cells and impressive safety to normal cells. Taken together, this study not only clarifies the chemical nature of the atom engineering of selenium nanocluster, but also elucidates its intracellular redox environment‐oriented anticancer mechanism.

D4-Chip Reveals Impaired T Cell Function in Sepsis: Insights from Plasma Microenvironment Analysis and Mitochondrial Targeted Therapy.

Sepsis, a systemic inflammation syndrome initiated by infection, poses significant challenges due to its intricate pathophysiology. T cells play a crucial role in combating infections during sepsis. Despite previous observations indicating T cell dysfunction in sepsis, reliable in-vitro detection methods were lacking, and the factors influencing these impairments remained unclear. We developed a novel method using the D4-Chip to assess sepsis T cell migration function. This microfluidic platform enabled precise analysis of migration function under controlled conditions. Additionally, We explored the impact of the plasma microenvironment on T cell behavior, along with the redox environment in sepsis, and assessed the potential efficacy of Mitoquinone mesylate (MitoQ), a mitochondrial-targeted drug. Our findings revealed impaired migration function in sepsis T cells compared to healthy controls. Interestingly, sepsis plasma enhanced the migration of healthy T cells, yet incubation with healthy plasma did not fully restore migration impairments in sepsis T cells. Subsequent investigations uncovered a significant increase in NADH/NAD+ levels in sepsis T cells, with healthy T cells exposed to various sepsis plasma conditions also showing elevated NADH/NAD+ levels. Importantly, MitoQ normalized abnormal intracellular NADH/NAD+ levels and enhanced the migration ability of T cells. Short-term incubation with sepsis plasma does not directly inhibit T cell migration but instead affects T cell function by disrupting the intracellular redox environment. Improving the intracellular redox environment of sepsis patients contributes to restoring impaired migration and proliferation, with MitoQ demonstrating therapeutic potential.

A reciprocal relationship between mitochondria and lipid peroxidation determines the chondrocyte intracellular redox environment

In orthopedic research, many studies have applied vitamin E as a protective antioxidant or used tert-butyl hydroperoxide to induce oxidative injury to chondrocytes. These studies often support the hypothesis that joint pathology causes oxidative stress and increased lipid peroxidation that might be prevented with lipid antioxidants to improve cell survival or function and joint health; however, lipid antioxidant supplementation was ineffective against osteoarthritis in clinical trials and animal data have been equivocal. Moreover, increased circulating vitamin E is associated with increased rates of osteoarthritis. This disconnect between benchtop and clinical results led us to hypothesize that oxidative stress-driven paradigms of chondrocyte redox function do not capture the metabolic and physiologic effects of lipid antioxidants and prooxidants on articular chondrocytes. We used ex vivo and in vivo cartilage models to investigate the effect of lipid antioxidants on healthy, primary, articular chondrocytes and applied immuno-spin trapping techniques to provide a broad indicator of high levels of oxidative stress independent of specific reactive oxygen species. Key findings demonstrate lipid antioxidants were pro-mitochondrial while lipid prooxidants decreased mitochondrial measures. In the absence of injury, radical formation was increased by lipid antioxidants; however, in the presence of injury, radical formation was decreased. In unstressed conditions, this relationship between chondrocyte mitochondria and redox regulation was reproduced in vivo with overexpression of glutathione peroxidase 4. In mice aged 18 months or more, overexpression of glutathione peroxidase 4 significantly decreased the presence of pro-mitochondrial peroxisome proliferation activated receptor gamma and deranged the relationship between mitochondria and the redox environment. This complex interaction suggests strategies targeting articular cartilage may benefit from adopting more nuanced paradigms of articular chondrocyte redox metabolism.

Gold(III) Porphyrin-Metal-Polyphenolic Nanocomplexes: Breaking Intracellular Redox Environment for Enhancing Mild-Temperature Photothermal Therapy.

Photothermal therapy (PTT) is a promising clinical antitumor strategy. However, local hyperthermia inevitably induces heat damage to adjacent normal tissues, while alternative mild-temperature therapy (MPTT, T < 45 °C) is also inefficient due to the overexpressed hyperthermia-induced heat shock proteins (HSPs) by cancer cells. Therefore, developing PTT strategies with minimizing damage to healthy tissues with improved cellular temperature sensitivity is extremely valuable for clinical application. Herein, we proposed the strategy of disrupting the intracellular redox environment via destroying the ROS-defending systems to promote MPTT. The gold(III) porphyrin-Fe3+-tannic acid nanocomplexes (AuTPP@TA-Fe NPs) were achieved via interfacial cohesion and supramolecular assembly of bioadhesive species, which could trigger the Fenton reaction to produce ·OH radicals and downregulation of reductive TrxR enzyme and mitochondrial chaperone protein Hsp60. The aggravation of oxides and the inactivation of Hsp60 provide favorable pathways for impeding the heat shock-induced self-repair mechanism of cancer cells, which strengthens AuTPP@TA-Fe NPs mediated MPTT.

A fluorescent probe for detecting H2O2 and delivering H2S in lysosomes and its application in maintaining the redox environments

Hydrogen peroxide (H2O2) is a reactive oxygen species (ROS) that can be used as a marker for the occurrence of oxidative stress in the organism. Lysosomes serve as intracellular digestive sites, and when the concentration of H2O2 in them is abnormal, lysosomal function is often impaired, leading to the development of diseases. Hydrogen sulfide (H2S) acts as a gaseous signaling molecule that scavenges H2O2 from cells and tissues, thereby maintaining the redox environment of the body. However, most of the reported hydrogen peroxide fluorescent probes so far can only detect H2O2, but cannot maintain the intracellular redox environment. In this paper, an H2O2 fluorescent probe LN-HOD with lysosomal targeting properties was designed and synthesized by combining the H2O2 recognition site with a naphthylamine fluorophore via a thiocarbamate moiety. The probe has the advantages of large Stokes shift (110 nm), high sensitivity and good H2S release capability. The probe LN-HOD can be used to detect H2O2 in cells, zebrafish and plant roots. In addition, LN-HOD detects changes in the concentration of H2O2 in plant roots when Arabidopsis is stressed by cadmium ion (Cd2+). And through its ability to release H2S, it can help to remove excess H2O2 and maintain the redox environment in cells, zebrafish and plant roots. The present work provides new ideas for the detection and assisted removal of H2O2, which contributes to the in-depth study of the cellular microenvironment in organisms.

The crystal structure of mycothiol disulfide reductase (Mtr) provides mechanistic insight into the specific low-molecular-weight thiol reductase activity of Actinobacteria.

Low-molecular-weight (LMW) thiols are involved in many processes in all organisms, playing a protective role against reactive species, heavy metals, toxins and antibiotics. Actinobacteria, such as Mycobacterium tuberculosis, use the LMW thiol mycothiol (MSH) to buffer the intracellular redox environment. The NADPH-dependent FAD-containing oxidoreductase mycothiol disulfide reductase (Mtr) is known to reduce oxidized mycothiol disulfide (MSSM) to MSH, which is crucial to maintain the cellular redox balance. In this work, the first crystal structures of Mtr are presented, expanding the structural knowledge and understanding of LMW thiol reductases. The structural analyses and docking calculations provide insight into the nature of Mtrs, with regard to thebinding and reduction of the MSSM substrate, in the context of related oxidoreductases. The putative binding site for MSSM suggests a similar binding to that described for the homologous glutathione reductase and its respective substrate glutathione disulfide, but with distinct structural differences shaped to fit the bulkier MSSM substrate, assigning Mtrs as uniquely functioning reductases. As MSH has been acknowledged as an attractive antitubercular target, the structural findings presented in this work may contribute towards future antituberculosis drug development.

Self-Supplied Reactive Oxygen Species-Responsive Mitoxantrone Polyprodrug for Chemosensitization-Enhanced Chemotherapy under Moderate Hyperthermia.

Currently, the secondary development and modification of clinical drugs has become one of the research priorities. Researchers have developed a variety of TME-responsive nanomedicine carriers to solve certain clinical problems. Unfortunately, endogenous stimuli such as reactive oxygen species (ROS), as an important prerequisite for effective therapeutic efficacy, are not enough to achieve the expected drug release process, therefore, it is difficult to achieve a continuous and efficient treatment process. Herein, a self-supply ROS-responsive cascade polyprodrug (PMTO) is designed. The encapsulation of the chemotherapy drug mitoxantrone (MTO) in a polymer backbone could effectively reduce systemic toxicity when transported in vivo. After PMTO is degraded by endogenous ROS of the TME, another part of the polyprodrug backbone becomes cinnamaldehyde (CA), which can further enhance intracellular ROS, thereby achieving a sustained drug release process. Meanwhile, due to the disruption of the intracellular redox environment, the efficacy of chemotherapy drugs is enhanced. Finally, the anticancer treatment efficacy is further enhanced due to the mild hyperthermia effect of PMTO. In conclusion, the designed PMTO demonstrates remarkable antitumor efficacy, effectively addressing the limitations associated with MTO.

Synergetic effects of conductive materials and bacterial population in inoculum on mixed-culture biohydrogen production

This study examined the effect of conductive materials (softwood pellet biochar pyrolyzed at 550 °C and 700 °C, powdered activated carbon and stainless-steel) on the two series of batch biohydrogen production inoculated with three types of heated-treated anaerobic digester sludge. Biochar pyrolyzed at 550 °C and stainless-steel exhibited the highest enhanced hydrogen yield up to 117 % in the first and second series of experiments, respectively. Importantly, the enhancement effect by the introduction of conductive materials was significantly affected by the microbial population in inoculum, particularly the relative abundance of electroactive H2-producing Clostridium sp. Metabolic flux analysis revealed that the enhanced H2 yield was concurrent with the decrease of lactate production and the increase of H2-producing acetogenesis. Conductive materials also improved electron transport system activity and NADH/NAD+ ratio, which are related with the metabolic activity. This study shows that introducing conductive material can control intracellular redox environment, thereby reinforcing the metabolic activity selectively.

Redox in Cancer Metabolism: Manipulation of Cancer Metabolism Through Exploitation of Redox Environments

AbstractThe use of bioelectronics is a quickly evolving and developing field offering novel application to solve problems across numerous biological disciplines. Cancer research has focussed on various biomarkers as a means for detection and for potential therapeutic treatments. Several therapies and medications focus on influencing redox state within the cellular environment, with some of these therapies utilising cyclic redox components, allowing for repeated oxidation/reduction at target sites. This offers great potential for electrical (DC and AC) and electrochemical control over the intracellular redox environment. Herein explores the redox circuits in cancer and its metabolism, the influence of mediated oxidative stress in redox altered environments, therapeutics that target specific redox pathways and their redox active proteins, and the implementation of electrochemical interrogation to control the cellular redox environment to manipulate cancer metabolism.

Intracellular Hyperbranched Polymerization for Circumventing Cancer Drug Resistance.

Polymerization inside living cells provides chemists with a multitude of possibilities to modulate cell activities. Considering the advantages of hyperbranched polymers, such as a large surface area for target sites and multilevel branched structures for resistance to the efflux effect, we reported a hyperbranched polymerization in living cells based on the oxidative polymerization of organotellurides and intracellular redox environment. The intracellular hyperbranched polymerization was triggered by reactive oxygen species (ROS) in the intracellular redox microenvironment, effectively disrupting antioxidant systems in cells by an interaction between Te (+4) and selenoproteins, thus inducing selective apoptosis of cancer cells. Importantly, the obtained hyperbranched polymer aggregated into branched nanostructures in cells, which could effectively evade drug pumps and decrease drug efflux, ensuring the polymerization for persistent treatment. Finally, in vitro and in vivo studies confirmed that our strategy presented selective anticancer efficacy and well biosafety. This approach provides a way for intracellular polymerization with desirable biological applications to regulate cell activities.

Redox states in the endoplasmic reticulum directly regulate the activity of calcium channel, inositol 1,4,5-trisphosphate receptors

Inositol 1,4,5-trisphosphate receptors (IP3Rs) are one of the two types of tetrameric ion channels that release calcium ion (Ca2+) from the endoplasmic reticulum (ER) into the cytosol. Ca2+ released via IP3Rs is a fundamental second messenger for numerous cell functions. Disturbances in the intracellular redox environment resulting from various diseases and aging interfere with proper calcium signaling, however, the details are unclear. Here, we elucidated the regulatory mechanisms of IP3Rs by protein disulfide isomerase family proteins localized in the ER by focusing on four cysteine residues residing in the ER lumen of IP3Rs. First, we revealed that two of the cysteine residues are essential for functional tetramer formation of IP3Rs. Two other cysteine residues, on the contrary, were revealed to be involved in the regulation of IP3Rs activity; its oxidation by ERp46 and the reduction by ERdj5 caused the activation and the inactivation of IP3Rs activity, respectively. We previously reported that ERdj5 can activate the sarco/endoplasmic reticulum Ca2+-ATPase isoform 2b (SERCA2b) using its reducing activity [Ushioda etal., Proc. Natl. Acad. Sci. U.S.A.113, E6055-E6063 (2016)]. Thus, we here established that ERdj5 exerts the reciprocal regulatory function for IP3Rs and SERCA2b by sensing the ER luminal Ca2+ concentration, which contributes to the calcium homeostasis in the ER.

Effect of RONS-Induced Intracellular Redox Homeostasis in 6-NBDG/Glucose Uptake in C2C12 Myotubes and Single Isolated Skeletal Muscle Fibres.

The glucose uptake in skeletal muscle is essential to produce energy through ATP, which is needed by this organ to maintain vital functions. The impairment of glucose uptake compromises the metabolism and function of skeletal muscle and other organs and is a feature of diabetes, obesity, and ageing. There is a need for research to uncover the mechanisms involved in the impairment of glucose uptake in skeletal muscle. In this study, we adapted, developed, optimised, and validated a methodology based on the fluorescence glucose analogue 6-NBDG, combined with a quantitative fluorescence microscopy image analysis, to determine the glucose uptake in two models of skeletal muscle cells: C2C12 myotubes and single fibres isolated from muscle. It was proposed that reactive oxygen and nitrogen species (RONS) and redox homeostasis play an important role in the modulation of intracellular redox signalling pathways associated with glucose uptake. In this study, we prove that the prooxidative intracellular redox environment under oxidative eustress produced by RONS such as hydrogen peroxide and nitric oxide improves glucose uptake in skeletal muscle cells. However, when oxidation is excessive, oxidative distress occurs, and cellular viability is compromised, although there might be an increase in the glucose uptake. Based on the results of this study, the determination of 6-NBDG/glucose uptake in myotubes and skeletal muscle cells is feasible, validated, and will contribute to improve future research.

Abstract 4772: β3-adrenoceptor minimize doxorubicin effect in Ewing sarcoma by UCP2 activation

Abstract The phenomenon of “Oxygen Paradox” arises when reactive oxygen species (ROS) overcome the cellular anti-oxidant defense system through either an escalation in ROS levels or a reduced capability of the cells to increase an antioxidant response. The deregulated redox signaling that stimulate an uncontrolled ROS increase, could induce both tumor initiation and progression, and cell death after chemotherapy treatment. In recent decades, the therapeutic choice for Ewing Sarcomas (ES) consisting of a multi-drug chemotherapy regimen combined with radiotherapy and surgery, has significantly improved the survival up to 70% in localized diseases. ES patients, often show resistance to multi chemotherapeutic agents since ES cells exhibit a high sensitivity to rapid changes in intracellular redox environment. In this context, an antioxidant-inhibiting strategy was evaluated in vitro to test chemotherapeutic efficacy used in the standard treatment of ES such as the anthracycline doxorubicin (DOX) that increases ROS generation and oxidative stress (OS) in mitochondria. DOX is a strong exogenous ROS generator but lacks target specificity thereby it also affects normal cells resulting in several side-effects. Literature shows that DOX ability to reduce tumor progression is due to a DOX-induced ROS overproduction that occurs in mitochondria, known to be the main site of constant ROS production, and this effect is mediated by the mitochondrial NADPH oxidase (NADPHox) activity. To investigate why DOX causes resistance in ES patients, experiments in vitro were conducted with A673 ES cell line. A673 cells express a high level of the β3-adrenergic receptor (β3-AR) and are high susceptible to OS. Recently, β3-AR has become highly attractive in cancer biology for its ability to reduce tumor growth, metastasis, and its antioxidant properties as main regulator of the cellular response to OS. β3-AR working as ROS sensor control the redox state of the cells, driving them to life or death through mitochondria bioenergetics function. In our experimental setting DOX induced β3-AR expression which influenced the uncoupling protein 2 (UCP2) expression. β3-AR/UCP2 axis strongly decreased the mitochondrial activity by reducing ATP synthesis and mitochondrial ROS content and this effect was reverted by β3-AR antagonist, SR59230A. In summary, the DOX chemotherapy promotes β3-AR expression that decreases ROS levels through β3-AR/UCP2 axis. Decreased ROS levels allow ES cells to survive chemotherapy. Citation Format: Claudia Masi, Amada Pasha, Francesco Carrozzo, Martina Rosati, Alessandro Pini, Maura Calvani, Claudio Favre. β3-adrenoceptor minimize doxorubicin effect in Ewing sarcoma by UCP2 activation. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4772.

A Diode-Like Dye-Cu Anisotropic Junction in a Coordination Polymer as a Logic State Ratchet for Intratumor Redox Photomodulation.

Redox logic materials offer new avenues to modulate intracellular pathologic redox environment area-specifically, but the unambiguity of redox logic states and their unidirectional and repetitive switchability are challenging to realize. By merging a bistable diisophthalic phenazine dye ligand with CuII salt, a multistable coordination polymer (CP) was constructed, of which the dye-Cu anisotropic junction achieved the diode-like unidirectional electron transfer and logic state ratchet for the first time. Radical cationic CP maintained OFF status with low toxicity in healthy tissues, but was reduced to the neutral SERVO state by the overexpressed glutathione (GSH) in hypoxic tumors. After photoirradiation, the stabilized charge-separated ON status promoted photo-Fenton reaction for reactive oxygen species (ROS) signal transduction, and simultaneously recovered the initial state for catalytic signal amplification of ROS, furnishing intratumor redox photomodulation for therapy.

A Diode‐Like Dye‐Cu Anisotropic Junction in a Coordination Polymer as a Logic State Ratchet for Intratumor Redox Photomodulation

AbstractRedox logic materials offer new avenues to modulate intracellular pathologic redox environment area‐specifically, but the unambiguity of redox logic states and their unidirectional and repetitive switchability are challenging to realize. By merging a bistable diisophthalic phenazine dye ligand with CuII salt, a multistable coordination polymer (CP) was constructed, of which the dye‐Cu anisotropic junction achieved the diode‐like unidirectional electron transfer and logic state ratchet for the first time. Radical cationic CP maintained OFF status with low toxicity in healthy tissues, but was reduced to the neutral SERVO state by the overexpressed glutathione (GSH) in hypoxic tumors. After photoirradiation, the stabilized charge‐separated ON status promoted photo‐Fenton reaction for reactive oxygen species (ROS) signal transduction, and simultaneously recovered the initial state for catalytic signal amplification of ROS, furnishing intratumor redox photomodulation for therapy.

Measuring the Oxidation State and Enzymatic Activity of Glyceraldehyde Phosphate Dehydrogenase (GAPDH).

Glyceraldehyde phosphate dehydrogenase (GAPDH) is a highly conserved, essential, and abundant enzyme that catalyzes a rate-determining step of glycolysis. GAPDH catalyzes the nicotinamide adenine dinucleotide (NAD+)- and inorganic phosphate-dependent oxidation and phosphorylation of glyceraldehyde phosphate (GAP) to form 1,3-bisphosphoglycerate (BPG). As part of its mechanism of action, GAPDH employs a redox-sensitive cysteine that serves as a nucleophile to form a covalent adduct with GAP in order to set-up subsequent oxidation and phosphorylation steps. As a result of the redox sensitivity of the active site cysteine residue, GAPDH is susceptible to oxidative inactivation by oxidants such as hydrogen peroxide (H2O2). Indeed, numerous studies have demonstrated that oxidative inactivation of GAPDH has important metabolic consequences for adaptation to life in air and oxidative stress since decreased GAPDH activity results in the rerouting of carbon flux away from glycolysis and toward the pentose phosphate pathway to produce the key cellular reductant and antioxidant, NADPH. Thus, the ability to probe GAPDH oxidation and activity provides an important snapshot of the intracellular redox environment and glycolytic flux. Herein, we describe methods to measure reduced and oxidized GAPDH using thiol alkylation assays as well as GAPDH enzymatic activity.

TNFα-induced IDH1 hyperacetylation reprograms redox homeostasis and promotes the chemotherapeutic sensitivity.

The heterogeneity and drug resistance of colorectal cancer (CRC) often lead to treatment failure. Isocitrate dehydrogenase 1 (IDH1), a rate-limiting enzyme in the tricarboxylic acid cycle, regulates the intracellular redox environment and mediates tumor cell resistance to chemotherapeutic drugs. The aim of this study was to elucidate the mechanism underlying the involvement of IDH1 acetylation in the development of CRC drug resistance under induction of TNFα. We found TNFα disrupted the interaction between SIRT1 and IDH1 and increased the level of acetylation at K115 of IDH1. Hyperacetylation of K115 was accompanied by protein ubiquitination, which increased its susceptibility to degradation compared to IDH1 K115R. TNFα-mediated hyperacetylation of K115 sensitized the CRC cells to 5FU and reduced the NADPH/NADP ratio to that of intracellular ROS. Furthermore, TNFα and 5FU inhibited CRC tumor growth in vivo, while the K115R-expressing tumor tissues developed 5FU resistance. In human CRC tissues, K115 acetylation was positively correlated with TNFα infiltration, and K115 hyperacetylation was associated with favorable prognosis compared to chemotherapy-induced deacetylation. Therefore, TNFα-induced hyperacetylation at the K115 site of IDH1 promotes antitumor redox homeostasis in CRC cells, and can be used as a marker to predict the response of CRC patients to chemotherapy.

Charge-Convertible and Reduction-Sensitive Cholesterol-Containing Amphiphilic Copolymers for Improved Doxorubicin Delivery.

For achieving successful chemotherapy against cancer, designing biocompatible drug delivery systems (DDSs) with long circulation times, high cellular endocytosis efficiency, and targeted drug release is of upmost importance. Herein, a well-defined PEG-b-P(MASSChol-co-MANBoc) block copolymer bearing redox-sensitive cholesteryl-side group was prepared via reversible addition-fragmentation chain transfer (RAFT) polymerization (with non-redox PEG-b-P(MACCChol-co-MAN-DCA) as the reference), and 1,2-dicarboxylic-cyclohexene acid (DCA) was then grafted onto the hydrophobic block to endow it with charge-convertible characteristics under a tumor microenvironment. The amphiphilic copolymer could be assembled into polymeric spherical micelles (SSMCs) with polyethylene glycol (PEG) as the corona/shell, and anti-cancer drug doxorubicin (DOX) was successfully encapsulated into the micellar core via strong hydrophobic and electrostatic interactions. This nanocarrier showed high stability in the physiological environment and demonstrated “smart” surface charge conversion from negative to positive in the slightly acidic environment of tumor tissues (pH 6.5~6.8), as determined by dynamic light scattering (DLS). Moreover, the cleavage of a disulfide bond linking the cholesterol grafts under an intracellular redox environment (10 mM GSH) resulted in micellar dissociation and accelerated drug release, with the non-redox-responsive micelles (CCMCs) as the control. Additionally, a cellular endocytosis and tumor proliferation inhibition study against MCF-7 tumor cells demonstrated the enhanced endocytosis and tumor cell inhibitory efficiency of dual-responsive SSMCs/DOX nanomedicines, revealing potentials as multifunctional nanoplatforms for effective oncology treatment.

PH/ROS dual-responsive nanoparticles with curcumin entrapment to promote antitumor efficiency in triple negative breast cancer

Triple negative breast cancer (TNBC) remains a serious carcinoma threatening women's life. Natural compounds such as curcumin (CUR) have shown promising potential in TNBC therapy without conventional toxicity like chemotherapeutics. To improve the therapeutic efficiency, a pH/redox nanocarrier (CUR@PCPP NPs) was developed for tumor specific delivery of CUR. CUR@PCPP NPs showed good size distribution, encapsulation efficiency and stability under physiological conditions. Detachment of polyethylene glycol (PEG) facilitated cellular uptake of CUR@PCPP NPs after exposure to extracellular tumor pH. Subsequently CUR was released due to the intracellular redox environment. Thereafter, released CUR could efficiently induce apoptosis and cycle arrest, and inhibit TNBC cells. We further verified the biodistribution and antitumor effects in vivo and the results showed that CUR@PCPP NPs demonstrated high tumor specific accumulation and effectively suppressed tumor growth without noticeable toxicity.