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As a vital biological molecule, H2O2(Hydrogen Peroxide) is involved in different physiological and pathological processes. And in addition to this, H2O2 is suitable for medical wound disinfection, environmental disinfection and food disinfection. Accordingly, it is of high significance to conveniently and effectively detect H2O2 in the environment and organisms. This subject synthesised a fluorescent probe Pyrimidine-Se by using selenomorpholine and pyrimidine dye, which detect H2O2 in an aqueous environment. Pyrimidine-Se has a large Stokes shift (Δλ = 155 nm), which can specifically and quickly quantitatively detect H2O2. When the probe Pyrimidine-Se reacted with H2O2, the Se(II) in the selenomorpholine was oxidised to Se(IV), so the electron withdrawing ability of the electron withdrawing group of Pyrimidine-Se was improved, and the fluorescence intensity of the probe were enhanced. Interestingly, Se(IV) can be reduced by GSH (Glutathione) to Se(II) to quench the fluorescence, and this redox cycle can continue several times, which indicated that it can have a potential of real-time monitoring the redox state in vivo. The probe was also satisfactorily used to detect H2O2 in Argentina Bloodfin larvaes and abnormal H2O2 content in some organs was detected. [ABSTRACT FROM AUTHOR]

Multidrug resistance (MDR) is frequently induced after long-term exposure to reduce the therapeutic effect of chemotherapeutic drugs, which is always associated with the overexpression of efflux proteins, such as P-glycoprotein (P-gp). Nano-delivery technology can be used as an efficient strategy to overcome tumor MDR. In this study, mesoporous silica nanoparticles (MSNs) were synthesized and linked with a disulfide bond and then coated with lipid bilayers. The functionalized shell/core delivery systems (HT-LMSNs-SS@DOX) were developed by loading drugs inside the pores of MSNs and conjugating with D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) and hyaluronic acid (HA) on the outer lipid surface. HT-LMSNs-SS and other carriers were characterized and assessed in terms of various characteristics. HT-LMSNs-SS@DOX exhibited a dual pH/reduction responsive drug release. The results also showed that modified LMSNs had good dispersity, biocompatibility, and drug-loading capacity. In vitro experiment results demonstrated that HT-LMSNs-SS were internalized by cells and mainly by clathrin-mediated endocytosis, with higher uptake efficiency than other carriers. Furthermore, HT-LMSNs-SS@DOX could effectively inhibit the expression of P-gp, increase the apoptosis ratios of MCF-7/ADR cells, and arrest cell cycle at the G0/G1 phase, with enhanced ability to induce excessive reactive oxygen species (ROS) production in cells. In tumor-bearing model mice, HT-LMSNs-SS@DOX similarly exhibited the highest inhibition activity against tumor growth, with good biosafety, among all of the treatment groups. Therefore, the nano-delivery systems developed herein achieve enhanced efficacy towards resistant tumors through targeted delivery and redox-responsive drug release, with broad application prospects. [ABSTRACT FROM AUTHOR]

ObjectivesTo explore the antitumor effects of redox-responsive nanoparticles containing platinum(Ⅳ)—NP@Pt(Ⅳ) in ovarian cancer.MethodsRedox-responsive polymer carriers were synthesized. Polymer carriers and platinum(Ⅳ)—Pt(Ⅳ) can self-assemble into NP@Pt(Ⅳ). Inductively coupled plasma mass spectrometry was performed to detect the platinum release from NP@Pt(Ⅳ) in reducing environment and the platinum content in ovarian cancer cells ES2 treated with cisplatin, Pt(Ⅳ) and NP@Pt(Ⅳ). The proliferation ability of the ovarian cancer cells were detected by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cellular apoptosis was assessed by flow cytometry. Collection of primary ovarian cancer tissues from patients with primary high-grade serous ovarian cancer who were surgically treated at the Cancer Hospital of the Chinese Academy of Medical Sciences from October to December 2022. The high-grade serous ovarian cancer patient-derived xenograft (PDX) mice were intravenously injected with Cy7.5 labeled NP@Pt(Ⅳ) followed by in vivo imaging system. Mice were treated with PBS, cisplatin and NP@Pt(Ⅳ). Tumor volume and weight were measured in each group. Necrosis, apoptosis and cell proliferation of tumor tissues were detected by hematoxylin-eosin (HE) staining, TUNEL fluorescence staining and Ki-67 immunohistochemistry staining. Body weight and HE staining of heart, liver, spleen, lung and kidney of mice in each group were measured.ResultsThe platinum release of NP@Pt(Ⅳ) after 48 hours in reducing environment was 76.29%, which was significantly higher than that of 26.82% in non-reducing environment ( P<0.001). The platinum content in ES2 cells after 4 hours and 7 hours of treatment with NP@Pt(Ⅳ) (308.59, 553.15 ng/million cells) were significantly higher than those of Pt(Ⅳ) (100.21, 180.31 ng/million cells) and cisplatin (43.36, 50.36 ng/million cells, P＜0.05). The half inhibitory concentrations of NP@Pt(Ⅳ) in ovarian cancer cells ES2, A2780, A2780DDP were 1.39, 1.42 and 4.62 μmol/L, respectively, which were lower than those of Pt(IV) (2.89, 7.27, and 16.74 μmol/L) and cisplatin (5.21, 11.85, and 71.98 μmol/L). The apoptosis rate of ES2 cells treated with NP@Pt(Ⅳ) was (33.91±3.80)%, which was significantly higher than that of Pt(Ⅳ) [(16.28±2.41)%] and cisplatin [(15.01±1.17)%, P＜0.05]. In high-grade serous ovarian cancer PDX model, targeted accumulation of Cy7.5 labeled NP@Pt(Ⅳ) at tumor tissue could be observed. After the treatment, the tumor volume of mice in NP@Pt(IV) group was (130±98) mm ³, which was significantly lower than those in control group [(1 349±161) mm ³, P<0.001] and cisplatin group [(715±293) mm ³, P=0.026]. The tumor weight of mice in NP@Pt(IV) group was (0.17±0.09)g, which was significantly lower than those in control group [(1.55±0.11)g, P<0.001] and cisplatin group [(0.82±0.38)g, P=0.029]. The areas of tumor necrosis and apoptosis in mice treated with NP@Pt(Ⅳ) were higher than those in mice treated with cisplatin. Immunohistochemical staining revealed that there were low expressions of Ki-67 at tumor tissues of mice treated with NP@Pt(Ⅳ) compared with cisplatin. The change in body weight of mice in NP@Pt(Ⅳ) group was not significantly different from that of the control group [(18.56±2.04)g vs.(20.87±0.79)g, P=0.063]. Moreover, the major organs of the heart, liver, spleen, lung, and kidney were also normal by HE staining. ConclusionRedox-responsive NP@Pt(Ⅳ), produced in this study can enhance the accumulation of cisplatin in ovarian cancer cells and improve the efficacy of ovarian cancer chemotherapy. [ABSTRACT FROM AUTHOR]

Nanomaterials able to scavenge biologically relevant oxidants (reactive oxygen species, ROS) can directly act as anti‐inflammatory agents. Here, micelles made of amphiphilic poly(ethylene glycol)(PEG)‐polysulfide block copolymers are focused on; the polysulfide blocks are responsible of ROS‐scavenging and are composed of propylene sulfide and ethylene sulfide units in ratios of 20:0, 15:5, 10:10. These polymers can be intramicellarly cross‐linked through thermal thiol‐yne reaction of terminal alkynes (trithiol cross‐linker). Self‐assembled and cross‐linked micelles are virtually identical in size and scavenging kinetics, but greatly differ in stability against dilution (critical aggregation concentration (CAC) respectively of ≈0.1 and <0.01 mg mL−1) and in the final state after oxidation (soluble polymers vs cross‐linked nanoparticles). Most importantly, self‐assembled micelles have significant toxicity and damage cell membranes already at 0.5 mg mL−1, which seriously hampers their anti‐inflammatory activity. On the contrary, cross‐linked micelles do not appreciably harm cells at least up to 1 mg mL−1, and effectively inhibit the production of inflammatory cytokines in activated macrophages. In this study, a detailed interpretation of the morphological evolution of the two types of micelles during oxidation is provided and it is proved that core cross‐linking significantly widens the therapeutic window. [ABSTRACT FROM AUTHOR]

A novel redox-responsive mPEG-SS-PLA (PSP) polymeric micelle was synthesized and prepared for the delivery of sorafenib (SAF) and curcumin (CUR). And a series of validations were conducted to confirm the structure of the synthesized polymer carriers. Using the Chou-Talalay approach, the combination indexes (CI) of SAF and CUR were determined, and explore the inhibitory effects of the two drugs on HepG2R cells at different ratios. SAF/CUR-PSP polymeric micelles were prepared by thin film hydration method, and the physicochemical properties of nanomicelles were evaluated. The biocompatibility, cell uptake, cell migration, and cytotoxicity assays were assessed in HepG2R cells. The expression of the phosphoinositol-3 kinase (PI3K)/serine/threonine kinase (Akt) signaling pathway was detected by Western blot assay. Additionally, the tumor suppressive effect of SAF/CUR-PSP micelles was clearly superior to free drug monotherapy or their physical combination in HepG2 cell-induced tumor xenografts. The current study revealed that mPEG-SS-PLA polymer micelles loaded with SAF and CUR showed the enhanced therapeutic effects against hepatocellular carcinoma in vitro and in vivo models. It has promising applications for cancer therapy. [ABSTRACT FROM AUTHOR]

One of the challenges in antitumor therapy is the precise delivery of the therapeutic agent to cancerous cells. The delivery of chemotherapy agents can benefit from nanoformulation of prodrugs, which integrates the benefits of nanotechnology and prodrugs, including enhanced drug loading, increased drug bioavailability, and targeted accumulation within cancerous cells. In this work, we designed a redox-responsive polymeric dual-prodrug nanocarrier, PL-ss-(C&J), for codelivery of a potent chemotherapeutic camptothecin (CPT) and an immune checkpoint inhibitor JQ1. Further investigations confirmed that the developed nanomedicine was able to respond to the highly reductive environment within tumor cells. Additionally, due to their quick reactions to the intracellular reducing microenvironment, cytotoxic CPT and JQ1 were simultaneously activated and released, exhibiting significant cytotoxicity. This dual-prodrug activation approach also demonstrated high efficiency in inhibiting tumor growth with satisfactory biocompatibility, pharmacokinetics, and safety in vivo. These results indicated that this type of redox-sensitive dual-prodrug codelivery system based on polymeric prodrug nanomicelles would be a promising technology in chemotherapy and immunotherapy. [ABSTRACT FROM AUTHOR]

Redox-responsive microemulsion was prepared using selenium-containing dipropanol and demonstrated to be favorable for the enhancement of antioxidant activity, stability and solubility of curcumin. [Display omitted] Stimulus-responsive microemulsions have aroused significant attention because of their versatile and reversible switchability between stable and unstable states. However, most stimuli-responsive microemulsions are based on stimuli-responsive surfactants. We posit that the change in the hydrophilicity of a selenium-containing alcohol triggered by a mild redox reaction could also influence the stability of microemulsions and provide a new nanoplatform for the delivery of bioactive substances. A selenium-containing diol (3,3′-selenobis(propan-1-ol), PSeP) was designed and used as a co-surfactant in a microemulsion with ethoxylated hydrogenated castor oil (HCO40), diethylene glycol monohexyl ether (DGME), 2- n -octyl-1-dodecanol (ODD) and water. The redox-induced transition in PSeP was characterized by 1H NMR, 77Se NMR, and MS. The redox-responsiveness of the ODD/HCO40/DGME/PSeP/water microemulsion was investigated through determination of a pseudo-ternary phase diagram, analysis by dynamic light scattering, and electrical conductivity, and its encapsulation performance was evaluated by determination of the solubility, stability, antioxidant activity, and skin penetrability of encapsulated curcumin. The redox conversion of PSeP enabled efficient switching of ODD/HCO40/DGME/PSeP/water microemulsions. Addition of oxidant (H 2 O 2), oxidized PSeP into more hydrophilic PSeP-Ox (selenoxide), disrupting the emulsifying capacity of the combination of HCO40/DGME/PSeP, markedly reducing the monophasic microemulsion region in the phase diagram, and inducing phase separation in some formulations. Addition of reductant (N 2 H 4 ·H 2 O), reduced PSeP-Ox and restored the emulsifying capacity of the combination of HCO40/DGME/PSeP. In addition, PSeP-based microemulsions can significantly enhance the solubility in oil (by 23 times), stability, antioxidant capacity (DPPH∙ radical scavenging by 91.74 %), and skin penetrability of curcumin, showing clear potential for encapsulation and delivery of curcumin and other bioactive substances. [ABSTRACT FROM AUTHOR]

The targeted delivery of anti-tumor drugs to diseased sites is significant in cancer therapy. Herein, a novel redox-responsive 5-fluorouracil (5-FU) prodrug delivery system based on mesoporous silica nanoparticles was proposed, in which polyethyleneimine (PEI, a bulky gatekeeper) and (3-aminopropyl) triethoxysilane-functionalized MCM41 were conjugated to an identical 3,3-diselanediyldipropionic acid linker via a condensation reaction between the amino group and carboxyl functional group. The chemotherapeutic reagent 5-FU was filled into the pores of Se-MCM41 nanocarriers as a model drug. The nanoparticles of PEI-Se-MCM41@5-FU exhibited a uniform and spherical morphology of approximately 175 nm. Under high concentrations of reactive oxygen species or glutathione (GSH) environments, such as the tumor microenvironment, 5-FU was rapidly released from the PEI-Se-MCM41 nanocarrier owing to its high sensitivity to both oxidizing and reducing agents. The release performance clearly verified the feasibility of PEI-Se-MCM41@5-FU nanoparticles for H2O2/GSH-triggered 5-FU release, particularly under GSH conditions. Additionally, the cytotoxic effects of PEI-Se-MCM41 nanoparticles findings indicating that there was no significant cytotoxicity against CT-26 colon cancer cells after 24 h incubation. However, PEI-Se-MCM41@5-FU nanoparticles exhibited a pronounced inhibitory effect on CT-26 cells at a concentration of 150 μg mL−1. Furthermore, the intracellular drug delivery performance of nanocarriers were evaluated using confocal laser scanning microscopy (CLSM), which disclosed that the PEI-Se-MCM41@RhB was successfully endocytosed into the CT-26 cells and released the loaded 5-FU. The conclusion was further proved by FACS analysis, which indicated that PEI-Se-MCM41@RhB was more easily uptaken into the CT-26 cells than free RhB. The findings of in vivo and in vitro studies suggest that PEI-Se-MCM41@5-FU holds great potential for effective tumor therapy. [ABSTRACT FROM AUTHOR]

Paclitaxel (PTX), a chemo-drug widely used in cancer chemotherapy for a variety of tumors, has been still faced with several problems in therapeutic applications due to its poor water solubility, low content in natural sources, expensive multistep processes of synthesis and side effects. In this study, a nanogel system based on the conjugation of Heparin and Pluronic F127 via disulphide bridges was developed for PTX delivery in a redox responsive way to over these mentioned drawbacks. The obtained Hep-F127 system were proved and characterized through H-NMR, zeta potential, DLS, TEM and FT-IR methods. TEM result showed that the nanogel Hep-F127 was spherical, non-agglomerated and relatively uniform with an average particle diameter of 80 nm. PTX was effectively encapsulated into the nanogel thanks to poly(propylene oxide) (PPO) units of F127 molecules with DLE and DLC values of about 92% and 18%, respectively. Meanwhile, the nanogel was stable in physiological condition but broken under reducing condition, leading to a well-controlled release in physiological condition and a fast release in simulating tumor-microenvironmental condition. This contributed to reducing side effects and increasing the effectiveness of treatment of PTX. In addition, cytotoxicity of Hep-F127 and PTX@Hep-F127 was in vitro tested on the L929 cell line. This study suggested that the nanogel Hep-F127 would to be a promising carrier for enhancing the solubility of PTX and release PTX in a redox-responsive way in cancer treatment. [ABSTRACT FROM AUTHOR]

Multifactor‐responsive nanomaterials have been playing a vital role in drug delivery developments. Given the advantages of nanotechnology‐based systems, employing stimuli‐sensitive agents could offer a step forward to targeted drug delivery. Hence, we targeted to apply both thermal and redox‐sensitive agents, which are poly(N‐isopropylacrylamide) (PNIPAM) and disulfide, onto a classic platform polyamidoamine (PAMAM) dendrimer. In particular, PAMAM G3.5 was first grafted by an outermost layer composed of cystamine moieties and partially grafted with PNIPAM segments. This novel nanomaterial was successfully verified by FTIR, 1H NMR, and Raman spectroscopy. Besides, morphological and surface characteristics were observed by DLS, TEM, and zeta potential. Our novel drug delivery system displayed a spherical shape with a hydrodynamic size of 43.61 ± 6.04 nm at 37°C and 68.99 ± 4.69 nm at 15°C, which proved its thermoresponsiveness. In parallel, the response of the nanoparticles toward redox concentration variation was testified that demonstrated a controlled drug release highly depending on physiological stimuli. We have also conducted in vitro DOX release and cytocompatibility of this drug delivery system, which can premise a smart strategy for nanoengineering in targeted drug delivery for cancer therapy. [ABSTRACT FROM AUTHOR]

The poor bioavailability of curcumin and its derivatives limits their antitumor efficacy and clinical translation. Although curcumin derivative C210 has more potent antitumor activity than curcumin, it has a similar deficiency to curcumin. In order to improve its bioavailability and accordingly enhance its antitumor activity in vivo, we developed a redox-responsive lipidic prodrug nano-delivery system of C210. Briefly, we synthesized three conjugates of C210 and oleyl alcohol (OA) via different linkages containing single sulfur/disulfide/carbon bonds and prepared their nanoparticles using a nanoprecipitation method. The prodrugs required only a very small amount of DSPE-PEG2000 as a stabilizer to self-assemble in aqueous solution to form nanoparticles (NPs) with a high drug loading capacity (~50%). Among them, the prodrug (single sulfur bond) nanoparticles (C210-S-OA NPs) were the most sensitive to the intracellular redox level of cancer cells; therefore, they could rapidly release C210 in cancer cells and thus had the strongest cytotoxicity to cancer cells. Furthermore, C210-S-OA NPs exerted a dramatic improvement in its pharmacokinetic behavior; that is, the area under the curve (AUC), mean retention time and accumulation in tumor tissue were 10, 7 and 3 folds that of free C210, respectively. Thus, C210-S-OA NPs exhibited the strongest antitumor activity in vivo than C210 or other prodrug NPs in mouse models of breast cancer and liver cancer. The results demonstrated that the novel prodrug self-assembled redox-responsive nano-delivery platform was able to improve the bioavailability and antitumor activity of curcumin derivative C210, which provides a basis for further clinical applications of curcumin and its derivatives. [ABSTRACT FROM AUTHOR]

A cancer‐selective self‐reporting sensor based on a redox‐responsive mineralized conductive hydrogel (M‐Hydrogel) is proposed with cancer‐specific viscosity, adhesive strength, stretchability, tunable conductivity, and fluorescence. The redox‐triggered release of carbonized polydopamine (cPDA) from the loaded disulfide‐crosslinked polymer dots (PD@cPDA) in the hydrogel matrix modulates the macroporous structure responsible for self‐recognizable cancer sensing and photothermal activity for cancer therapy. The self‐reporting nature of the M‐Hydrogel sensor is highlighted when in vicinity of a high glutathione (GSH) level owing to the controllable pore size and H‐bonding by cPDA, as confirmed by experiments on cancer cells (HeLa, PC3, B16‐F10‐GFP, and SNU‐C2A) and normal cells (CHO‐K1). The lower viscosity during syringe test along with the exceptional adhesiveness and stretchability with various cancer cells, combined with a high wireless pressure‐sensing response absent in normal conditions, confirms the dependence of self‐recognizable behavior on the cancer microenvironment. The M‐Hydrogel demonstrates excellent ex situ sensing with tumor ablation, after implantation in mice xenografted with HeLa cells, with the wireless sensing system, enabling real‐time analysis coupled with the upregulation of pro‐apoptotic markers P53 and BAX in the tumor. Therefore, this self‐reporting sensor may facilitate a strategy for innovative and convenient cancer diagnostics. [ABSTRACT FROM AUTHOR]

In this study, diselenide (Se–Se) and disulfide (S–S) redox-responsive core-cross-linked (CCL) micelles were synthesized using poly(ethylene oxide)2k-b-poly(furfuryl methacrylate)1.5k (PEO2k-b-PFMA1.5k), and their redox sensitivity was compared. A single electron transfer-living radical polymerization technique was used to prepare PEO2k-b-PFMA1.5k from FMA monomers and PEO2k-Br initiators. An anti-cancer drug, doxorubicin (DOX), was incorporated into PFMA hydrophobic parts of the polymeric micelles, which were then cross-linked with maleimide cross-linkers, 1,6-bis(maleimide) hexane, dithiobis(maleimido) ethane and diselenobis(maleimido) ethane via Diels–Alder reaction. Under physiological conditions, the structural stability of both S–S and Se–Se CCL micelles was maintained; however, treatments with 10 mM GSH induced redox-responsive de-cross-linking of S–S and Se–Se bonds. In contrast, the S–S bond was intact in the presence of 100 mM H2O2, while the Se–Se bond underwent de-crosslinking upon the treatment. DLS studies revealed that the size and PDI of (PEO2k-b-PFMA1.5k-Se)2 micelles varied more significantly in response to changes in the redox environment than (PEO2k-b-PFMA1.5k-S)2 micelles. In vitro release studies showed that the developed micelles had a lower drug release rate at pH 7.4, whereas a higher release was observed at pH 5.0 (tumor environment). The micelles were non-toxic against HEK-293 normal cells, which revealed that they could be safe for use. Nevertheless, DOX-loaded S–S/Se–Se CCL micelles exhibited potent cytotoxicity against BT-20 cancer cells. Based on these results, the (PEO2k-b-PFMA1.5k-Se)2 micelles can be more sensitive drug carriers than (PEO2k-b-PFMA1.5k-S)2 micelles. [ABSTRACT FROM AUTHOR]

Hydrogels are crosslinked, three-dimensional hydrophilic polymeric networks which possess similarity in structure to human soft tissue, and thus have found a great number of applications as biomaterials. Hydrogels can also act as depot for therapeutic cargo, where small molecule drugs to biomolecules can be encapsulated within their porous structure. The aim of this work is to fabricate redox-responsive hydrogels that can dissolve and release biomacromolecules upon exposure to a reducing environment. In particular, hyaluronic acid (HA), was modified with electron-rich furan groups to yield hydrogels through the Diels-Alder (DA) reaction with a maleimide group containing redox-responsive polyethylene glycol (PEG) based crosslinker. Redox-responsive hydrogels were obtained with high conversions (87–95%) at 37 °C, in a catalyst-free fashion. The stimuli-responsive degradation of hydrogels could be tuned by varying the amount of crosslinker. To examine the passive and on-demand delivery of biomacromolecules, a model protein, fluorescein isothiocyanate conjugated bovine serum albumin (FITC-BSA), was encapsulated within the hydrogels. While a sustained passive release was observed in PBS, a rapid on-demand release was obtained upon exposure to the reducing agent 1,4-dithiothreitol (DTT). Furthermore, the complete dissolution of the hydrogel was accomplished upon exposure to a solution containing the reducing agent. [ABSTRACT FROM AUTHOR]

A new PEGylated redox/pH dual‐responsive dendritic prodrug (H40‐SS‐PTX/PEG) based on commercially available dendritic polyester, boltorn® H40 (H40), as starting core template was developed and characterized for tumor triggered paclitaxel delivery. The size of the nanocarrier was determined 100 nm by TEM. The results of in vitro drug release study showed that the designed prodrugs exhibit quite intelligent behavior. Thus, under normal physiological conditions (pH=7.4), a very small amount of the drug was released, while in the case of tumor tissue (pH=5.5 and 10 mM DTT) a significant percentage of the drug was released in a same time. Also, the study of the effectiveness of the prodrugs under in vitro condition showed very good results on human breast adenocarcinoma cells. These results suggest that H40‐SS‐PTX/PEG could be a promising multifunctional nanocarrier with excellent stability for safely delivering and releasing of the drug molecules inside the cancerous cells. [ABSTRACT FROM AUTHOR]

Nano drug delivery systems have made significant progress in delivering anticancer drugs camptothecin (CPT). However, many challenges for CPT delivery remain, including low drug loading efficiency, premature drug leakage, and poor cellular internalization. Herein, we report a novel dual-sensitive polypeptide-based micelle with remarkably high drug loading of CPT for cancer therapy. This self-assembled micelle possesses the following essential components for CPT: (1) pH-sensitive PEG (OHC-PEG-CHO) for prolonging blood circulation and allowing biocompatibility by shielding the cationic micelles, which can be detached under the tumor acidic microenvironment and facilitates the cellular uptake; (2) polypeptide polylysine-polyphenylalanine (PKF) synthesized via ring-opening polymerization for micelle formation and CPT analogue loading; (3) dimeric CPT (DCPT) with redox-sensitive linker for increasing CPT loading and ensuring drug release at tumor sites. Interestingly, the linear-like morphology of PEG-PKF/DCPT micelles was able to enhance their cellular internalization when compared with the spherical blank PKF micelles. Also, the anticancer efficacy of DCPT against lung cancer cells was significantly improved by the micelle formation. In conclusion, this work provides a promising strategy facilitating the safety and effective application of CPT in cancer therapy. [ABSTRACT FROM AUTHOR]

The development of stimuli-responsive controlled release formulations is a potential method of improving pesticide utilization efficiency and alleviating current pesticide-related environmental pollution. In this study, a self-destruction redox-responsive pesticide delivery system using biodegradable disulfide-bond-bridged mesoporous organosilica (DMON) nanoparticles as the porous carriers and coordination complexes of gallic acid (GA) and Fe(III) ions as the capping agents were established for controlling prochloraz (PRO) release. The GA–Fe(III) complexes deposited onto the surface of DMON nanoparticles could effectively improve the light stability of prochloraz. Due to the decomposition of GA–Fe(III) complexes, the nano-vehicles had excellent redox-responsive performance under the reducing environments generated by the fungus. The spreadability of PRO@DMON–GA–Fe(III) nanoparticles on the rice leaves was increased due to the hydrogen bonds between GA and rice leaves. Compared with prochloraz emulsifiable concentrate, PRO@DMON–GA–Fe(III) nanoparticles showed better fungicidal activity against Magnaporthe oryzae with a longer duration under the same concentration of prochloraz. More importantly, DMON–GA–Fe(III) nanocarriers did not observe obvious toxicity to the growth of rice seedlings. Considering non-toxic organic solvents and excellent antifungal activity, redox-responsive pesticide controlled release systems with self-destruction properties have great application prospects in the field of plant disease management. [ABSTRACT FROM AUTHOR]

Purpose: Many non-viral vectors with positive charge and physical encapsulation of siRNA have been reported. However, the studies of non-viral vectors with chemical conjugation of siRNA and neutral charge were rarely reported. Methods: A redox-responsive and neutral nanoparticle (NP) was designed using poly(d,l-lactide-co-glycolide) (PLGA)-conjugated siRNA, PLGA, and Chitosan oligosaccharide. The physicochemical properties, stability, permeation ability, redox responsiveness, and in vitro free siRNA release of the NPs were evaluated. In vitro cellular uptake and gene silencing activity of the NPs were also investigated in four cervical cancer cell lines (SiHa, CaSki, HeLa, and c33a). Results: Redox-responsive and electrically neutral PLGA NPs encapsulating siRNA targeting the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) gene were formulated. The NPs were modified with chitosan oligosaccharide in order to achieve a neutral surface charge, at a nitrogen/phosphate (N/P) ratio of 20:1, and they had the desired size of ~ 90 nm. They were characterized by a high encapsulation efficiency (approximately 70%), in vitro stability in physiologic conditions, long-term shelf-life stability (> 18 months), and rapid permeation ability through mucus. NP disassembly in reducing environments was rapid. A sustained release phenomenon was observed, which contributed to higher concentrations and prolonged activity of the NPs. The GAPDH silencing efficiency of the NPs was both N/P ratio- and cell type-dependent, and it was as efficient as lipofectamine 2000 in SiHa, CaSki, HeLa, and c33a cells at an N/P ratio of 20:1. Conclusion: Our findings indicate that redox-responsive and electrically neutral NPs are promising nanocarriers for siRNA delivery to potentially treat human cervical carcinoma. [ABSTRACT FROM AUTHOR]

[Display omitted] A sodium alginate (Alg) based REDOX (reduction and oxidation)-responsive and fluorescent active microgel was prepared via water in oil (w/o) mini-emulsion polymerization technique. Here, we initially synthesized sodium alginate-based disulfide cross linked microgels and after that those microgels were tagged with rhodamine amine derivative (RhB-NH 2) by ionic interaction to get the pH-responsive fluorescent property. Functionalized microgels were characterized using 1H NMR, FTIR, DLS, HRTEM, FESEM, UV–vis, and fluorescence spectroscopy analyses. Presence of the REDOX-responsive disulfide-containing crosslinkers in the microgels enhances the release of doxorubicin (DOX), an anti-cancer drug in the reducing environment of the cancer-cells (simulated). Existence of the rhodamine-amine derivative in the microgels triggers the pH-dependent fluorescence property by showing fluorescence emission at 560–580 nm at pH 5.5 (cancer cell pH). The cytotoxicity of the biopolymer based microgel was assessed over both cancerous HeLa (IC 50 100 µg/mL) and non-cancerous MDCK (IC 50 200 µg/mL) cells by MTT assay which showed the synthesized microgel is non-toxic whereas DOX-loaded microgels showed significant toxicity. FACS and cell uptake (in vitro) analyses were conducted to understand the cell apoptosis cycle and behavior of the cancer cells in presence of the DOX-loaded microgels. This pH-responsive fluorescent active alginate-based biomaterial could be a promising material for the anti-cancer drug delivery and other medical fields. [ABSTRACT FROM AUTHOR]

[Display omitted] • GSH-triggered degradation of DNA@MnO 2 fluorescence nanoprobe was researched. • A nanoprobe based on DNAzyme amplification and MnO 2 nanosheets was proposed. • Sensitive and label-free detection of GSH in serum samples was realized. In this work, a novel fluorescence nanoprobe based on MnO 2 nanosheets and DNAzyme cyclic amplification was developed for label-free detection of GSH. In our design, the DNA@MnO 2 nanoprobe was facilely prepared through the adsorption of DNA probes on the surface of MnO 2 nanosheets. Importantly, MnO 2 nanosheets in the DNA@MnO 2 nanoprobe can act as the recognizer of analytical target GSH. In the presence of GSH, the DNA@MnO 2 nanoprobe are decomposed owing to redox-responsive reaction between GSH and MnO 2 nanosheets, resulting in the generation of abundant Mn2+ and the desorption of DNA probes. Subsequently, the Mn2+-dependent DNAzyme recycling amplification was rapidly initiated and a large number of the blocked G-rich sequences in DNA probes was released. The G-rich sequences were efficiently folded into G-quadruplex structures, which can remarkably light up the fluorescence intensity of thioflavin T (ThT). Experimental data demonstrated that the DNA@MnO 2 nanoprobes for GSH detection have a wide linear range from 0 to 2000 µM. Moreover, this fluorescence sensing strategy was successfully applied for the detection of GSH in complex biological media with satisfying results, providing a simple, facile and cost-efficient nanoplatform for GSH-related clinical disease diagnosis. [ABSTRACT FROM AUTHOR]

Abstract Redox-responsive drug delivery system emerges as a hopeful platform for tumor treatment. Dihydroartemisinin (DHA) has been investigated as an innovative tumor therapeutic agent. Herein, a DHA dimeric prodrug bridged with disulfide bond as linker (DHA2-SS) has been designed and synthesized. The prepared prodrugs could self-assemble into nanoparticles (SS NPs) with high DHA content (> 90%) and robust stability. These SS NPs display sensitive redox responsive capability and can release DHA under the tumor heterogeneity microenvironment. SS NPs possess preferable antitumor therapeutic activity in contrast with free DHA. Moreover, the possible anti-cancer mechanism of SS NPs was investigated through RNA-seq analysis, bioinformatics and molecular biological method. SS NPs could induce apoptosis via mitochondrial apoptosis pathway, as well as glycolysis inhibition associate with the regulation of PI3K/AKT/HIF-1α signal path, which may offer an underlying therapeutic target for liver cancer. Our study highlights the potential of using redox responsive prodrug nanoparticles to treat cancer, meanwhile provides insights into the anti-cancer mechanism of DHA prodrug. Graphical Abstract

The starvation therapy mediated by the lonidamine (LND) was limited by the low drug delivery efficiency, off-target effect and compensative glutamine metabolism. Herein, a hyaluronic acid (HA)-modified reduction-responsive micellar nanosystem co-loaded with glycolysis and glutamine metabolism inhibitor (LND and bis-2-(5-phenylacetmido-1,2,4-thiadiazol-2-yl)ethyl sulfide, BPTES) was constructed for tumor-targeted dual-starvation therapy. The in vitro and in vivo results collectively suggested that the fabricated nanosystem could effectively endocytosed by tumor cells via HA receptor-ligand recognition, and rapidly release starvation-inducers LND and BPTES in response to the GSH-rich intratumoral cytoplasm. Furthermore, the released LND and BPTES were capable of inducing glycolysis and glutamine metabolism suppression, and accompanied by significant mitochondrial damage, cell cycle arrest and tumor cells apoptosis, eventually devoting to the blockade of the energy and substance supply and tumor killing with high efficiency. In summary, HPPPH@L@B nanosystem significantly inhibited the compensatory glycolysis and glutamine metabolism via the dual-starvation therapy strategy, blocked the indispensable energy and substance supply of tumors, consequently leading to the desired tumor starvation and effective tumor killing with reliable biosafety.

novel kind of redox-responsive amphiphilic polyurethane triblock copolymer, PEG-PU(SS)-PEG, was designed and synthesized, in which PEG was the hydrophilic polyethylene glycol at both ends of the copolymer chain, and the middle hydrophobic polyurethane block PU(SS) was prepared from bis(2-hydroxyethyl) disulfide and hexamethylene diisocyanate (HDI) via step-growth polymerization. PEG-PU(SS)-PEG could self-assemble into stable micelles with the average diameter of about 100 nm through nano-precipitation method in aqueous solution, in which the hydrophilic corona and the hydrophobic cores were composed of PEG and PU(SS) blocks, respectively. Hydrophobic anti-cancer drugs, such as curcumin, could be loaded into the hydrophobic micellar cores to construct redox-responsive drug nanocarriers with the drug loading content and the drug loading efficiency as high as 22.2% and 71.3%, respectively. Due to the existence of the disulfide linkages in the hydrophobic PU(SS) blocks, in the presence of glutathione (GSH), the copolymer chains could be triggered to depolymerize, resulting in the disintegration of the nano-micelles and release of loaded curcumin. After being co-incubated with GSH for 6 h, the cumulative release amount of curcumin could reach about 90%. Therefore, PEG-PU(SS)-PEG was a potential candidate for the fabrication of drug nanocarriers. [ABSTRACT FROM AUTHOR]

Based on the modified cross-linking of the degradable natural polymers chitosan oligosaccharides (COS) and gelatin (GEL) via introduction of a functional bridge 3,3'-dithiodipropionic acid, this study constructed an environmentally responsive dinotefuran (DNF) delivery system (DNF@COS-SS-GEL). The introduction of the disulfide bond (-S-S-) endowed DNF@COS-SS-GEL with redox-responsive properties, allowing for the rapid release of pesticides when stimulated by glutathione (GSH) in the simulated insect. Compared with commercial DNF suspension concentrate (DNF-SC), DNF@COS-SS-GEL showed superior wet spreading and retention performance on cabbage leaves with a reduced contact angle (57°) at 180 s and 4-fold increased retention capacity after rainfall washout. Nanoencapsulation effectively improved the UV-photostability with only a 31.4% decomposition rate of DNF@COS-SS-GEL at 96 h. The small scale and large specific surface area resulted in excellent uptake and transportation properties in plants as well as higher bioactivity against Plutella xylostella larvae. This study will help promote sustainable agricultural development by reducing environmental pollution through improved pesticide utilization.

Stimuli-responsive polymersomes have emerged as smart drug delivery systems for programmed release of highly cytotoxic anticancer agents such as doxorubicin hydrochloride (Dox·HCl). Recently, a biodegradable redox-responsive triblock copolymer (mPEG–PDH–mPEG) was synthesized with a central hydrophobic block containing disulfide linkages and two hydrophilic segments of poly(ethylene glycol) methyl ether. Taking advantage of the self-assembly of this amphiphilic copolymer in aqueous solution, in the present investigation we introduce a solvent-exchange method that simultaneously achieves polymersome formation and drug loading in phosphate buffer saline (10 mM, pH 7.4). Blank and drug-loaded polymersomes (5 and 10 wt.% feeding ratios) were prepared and characterized for morphology, particle size, surface charge, encapsulation efficiency and drug release behavior. Spherical vesicles of uniform size (120–190 nm) and negative zeta potentials were obtained. Dox·HCl was encapsulated into polymersomes with a remarkably high efficiency (up to 98 wt.%). In vitro drug release studies demonstrated a prolonged and diffusion-driven release at physiological conditions (~34% after 48 h). Cleavage of the disulfide bonds in the presence of 50 mM glutathione (GSH) enhanced drug release (~77%) due to the contribution of the erosion mechanism. Therefore, the designed polymersomes are promising candidates for selective drug release in the reductive environment of cancer cells. [ABSTRACT FROM AUTHOR]

Herein, we reported a novel tri-block copolymer synthesized by segmented ring-opening polymerization of temperature-sensitive 5-(pyrrolidine-1-carbonyl) oxepan-2-one monomer (VPyCL) and redox-sensitive macrocyclic disulfide-substituted carbonate monomer (MSS). The structure of the copolymers was confirmed by GPC, 1H NMR and 13C NMR. The obtained tri-block copolymers could self-assemble in aqueous solution to form well-structured micelles, with the mPEG-b-PVPyCL block acting as the hydrophilic coronal and the PSS block acting as the hydrophobic core. Dynamic light scattering (DLS) studies confirmed that micelles formed by these tri-block copolymers with different block ratios could respond to different temperature ranges during the heating/cooling process and respond to reducing agent glutathione (GSH). In addition, transmission electron microscopy (TEM) results further confirmed the polymeric micelles' dual-stimuli responsiveness. The potential application of this type of dual-stimuli responsive micelles in drug delivery systems was evaluated using doxorubicin (DOX) as the model molecule. The stimulus-dependent responsive behaviors of obtained micelles can be applied to the construction of smart materials capable of performing multiple functions under the appropriate conditions. [ABSTRACT FROM AUTHOR]

Abstract. The combination of functionalized nanoparticles and chemotherapy drugs can effectively target tumor tissue, which can improve efficacy and reduce toxicity. In this article, pPeptide-PDA@HMONs-DOX nanoparticles (phosphopeptide-modified polydopamine encapsulates doxorubicin-loaded hollow mesoporous organosilica nanoparticles) were constructed that based on multiple modification hollow mesoporous organosilica nanoparticles (HMONs). The pPeptide-PDA@HMONs-DOX nanoparticles retain the biological functions of phosphorylated peptide while exhibiting biological safety that are suitable for effective drug delivery and stimulus responsive release. The degradation behaviors showed that pPeptide-PDA@HMONs-DOX has dual-responsive to drug release characteristics of pH and glutathione (GSH). In addition, the prepared pPeptide-PDA@HMONs-DOX nanoparticles have good biological safety, and their anti-tumor efficacy was significantly better than doxorubicin (DOX). This provided new research ideas for the construction of targeted nanodrug delivery systems based on mesoporous silicon. [ABSTRACT FROM AUTHOR]

Despite the diversified therapeutic approaches for malignant tumors, chemotherapy remains the backbone of current cancer treatment. However, conventional chemotherapeutics was found to be associated with deficient recognition of tumor, low uptake efficiency, insolubility, short circulation, poor biocompatibility and low therapeutic outcomes. Herein, the active targeting redox-responsive mannosylated prodrug nanocolloids (HM NCs) were constructed for enhanced chemotherapy of colon cancer. HM NCs were prepared by the covalent cross-linking of 10-hydroxycamptothecin (HCPT) and mannose (MAN) via a redox-responsive cross-linker containing disulfide bonds, and modified with a moderate amount of polyethylene glycol (PEG). The large amount of mannose contained in HM NCs could actively target overexpressed mannose receptors on the surface of cancer cells and enhance cancer cell internalization through mannose receptor-mediated endocytosis. Owing to the combination of active targeting and the enhanced permeability and retention (EPR) passive targeting, HM NCs could effectively accumulate in tumors and high glutathione (GSH) in tumor microenvironment triggered cleavage of redox-responsive bonds and precise drug release. HM NCs exhibited superior antitumor activity both in vitro and in vivo and appreciably extended the mouse survival rate with good biocompatibility. The innovative HM NCs are expected to be conducive to overcoming the limitations of conventional chemotherapy for colon cancer and providing more choices for future clinical translation. Despite the enhanced permeability and retention effect, the passive targeting can be interfered with by the complex biologic barriers in the body. In this study, an active targeting system (HM NCs) was constructed by covalent cross-linking of mannose and anticancer drug 10-hydroxycamptothecin via redox-responsive disulfide bonds for enhanced colon cancer chemotherapy. Mannosylation could promote hydrophilia and stability for prolonged blood circulation. Mannose could promote tumor recognition and cell internalization via mannose receptor-mediated endocytosis. High glutathione level could trigger the redox-responsive release of anticancer drugs and further induce cell apoptosis via DNA damage. The HM NCs exhibited superior antitumor activity both in vitro and in vivo and appreciably extended the mouse survival rate with good biocompatibility. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract Background Mitochondria play a role in the occurrence, development, drug resistance, metastasis, and other functions of cancer and thus are a drug target. An acid-activated mitochondria-targeting drug nanocarrier with redox-responsive function was constructed in the present study. However, whether this vector can precisely delivery paclitaxel (PTX) to enhance therapeutic efficacy in drug-resistant lung cancer is unknown. Results Acid-cleavable dimethylmaleic anhydride (DA) was used to modify pluronic P85-conjugated mitochondria-targeting triphenylphosphonium (TPP) using disulfide bonds as intermediate linkers (DA-P85-SS-TPP and DA-P-SS-T). The constructed nanocarriers demonstrated enhanced cellular uptake and selective mitochondrial targeting at extracellular pH characteristic for a tumor (6.5) and were characterized by extended circulation in the blood. TPP promoted the targeting of the DA-P-SS-T/PTX nanomicelles to the mitochondrial outer membrane to decrease the membrane potential and ATP level, resulting in inhibition of P-glycoprotein and suppression of drug resistance and cancer metastasis. PTX was also rapidly released in the presence of high glutathione (GSH) levels and directly diffused into the mitochondria, resulting in apoptosis of drug-resistant lung cancer cells. Conclusions These promising results indicated that acid-activated mitochondria-targeting and redox-responsive nanomicelles potentially represent a significant advancement in cancer treatment. Graphic Abstarct

The poor bioavailability of curcumin and its derivatives limits their antitumor efficacy and clinical translation. Although curcumin derivative C210 has more potent antitumor activity than curcumin, it has a similar deficiency to curcumin. In order to improve its bioavailability and accordingly enhance its antitumor activity in vivo, we developed a redox-responsive lipidic prodrug nano-delivery system of C210. Briefly, we synthesized three conjugates of C210 and oleyl alcohol (OA) via different linkages containing single sulfur/disulfide/carbon bonds and prepared their nanoparticles using a nanoprecipitation method. The prodrugs required only a very small amount of DSPE-PEG2000 as a stabilizer to self-assemble in aqueous solution to form nanoparticles (NPs) with a high drug loading capacity (~50%). Among them, the prodrug (single sulfur bond) nanoparticles (C210-S-OA NPs) were the most sensitive to the intracellular redox level of cancer cells; therefore, they could rapidly release C210 in cancer cells and thus had the strongest cytotoxicity to cancer cells. Furthermore, C210-S-OA NPs exerted a dramatic improvement in its pharmacokinetic behavior; that is, the area under the curve (AUC), mean retention time and accumulation in tumor tissue were 10, 7 and 3 folds that of free C210, respectively. Thus, C210-S-OA NPs exhibited the strongest antitumor activity in vivo than C210 or other prodrug NPs in mouse models of breast cancer and liver cancer. The results demonstrated that the novel prodrug self-assembled redox-responsive nano-delivery platform was able to improve the bioavailability and antitumor activity of curcumin derivative C210, which provides a basis for further clinical applications of curcumin and its derivatives.

• A polymer with diselenide bonds was applied as a shell on IL-4@ZIF-8@SHP. • IL-4 delivery system was obtained with stepwise pH and redox responsive release. • This targeted release alleviated IL-4 side effects in normal tissues. • IL-4@ZIF-8@SHP modulated the temporal polarization of macrophages from M1 to M2. Multi-responsive drug-delivery systems have been widely explored to enable specific delivery to target sites. Here, interleukin-4 (IL-4), an anti-inflammatory cytokine, is first encapsulated in situ inside a zeolitic imidazolate framework (ZIF-8) to form IL-4@ZIF-8, which is subsequently coated with a diselenide block copolymer to obtain IL-4@ZIF-8@Se-Se-polymer. This delivery system enables redox-responsive release of IL-4 by the diselenide copolymer and a pH-triggered release by ZIF-8. Moreover, IL-4 release is precisely controlled stepwise by the stimuli response, with the dissociation of the diselenide copolymer, and breakdown of the ZIF-8 structure. The targeted release property of the IL-4@ZIF-8@Se-Se-polymer endows the materials with efficient macrophage immune regulation, as systematically demonstrated in vitro. This study provides an effective example of the delivery and on-demand release of IL-4, and may find promising applications in tissue engineering for the management of inflammation. [ABSTRACT FROM AUTHOR]

[Display omitted] • Nanogel carriers can protect proteins from degradation and provide controlled release. • This work developed redox-responsive nanogels for targeted intracellular protein delivery. • Redox-responsive nanogels were successfully developed for targeted intracellular protein delivery. • Precision protein release inside cells was achieved via incorporation of disulfide crosslinkers. • These nanocarriers have promising applications for enhanced efficacy of protein therapeutics. Redox-responsive drug carriers present a therapeutically viable delivery platform owing to their ability to leverage the intracellular redox environment. In this work, we describe a facile, one-pot aqueous-based synthetic methodology for encapsulating sensitive biological payloads within redox-responsive crosslinked nanogels. We systematically evaluate the impact of various disulphide-based crosslinkers on the morphology, stability, encapsulation and loading capacities of these nanogels. In vitro assessments were conducted to elucidate the ease of delivery of functional protein payloads, using fluorescently-labelled bovine serum albumin and the enzyme, paraoxonase-1. The nanogels demonstrate promising delivery efficiencies with minimal cytotoxicity in vitro. The simplicity of their synthesis, along with the precise control achieved in nanogel degradation and payload release kinetics, not only enriches our understanding of redox-responsive nanosystems but also underscores their potential to catalyze transformative advancements in intracellular protein delivery. [ABSTRACT FROM AUTHOR]

In this study, diselenide (Se–Se) and disulfide (S–S) redox-responsive core-cross-linked (CCL) micelles were synthesized using poly(ethylene oxide)2k-b-poly(furfuryl methacrylate)1.5k (PEO2k-b-PFMA1.5k), and their redox sensitivity was compared. A single electron transfer-living radical polymerization technique was used to prepare PEO2k-b-PFMA1.5k from FMA monomers and PEO2k-Br initiators. An anti-cancer drug, doxorubicin (DOX), was incorporated into PFMA hydrophobic parts of the polymeric micelles, which were then cross-linked with maleimide cross-linkers, 1,6-bis(maleimide) hexane, dithiobis(maleimido) ethane and diselenobis(maleimido) ethane via Diels–Alder reaction. Under physiological conditions, the structural stability of both S–S and Se–Se CCL micelles was maintained; however, treatments with 10 mM GSH induced redox-responsive de-cross-linking of S–S and Se–Se bonds. In contrast, the S–S bond was intact in the presence of 100 mM H2O2, while the Se–Se bond underwent de-crosslinking upon the treatment. DLS studies revealed that the size and PDI of (PEO2k-b-PFMA1.5k-Se)2 micelles varied more significantly in response to changes in the redox environment than (PEO2k-b-PFMA1.5k-S)2 micelles. In vitro release studies showed that the developed micelles had a lower drug release rate at pH 7.4, whereas a higher release was observed at pH 5.0 (tumor environment). The micelles were non-toxic against HEK-293 normal cells, which revealed that they could be safe for use. Nevertheless, DOX-loaded S–S/Se–Se CCL micelles exhibited potent cytotoxicity against BT-20 cancer cells. Based on these results, the (PEO2k-b-PFMA1.5k-Se)2 micelles can be more sensitive drug carriers than (PEO2k-b-PFMA1.5k-S)2 micelles.

Many anticancer drugs have limited clinical applications owing to their unsatisfactory therapeutic efficacy or side effects. This situation can be improved by drug delivery systems or drug modification strategies. Herein, to improve the therapeutic efficacy and safety of the traditional anticancer drug 6-mercaptopurine (6-MP), we dimerized 6-MP to form a disulfide bond-containing drug dimer and prepared a cysteine-based poly (disulfide amide) with redox-responsive capability as a drug carrier. Briefly, dimeric 6-MP (DMP) was synthesized via the oxidization of iodine and self-assembled with the poly (disulfide amide) to form dual redox-responsive DMP-loaded NPs (DMP-NPs). The 6-MP itself could hardly be loaded into nanoparticles (NPs) owing to its hydrophobicity, while the DMP-NPs showed a higher drug loading capacity over 6-MP, small particle size, and favorable stability. With abundant disulfide bonds in polymer backbones and drug payloads, DMP-NPs could rapidly respond to high levels of glutathione (GSH) and release drugs in a controllable manner. More importantly, both cellular and animal experiments demonstrated the enhanced anticancer efficacy of DMP-NPs against lymphoma and their high safety. Overall, this drug dimer-loaded dual redox-responsive drug delivery system provides new options for improving the applications of traditional drugs and developing drug delivery systems with enhanced drug effects and high safety. [ABSTRACT FROM AUTHOR]

The continuously increasing bacterial resistance has become a big threat to public health worldwide, which makes it urgent to develop innovative antibacterial strategies. Nanotechnology‐based drug delivery systems are considered as promising strategies in combating bacterial infections which are expected to improve the therapeutic efficacy and minimize the side effects. Unfortunately, the conventional nanodrug delivery systems always suffer from practical dilemmas, including incomplete and slow drug release, insufficient accumulation in infected sites, and weak biofilm penetration ability. Stimuli‐responsive nanoplatforms are hence developed to overcome the disadvantages of conventional nanoparticles. In this review, we provide an extensive review of the recent progress of endogenous and exogenous stimuli‐responsive nanoplatforms in the antibacterial area, including planktonic bacteria, intracellular bacteria, and bacterial biofilms. Taking advantage of the specific infected microenvironment (pH, enzyme, redox, and toxin), the mechanisms and strategies of the design of endogenous stimuli‐responsive nanoplatforms are discussed, with an emphasis on how to improve the therapeutic efficacy and minimize side effects. How to realize controlled drug delivery using exogenous stimuli‐responsive nanoplatforms especially light‐responsive nanoparticles for improved antibacterial effects is another topic of this review. We especially highlight photothermal‐triggered drug delivery systems by the combination of photothermal agents and thermo‐responsive materials. This article is categorized under:Therapeutic Approaches and Drug Discovery > Nanomedicine for Infectious DiseaseTherapeutic Approaches and Drug Discovery > Emerging Technologies [ABSTRACT FROM AUTHOR]

Ursolic acid (UA), found widely in nature, exerts effective anti-tumoral activity against various malignant tumors. However, the low water solubility and poor bioavailability of UA have greatly hindered its translation to the clinic. To overcome these drawbacks, a simple redox-sensitive UA polymeric prodrug was synthesized by conjugating UA to polyethylene glycol using a disulfide bond. This formulation can self-assemble into micelles (U-SS-M) in aqueous solutions to produce small size micelles (∼62.5 nm in diameter) with high drug loading efficiency (∼16.7%) that exhibit pH and reduction dual-sensitivity. The cell and animal studies performed using the osteosarcoma MG-63 cell line and MG-63 cancer xenograft mice as the model systems consistently confirmed that the U-SS-M formulation could significantly prolong the circulation in blood and favor accumulation in tumor tissue. Targeted accumulation allows the U-SS-M to be effectively internalized by cancer cells, where the rapid release of UA is favored by a glutathione-rich and acidic intracellular environment, and ultimately achieves potent antitumor efficacy.

Redox-responsive drug delivery system emerges as a hopeful platform for tumor treatment. Dihydroartemisinin (DHA) has been investigated as an innovative tumor therapeutic agent. Herein, a DHA dimeric prodrug bridged with disulfide bond as linker (DHA2-SS) has been designed and synthesized. The prepared prodrugs could self-assemble into nanoparticles (SS NPs) with high DHA content (> 90%) and robust stability. These SS NPs display sensitive redox responsive capability and can release DHA under the tumor heterogeneity microenvironment. SS NPs possess preferable antitumor therapeutic activity in contrast with free DHA. Moreover, the possible anti-cancer mechanism of SS NPs was investigated through RNA-seq analysis, bioinformatics and molecular biological method. SS NPs could induce apoptosis via mitochondrial apoptosis pathway, as well as glycolysis inhibition associate with the regulation of PI3K/AKT/HIF-1α signal path, which may offer an underlying therapeutic target for liver cancer. Our study highlights the potential of using redox responsive prodrug nanoparticles to treat cancer, meanwhile provides insights into the anti-cancer mechanism of DHA prodrug. [ABSTRACT FROM AUTHOR]

Stimuli-responsive drug delivery systems based on polymeric micelles can achieve controlled drug release to improve the therapeutic outcome and reduce unwanted systematic toxicity and side effects of the cytotoxic drug in chemotherapy but often face challenging synthesis and purification of functionalized biocompatible polymer materials and low drug loading efficiency. In the present study, we reported a novel redox-responsive self-assembly polymeric micelle system, mPEG-p-CD/Ad-SS-CPT, to achieve high loading efficiency and selective delivery of camptothecin (CPT) in a reductive environment inside cancer cells. The host-guest supramolecular micelles utilized a simple β-CD modified PEG, mPEG-p-cyclodextrin (mPEG-p-CD), as the polymeric host with the ease of synthesis and purification. The guest prodrug Ad-SS-CPT contained the disulfide bond as the redox sensitivity group. The selective cleavage of disulfide bond and subsequent drug release in a reductive environment could potentially reduce system toxicity and improve the therapeutic outcome of CPT. In vitro studies showed that the micelles exhibited excellent cytotoxicity against HeLa cells comparable to the free drug. The host-guest polymeric micelles also showed great potentials for multi-drug co-delivery. Collectively, our current findings provided a general and convenient approach to design drug delivery systems based on stimuli-responsive polymeric micelles for disease treatment. [ABSTRACT FROM AUTHOR]

Osteosarcoma is the most common primary malignant bone tumor in childhood and adolescence. Currently, surgery combined with chemotherapy is the main treatment for osteosarcoma. However, the long-term survival of patients with metastatic osteosarcoma is unsatisfactory. Therefore, new treatment methods to improve the prognosis of patients with osteosarcoma are required. The present study aimed to develop nanocarriers with both tumor targeting and reduction responsiveness abilities, and to improve the therapeutic effect and reduce toxicity by loading traditional small molecule antitumor drugs. The tumor targeting peptide-decorated, doxorubicin (DOX)-loaded mPEG-P(Phe-co-Cys) nanoparticles were developed successfully through the ring-opening polymerization of amino acids. The peptide VATANST (STP) can specifically bind with vimentin, which is highly expressed on the osteosarcoma cell surface, resulting in tumor targeting effects. The nanoparticle is core–shell structured to protect the loaded DOX during blood flow. The disulfide bonds within the nanoparticles are sensitive to the osteosarcoma microenvironment, which has high glutathione (GSH) levels. Under the enhanced permeability and retention and active tumor targeting effects, the STP-decorated DOX-loaded nanoparticles accumulated in tumor tissues. High GSH levels can rupture disulfide bonds, resulting in the controlled release of DOX, which will cause necrosis of tumor cells. The characteristics of the synthesized nanoparticles, DOX release profiles in vitro and in vivo, cytotoxicity analysis, animal study, and safety evaluation were performed. The nanoparticles could increase the tumor inhibition efficiency against osteosarcoma and reduce the side effects of DOX to major organs. The STP-decorated mPEG-P(Phe-co-Cys) nanoparticles might be a suitable drug delivery system for DOX to treat osteosarcoma.

A pH and redox dual responsive amphiphilic viologen is synthesized, which can be reversibly transformed among the zwitterionic (SVa), monovalent anionic (SV + ), and divalent anionic (SVH 2+ ) forms upon pH variation, exhibiting pH-controllable redox responsive properties. Switchable Pickering emulsions with different droplet size and viscosity are prepared by the mixture of hydrophilic silica nanoparticles and the viologens (SV + or SVH 2+ ) at acidic conditions, while such combination yielded an oil-in-dispersion emulsion at neutral pH value. Not only can rapid reversible demulsification/stabilization of the Pickering emulsions be achieved by redox reactions, but the rate of redox-demulsification can also be controlled by pH trigger. The dual-responsive amphiphilic viologens have potential applications in developing intelligent colloid materials and molecular logic systems., (© 2024 Wiley‐VCH GmbH.)

Combretastatin A‐4 (CA4), a tubulin inhibitor, binds to the colchicine site of tubulin, inhibits tubulin polymerization, and leads to the apoptosis of tumor cells. However, the poor hydrophilicity and blood–brain barrier (BBB) penetration ability of CA4 hampers its application in the treatment of glioma. In this study, a novel combretastatin A‐4 derivative (CA4D) was designed and developed, which was further conjugated with glucose via disulfide‐bond‐bridged (CA4D‐SS‐Glu) to enhance the BBB penetration capacity. The obtained CA4D‐SS‐Glu conjugate displayed a suitable water partition coefficient and the superior ability across BBB in vitro and in vivo. In addition, the CA4D‐SS‐Glu exhibited rapid redox‐responsive drug release in the presence of glutathione, enhanced in vitro cytotoxicity, and cell apoptosis. Our data further confirmed that CA4D‐SS‐Glu inhibited proliferation, and restrained migration via affecting microtubule stabilization. Additionally, the conjugate also showed the highest antiproliferative and antitumor action on glioma in vivo as compared to CA4D and CA4. Taken together, the novel CA4D‐SS‐Glu conjugate possess improved physicochemical property and BBB penetration ability, reduction triggered release of CA4D, and efficient antiproliferative activity. These results provided a novel and effective entry to the treatment of glioma. [ABSTRACT FROM AUTHOR]

Redox-responsive prodrugs were synthesized by conjugating dasatinib (Das)/cholesterol (Chol) to hyaluronic acid (HA) via the cystamine dihydrochloride (Cys), and hexamethylene diamine (Hda) linkers. In a redox environment (10 mM dithiothreitol, DTT), a substantial amount of the grafted Das was released and faster than that observed under physiological conditions. The cytotoxicity of redox-sensitive HA-Cys-P(SSDas/CCChol) was greater than that of redox-insensitive HA-Hda-PCCDas. Flow cytometry showed that the uptake of HA-targeted DOX–encapsulated micelles was faster than that of free DOX. [ABSTRACT FROM AUTHOR]

[Display omitted] Specific cellular uptake and sufficient drug release in tumor tissues are important for effective cancer therapy. Hyaluronic acid (HA), a skeleton material, could specifically bind to cluster determinant 44 (CD44) receptors highly expressed on the surface of tumor cells to realize active targeting. Cystamine (cys) is sensitive highly reductive environment inside tumor cells and was used as a connecting arm to connect docosahexaenoic acid (DHA) and chlorin e6 (Ce6) to the HA skeleton to obtain redox-sensitive polymer HA-cys-DHA/Ce6 (CHD). Nanoparticles were fabricated and loaded with chemotherapeutic drug docetaxel (DTX) by physical encapsulation. The prepared nanoparticles had significantly increased uptake by MCF-7 cells that overexpressed CD44 receptors, and DTX was effectively released at high reducing condition. Compared with mono-photodynamic therapy (PDT) or mono-chemotherapy, the prepared nanoparticles exhibited superior anti-tumor effect by inhibiting microtubule depolymerization, blocking cell cycle and generating reactive oxygen species (ROS). In vivo anti-tumor experiments proved that DTX/CHD nanoparticles had the best antitumor response versus DTX and CHD nanoparticles under near-infrared (NIR) irradiation. These studies revealed that redox-responsive DTX-loaded CHD nanoparticles held great potential for the treatment of breast cancer. [ABSTRACT FROM AUTHOR]

The development of stimuli-responsive controlled release formulations is a potential method of improving pesticide utilization efficiency and alleviating current pesticide-related environmental pollution. In this study, a self-destruction redox-responsive pesticide delivery system using biodegradable disulfide-bond-bridged mesoporous organosilica (DMON) nanoparticles as the porous carriers and coordination complexes of gallic acid (GA) and Fe(III) ions as the capping agents were established for controlling prochloraz (PRO) release. The GA–Fe(III) complexes deposited onto the surface of DMON nanoparticles could effectively improve the light stability of prochloraz. Due to the decomposition of GA–Fe(III) complexes, the nano-vehicles had excellent redox-responsive performance under the reducing environments generated by the fungus. The spreadability of PRO@DMON–GA–Fe(III) nanoparticles on the rice leaves was increased due to the hydrogen bonds between GA and rice leaves. Compared with prochloraz emulsifiable concentrate, PRO@DMON–GA–Fe(III) nanoparticles showed better fungicidal activity against Magnaporthe oryzae with a longer duration under the same concentration of prochloraz. More importantly, DMON–GA–Fe(III) nanocarriers did not observe obvious toxicity to the growth of rice seedlings. Considering non-toxic organic solvents and excellent antifungal activity, redox-responsive pesticide controlled release systems with self-destruction properties have great application prospects in the field of plant disease management.

With the widespread global impact of cancer on humans and the extensive side effects associated with current cancer treatments, a novel, effective, and safe treatment is needed. Redox-responsive drug delivery systems (DDSs) have emerged as a potential cancer treatment with minimal side effects and enhanced site-specific targeted delivery. This paper explores the physiological and biochemical nature of tumors that allow for redox-responsive drug delivery systems and reviews recent advances in the chemical composition and design of such systems. The five main redox-responsive chemical entities that are the focus of this paper are disulfide bonds, diselenide bonds, succinimide–thioether linkages, tetrasulfide bonds, and platin conjugates. Moreover, as disulfide bonds are the most commonly used entities, the review explored disulfide-containing liposomes, polymeric micelles, and nanogels. While various systems have been devised, further research is needed to advance redox-responsive drug delivery systems for cancer treatment clinical applications.

One possibility for the non‐invasive imaging of encapsulated cell grafts is to label the lumen of cell embedding capsules with a redox‐responsive probe, as an increased extracellular reducing potential can be considered as a marker of hypoxia‐induced necrosis. A Gd(III)‐HPDO3A‐like chelate has been conjugated to glycol‐chitosan through a redox‐responsive disulphide bond to obtain a contrast agent for Magnetic Resonance Imaging (MRI). Such a compound can be interspersed with fibroblasts within the lumen of alginate‐chitosan capsules. Increasing reducing conditions within the extracellular microenvironment lead to the reductive cleavage of the disulphide bond and to the release of gadolinium in the form of a low molecular weight, non‐ionic chelate. The efflux of such chelate from capsules is readily detected by a decrease of contrast enhancement in T1‐weighted MR images. [ABSTRACT FROM AUTHOR]

With a number of outstanding properties, gelatin is an ideal candidate for assembling nanoplatforms in biomedical applications. Generally, gelatin nanocarriers are cross-linked by aldehydes to improve their stability in water solution. However, aldehydes could cause multiple toxicities and their cross-linking products are uncontrollable. Here, we first used a self-immolative cross-linker to assemble gelatin nanocarriers for the controlled release of drugs and targeted cancer therapy. The cross-linker contains a disulphide bridge and two symmetrical succinimidyl-esters, endowing it with multiple functions: 1) to cross-link the gelatin nanocarriers and thus improve their stability in water; 2) to conjugate the drug and tumor-targeting ligands with nanocarriers through covalent linkage; 3) to redox-responsively degrade the nanocarriers through hydrolysis of disulphide bridge; and 4) to produce traceless drug molecules through self-immolative reaction. Good biocompatibility and controllable drug release were demonstrated by in vitro experiments. Both qualitative and quantitative analyses confirmed the intracellular uptake of the nanocarriers by using doxorubicin (DOX) as a drug model and phenylboronic acid (PBA) as the targeting ligand. In vivo results demonstrated high therapeutic efficiency and low toxic side effects of the DOX loaded nanocarriers against artificial liver tumors. [ABSTRACT FROM AUTHOR]

[Display omitted] Controlling the drug release and restricting its presence in healthy organs is extremely valuable. In this study, mesoporous silica nanoparticles (MSN) as the core, loaded with paclitaxel (PTX), were coated with a non-porous silica shell functionalized with disulfide bonds. The nanoparticles were further coated with polyethylene glycol (PEG) via disulfide linkages. We analyzed the physicochemical properties of nanoparticles, including hydrodynamic size via Dynamic Light Scattering (DLS), zeta potential, X-ray Diffraction (XRD) patterns, Fourier-Transform Infrared (FTIR) spectra, and imaging through Transmission Electron Microscopy (TEM) and Scanning Electron Microscopy (SEM). The drug release profile in two distinct glutathione (GSH) concentrations of 2 µM and 10 µM was measured. The cellular uptake of nanoparticles by MCF-7 cell line was determined using Confocal Laser Scanning Microscopy (CLSM) images and flow cytometry. Furthermore, the cell viability and the capability of nanoparticles to induce apoptosis in MCF-7 cell line were studied using the MTT assay and flow cytometry, respectively. Our investigations revealed that the release of PTX from the drug delivery system was redox-responsive. Also, results indicated an elevated level of cellular uptake and efficient induction of apoptosis, underscoring the promising potential of this redox-responsive drug delivery system for breast cancer therapy. [ABSTRACT FROM AUTHOR]