Redox-responsive Nanocarriers Research Articles

Disulfide Cross-Linked Polymeric Redox-Responsive Nanocarrier Based on Heparin, Chitosan and Lipoic Acid Improved Drug Accumulation, Increased Cytotoxicity and Selectivity to Leukemia Cells by Tumor Targeting via "Aikido" Principle.

We have developed a micellar formulation of anticancer drugs based on chitosan and heparin grafted with lipoic and oleic acids that can release the cytotoxic cargo (doxorubicin) in response to external stimuli, such as increased glutathione concentration-a hallmark of cancer. Natural polysaccharides (heparin and chitosan) provide the pH sensitivity of the nanocarrier: the release of doxorubicin (Dox) is enhanced in a slightly acidic environment (tumor microenvironment). Fatty acid residues are necessary for the formation of nanoparticles (micelles) and solubilization of cytostatics in a hydrophobic core. Lipoic acid residues provide the formation of a labile S-S cross-linking between polymer chains (the first variant) or covalently attached doxorubicin molecules through glutathione-sensitive S-S bridges (the second variant)-both determine Redox sensitivity of the anticancer drugs carriers stable in blood circulation and disintegrate after intracellular uptake in the tumor cells. The release of doxorubicin from micelles occurs slowly (20%/6 h) in an environment with a pH of 7.4 and the absence of glutathione, while in a slightly acidic environment and in the presence of 10 mM glutathione, the rate increases up to 6 times, with an increase in the effective concentration up to 5 times after 7 h. The permeability of doxorubicin in micellar formulations (covalent S-S cross-linked and not) into Raji, K562, and A875 cancer cells was studied using FTIR, fluorescence spectroscopy and confocal laser scanning microscopy (CLSM). We have shown dramatically improved accumulation, decreased efflux, and increased cytotoxicity compared to doxorubicin control with three tumor cell lines: Raji, K562, and A875. At the same time, cytotoxicity and permeability for non-tumor cells (HEK293T) are significantly lower, increasing the selectivity index against tumor cells by several times.

(Nano)biotechnological approaches in the treatment of cervical cancer: integration of engineering and biology.

Cervical cancer is one of the most malignant gynaecological tumors characterised with the aggressive behaviour of the tumor cells. In spite of the development of different strategies for the treatment of cervical cancer, the tumor cells have developed resistance to conventional therapeutics. On the other hand, nanoparticles have been recently applied for the treatment of human cancers through delivery of drugs and facilitate tumor suppression. The stimuli-sensitive nanostructures can improve the release of therapeutics at the tumor site. In the present review, the nanostructures for the treatment of cervical cancer are discussed. Nanostructures can deliver both chemotherapy drugs and natural compounds to increase anti-cancer activity and prevent drug resistance in cervical tumor. Moreover, the genetic tools such as siRNA can be delivered by nanoparticles to enhance their accumulation at tumor site. In order to enhance selectivity, the stimuli-responsive nanoparticles such as pH- and redox-responsive nanocarriers have been developed to suppress cervical tumor. Moreover, nanoparticles can induce photo-thermal and photodynamic therapy to accelerate cell death in cervical tumor. In addition, nanobiotechnology demonstrates tremendous potential in the treatment of cervical cancer, especially in the context of tumor immunotherapy. Overall, metal-, carbon-, lipid- and polymer-based nanostructures have been utilized in cervical cancer therapy. Finally, hydrogels have been developed as novel kinds of carriers to encapsulate therapeutics and improve anti-cancer activity.

Cabazitaxel-loaded redox-responsive nanocarrier based on d-alpha-tocopheryl-chitosan and hyaluronic acid for improved anti-tumor efficacy in DMBA-induced breast cancer model

The study involved the formulation and evaluation of cabazitaxel loaded d-alpha-tocopheryl succinate/chitosan conjugate (CSVE) and hyaluronic acid (HA) based redox-responsive nanoparticle crosslinked using 3,3′-dithiodipropionic acid (DTPA).

Controlling Morphologies of Redox-Responsive Polymeric Nanocarriers for a Smart Drug Delivery System.

Redox-responsive nanocarriers using disulfides or thiols have received considerable attention owing to the higher levels of glutathione (GSH) in cancer cells than those in extracellular fluids. Nevertheless, the normal-to-cancer-cell selectivity of these nanocarriers has not yet been clarified. Nanocarriers exhibit different cytotoxicities depending on the morphologies they adopt under the redox-active conditions typically existing in cancerous cells. Therefore, not only GSH levels but also reactive oxygen species (ROS) levels and other complex cancerous cell conditions must be considered for the development of smart drug delivery systems. In this article, we review the structural design of redox-responsive polymers that exhibit different morphological changes in environments akin to cancerous cells (e. g., GSH- and ROS-abundant conditions). In addition, we propose a molecular design for the spatiotemporal control of nanocarrier morphology depending on the levels of both GSH and ROS upon photoirradiation to increase the cytotoxicity difference between normal and cancer cells.

Quantitative Measurement of Drug Release Dynamics within Targeted Organelles Using Förster Resonance Energy Transfer.

Measuring the release dynamics of drug molecules after their delivery to the target organelle is critical to improve therapeutic efficacy and reduce side effects. However, it remains challenging to quantitatively monitor subcellular drug release in real time. To address the knowledge gap, a novel gemini fluorescent surfactant capable of forming mitochondria-targeted and redox-responsive nanocarriers is designed. A quantitative Förster resonance energy transfer (FRET) platform is fabricated using this mitochondria-anchored fluorescent nanocarrier as a FRET donor and fluorescent drugs as a FRET acceptor. The FRET platform enables real-time measurement of drug release from organelle-targeted nanocarriers. Moreover, the obtained drug release dynamics can evaluate the duration of drug release at the subcellular level, which established a new quantitative method for organelle-targeted drug release. This quantitative FRET platform can compensate for the absent assessment of the targeted release performances of nanocarriers, offering in-depth understanding of the drug release behaviors at the subcellular targets.

Stimuli-responsive nanocarrier delivery systems for Pt-based antitumor complexes: a review.

Platinum-based anticancer drugs play a crucial role in the clinical treatment of various cancers. However, the application of platinum-based drugs is heavily restricted by their severe toxicity and drug resistance/cross resistance. Various drug delivery systems have been developed to overcome these limitations of platinum-based chemotherapy. Stimuli-responsive nanocarrier drug delivery systems as one of the most promising strategies attract more attention. And huge progress in stimuli-responsive nanocarrier delivery systems of platinum-based drugs has been made. In these systems, a variety of triggers including endogenous and extracorporeal stimuli have been employed. Endogenous stimuli mainly include pH-, thermo-, enzyme- and redox-responsive nanocarriers. Extracorporeal stimuli include light-, magnetic field- and ultrasound responsive nanocarriers. In this review, we present the recent advances in stimuli-responsive drug delivery systems with different nanocarriers for improving the efficacy and reducing the side effects of platinum-based anticancer drugs.

Multicomponent encapsulation into fully degradable protein nanocarriers via interfacial azide-alkyne click reaction in miniemulsion allows the co-delivery of immunotherapeutics.

Encapsulation of multiple adjuvants along with antigens into nanocarriers allows a co-delivery to antigen-presenting cells for the synergistic induction of robust immune responses. However, loading cargoes of different molar masses, polarities, and solubilities in high efficiencies remains a challenge. Therefore, we developed a strategy to encapsulate a triple combination of the so-called adjuvants, i.e. with Resiquimod (R848), muramyl dipeptide (MDP) and polyinosinic-polycytidylic acid (Poly(I : C)) into human serum albumin (HSA) nanocarriers. The loading is conducted in situ while the nanocarrier is formed by an orthogonal and metal-free click reaction at the interface of an inverse miniemulsion. By this unique approach, high encapsulation efficiency without harming the cargo during the nanocarrier formation process and regardless of their physical properties is achieved, thus keeping their bioactivity. Furthermore, we demonstrated high control over the encapsulation efficiency and varying the amount of each cargo did not influence the efficiency of multicomponent encapsulation. Azide-modified HSA was crosslinked with hexanediol dipropiolate (HDDP) at the interface of a water-in-oil miniemulsion. Varying the crosslinker amount allowed us to tailor the density and degradation rates of the protein shell. Additional installation of disulfide bonds into the crosslinker created redox-responsive nanocarriers, which degraded both by protease and under reducing conditions with dithiothreitol. The prepared HSA nanocarriers were efficiently taken up by dendritic cells and exhibited an additive cell activation and maturation, exceeding the nanocarriers loaded with only a single drug. This general protocol allows the orthogonal and metal-free encapsulation of various drugs or adjuvants at defined concentrations into the protein nanocarriers.

Dually Cross-Linked Core-Shell Structure Nanohydrogel with Redox-Responsive Degradability for Intracellular Delivery.

A redox-responsive nanocarrier is a promising strategy for the intracellular drug release because it protects the payload, prevents its undesirable leakage during extracellular transport, and favors site-specific drug delivery. In this study, we developed a novel redox responsive core-shell structure nanohydrogel prepared by a water in oil nanoemulsion method using two biocompatible synthetic polymers: vinyl sulfonated poly(N-(2-hydroxypropyl) methacrylamide mono/dilactate)-polyethylene glycol-poly(N-(2-hydroxypropyl) methacrylamide mono/dilactate) triblock copolymer, and thiolated hyaluronic acid. The influence on the nanohydrogel particle size and distribution of formulation parameters was investigated by a three-level full factorial design to optimize the preparation conditions. The surface and core-shell morphology of the nanohydrogel were observed by scanning electron microscope, transmission electron microscopy, and further confirmed by Fourier transform infrared spectroscopy and Raman spectroscopy from the standpoint of chemical composition. The redox-responsive biodegradability of the nanohydrogel in reducing environments was determined using glutathione as reducing agent. A nanohydrogel with particle size around 250 nm and polydispersity index around 0.1 is characterized by a thermosensitive shell which jellifies at body temperature and crosslinks at the interface of a redox-responsive hyaluronic acid core via the Michael addition reaction. The nanohydrogel showed good encapsulation efficiency for model macromolecules of different molecular weight (93% for cytochrome C, 47% for horseradish peroxidase, and 90% for bovine serum albumin), capacity to retain the peroxidase-like enzymatic activity (around 90%) of cytochrome C and horseradish peroxidase, and specific redox-responsive release behavior. Additionally, the nanohydrogel exhibited excellent cytocompatibility and internalization efficiency into macrophages. Therefore, the developed core-shell structure nanohydrogel can be considered a promising tool for the potential intracellular delivery of different pharmaceutical applications, including for cancer therapy.

EDTA-Gradient Loading of Doxorubicin into Ferrocene-Containing Liposomes: Effect of Lipid Composition and Visualization of Triggered Release by Cryo-TEM.

Efficient delivery of therapeutic compounds to their sites of action has been a ubiquitous concern throughout the history of human medicine. The tumor microenvironment offers a variety of endogenous stimuli that may be exploited by a responsive nanocarrier, including heterogeneities in redox potential. In the early stages of the design of such responsive delivery systems, it is necessary to develop a comprehensive understanding of the biophysical mechanism by which the stimulus response occurs, as well as how the response may change from the inclusion of cargo compounds. We describe the optimization of lipid compositions for liposomes containing synthetic ferrocene-appended lipids to achieve highly efficient loading of doxorubicin via an ethylenediaminetetraacetic acid (EDTA) gradient. Liposomes containing ferrocenylated phospholipid are shown to be unstable to the loading conditions, while those including a ferrocenylated alkylammonium amphiphile obtain a near-quantitative loading efficiency. Calorimetric studies demonstrate that this instability is the consequence of the relative degree of lipid hydrolysis that occurs under the acidic loading conditions. Drug-loaded liposomes of the optimized composition are studied by cryo-TEM; the presence of doxorubicin aggregates is observed inside vesicles, and doxorubicin release, as well as the changes in membrane structure resulting from oxidant treatment, is also observed by cryogenic transmission electron microscopy (cryo-TEM). These results further demonstrate the potential of ferrocene lipids in the design of redox-responsive nanocarriers and begin to explore their possible role as probes of membrane dynamics.

Redox-Responsive Nanocarrier for Controlled Release of Drugs in Inflammatory Skin Diseases.

A synthetic route for redox-sensitive and non-sensitive core multi-shell (CMS) carriers with sizes below 20 nm and narrow molecular weight distributions was established. Cyclic voltammetric measurements were conducted characterizing the redox potentials of reduction-sensitive CMS while showcasing its reducibility through glutathione and tris(2-carboxyethyl)-phosphine as a proof of concept. Measurements of reduction-initiated release of the model dye Nile red by time-dependent fluorescence spectroscopy showed a pronounced release for the redox-sensitive CMS nanocarrier (up to 90% within 24 h) while the non-sensitive nanocarriers showed no release in PBS. Penetration experiments using ex vivo human skin showed that the redox-sensitive CMS nanocarrier could deliver higher percentages of the loaded macrocyclic dye meso-tetra (m-hydroxyphenyl) porphyrin (mTHPP) to the skin as compared to the non-sensitive CMS nanocarrier. Encapsulation experiments showed that these CMS nanocarriers can encapsulate dyes or drugs with different molecular weights and hydrophobicity. A drug content of 1 to 6 wt% was achieved for the anti-inflammatory drugs dexamethasone and rapamycin as well as fluorescent dyes such as Nile red and porphyrins. These results show that redox-initiated drug release is a promising strategy to improve the topical drug delivery of macrolide drugs.

Targeting Delivery Nanocarriers for (+)-Terrein to Enhance Its Anticancer Effects.

As a compound from marine fungi, (+)-terrein showed significant anticancer activity. In this study, (+)-terrein was extracted from the marine-derived fungus and showed significant cytotoxicity against cancer cells, especially in A549 cells. To enhance its anticancer effects, redox-responsive nanocarriers based on folic acid-chitosan decorating the mesoporous silica nanoparticles were designed to control (+)-terrein target delivery into cancer cells. (+)-Terrein was loaded in the holes, and folic acid-chitosan worked as a gatekeeper by disulfide linkage controlling (+)-terrein release in the tumor microenvironment. The (+)-terrein drug delivery systems exhibited cytotoxicity toward A549 cells through induction of apoptosis. The apoptosis effect was confirmed by the increase in the expression of cleaved caspase-3, caspase-9, and PARP. Taken together, this work evaluates for the first time the (+)-terrein delivery system and provides a promising nanomedicine platform for (+)-terrein.

PH and redox dual-responsive polymeric micelles with charge conversion for paclitaxel delivery

Here we demonstrate a type of pH and redox dual-responsive micelles, which were self-assembled in aqueous solution by an amphiphilic polymer, methoxypoly(ethylene glycol)-cystamine-poly(L-glutamic acid)-imidazole (mPEG-SS-PGA-IM). Considering tumor cells or tissues exhibiting low pH values and high glutathione (GSH) concentration, mPEG-SS-PGA-IM micelles possessed the charge conversion at pH of tumor tissues, which can facilitate cellular uptake of tumor cells. Furthermore, mPEG-SS-PGA-IM micelles can escape from endo/lysosomes based on the proton sponge effect, following degraded by higher concentration of GSH in cytoplasm. CLSM images of HCT116 cells indicated that mPEG-SS-PGA-IM micelles can escape from endo/lysosomes and enter cytoplasm. MTT assay showed that (paclitaxel) PTX-loaded mPEG-SS-PGA-IM micelles had higher cytotoxicity against HCT116 cells compared with PTX-loaded mPEG-PBLG and mPEG-SS-PBLG micelles. These results indicated that these mPEG-SS-PGA-IM micelles, as novel and effective pH- and redox-responsive nanocarriers, have great potential to both improve drug targeting efficiency while also enhancing the antitumor efficacy of PTX.

Dual-Functional Redox-Responsive Nanocarriers for Loading Phytohormone and Complexation with Heavy Metal Ions.

This work focused on designing a novel redox-responsive nanocarrier synthesized from carboxymethyl-β-cyclodextrin-modified nanosilica, which could load and release plant hormones, such as salicylic acid (SA), in plant cells. When the SA-loaded nanoparticles cross the plant cell wall, the disulfide bond can be broken to form sulfhydryl groups under the action of reduced glutathione (GSH), thus releasing SA. Meanwhile, the resulting thiol groups exhibited strong affinity toward several heavy metal ions, mercury ions in particular, thus playing a role similar to phytochelatins for detoxification. The results of SA release in vitro proved that the release proceeded much faster in GSH-rich than in GSH-free environments. The adsorption behaviors of the redox-responsive nanoparticles toward heavy metal ions, after phytohormones release, were systematically investigated. Moreover, the synergetic effects on sustained release and metal ion capture enable the redox-responsive cyclodextrin-modified silica to be an effective and dual-functional nanocarrier that has great potential for agricultural applications.

Introducing the One-Pot-Amine-Thiol-Ene Reaction to Develop Redox Responsive Nanocarriers for its Potential Use in Anticancer Drug Release

Introducing the One-Pot-Amine-Thiol-Ene Reaction to Develop Redox Responsive Nanocarriers for its Potential Use in Anticancer Drug Release

Triggered All-Active Metal Organic Framework: Ferroptosis Machinery Contributes to the Apoptotic Photodynamic Antitumor Therapy.

Nanoscale photodynamic therapy (PDT) is an appealing antitumor modality for which apoptosis is the major mechanism of toxicity induction. It was postulated that the highly reactive singlet oxygen in PDT could deplete glutathione (GSH) and activate ferroptosis, the extent to which could be further manipulated by a redox-responsive nanocarrier. To validate this, a disulfide-bearing imidazole ligand coordinated with zinc to form an all-active metal organic framework (MOF) nanocarrier where a photosensitizer (chlorin e6/Ce6) was encapsulated. Regardless of light irradiation, the Ce6-loaded nanocarrier caused the depletion of intracellular GSH via the disulfide-thiol exchange reaction in a murine mammary carcinoma cell line (4T1). The GSH depletion further caused the inactivation of glutathione peroxide 4 (GPX4) and the enhancement of cytotoxicity that was alleviated by ferroptosis inhibitors. The superior in vivo antitumor efficacy of the all-active nanocarrier was corroborated in a 4T1 tumor-bearing mice model regarding tumor growth suppression and animal survival rate. The coadministration of an iron chelator weakened the antitumor potency of the nanocarrier due to ferroptosis inhibition, which was supported by the fact of tumor growth upsurge and the recovered GPX4 activity. The current work highlights the contribution of ferroptotic machinery to antitumor PDT via an activatable, adaptable, all-active MOF nanocarrier.

Hypoxia-activated prodrugs and redox-responsive nanocarriers.

Hypoxia is one of the marked features of malignant tumors, which is associated with several adaptation changes in the microenvironment of tumor cells. Therefore, targeting tumor hypoxia is a research hotspot for cancer therapy. In this review, we summarize the developing chemotherapeutic drugs for targeting hypoxia, including quinones, nitroaromatic/nitroimidazole, N-oxides, and transition metal complexes. In addition, redox-responsive bonds, such as nitroimidazole groups, azogroups, and disulfide bonds, are frequently used in drug delivery systems for targeting the redox environment of tumors. Both hypoxia-activated prodrugs and redox-responsive drug delivery nanocarriers have significant effects on targeting tumor hypoxia for cancer therapy. Hypoxia-activated prodrugs are commonly used in clinical trials with favorable prospects, while redox-responsive nanocarriers are currently at the experimental stage.

Redox Nano-Architectures: Perspectives and Implications in Diagnosis and Treatment of Human Diseases.

Efficient targeted therapy with minimal side-effects is the need of the hour. Locally altered redox state is observed in several human ailments, such as inflammation, sepsis, and cancer. This has been taken advantage of in designing redox-responsive nanodrug carriers. Redox-responsive nanosystems open a door to a multitude of possibilities for the control of diseases over other drug delivery systems. Recent Advances: The first-generation nanotherapy relies on novel properties of nanomaterials to shield the drug and deliver it to the diseased tissue or organ. The second generation is based on targeting the drug or diagnostic material to the diseased cell-specific receptors, or to a particular organ to improve the efficacy of the drug. The third and the latest generation of nanocarriers, the stimuli-responsive nanocarriers exploit the disease condition or environment to specifically deliver the drug or diagnostic probe for the best diagnosis and treatment. Several different kinds of stimuli such as temperature, magnetic field, pH, and altered redox state-responsive nanosystems have educed immense promise in the field of nanomedicine and therapy. We describe the evolution of nanomaterial since its inception with an emphasis on stimuli-responsive nanocarriers, especially redox-sensitive nanocarriers. Importantly, we discuss the future perspectives of redox-responsive nanocarriers and their implications. Redox-responsive nanocarriers achieve a near-to-zero premature release of the drug, thus avoiding off-site toxicity associated with the free drug. This bears great potential for the development of more effective drug delivery with better pharmacokinetics and pharmacodynamics.

MPEGylated solanesol micelles as redox-responsive nanocarriers with synergistic anticancer effect.

Various nanoscale drug carriers were used to enhance therapeutic effect of many drugs. While, the metabolites of high quantities of carriers may cause additional short- or long-term toxicities. In this study, a new systems based on solanesol derivatives was developed for anticancer drug delivery. There are two features for this system. One is solanesol originated bioactivity of the carrier, which will synergistically facilitate therapeutic effect of the encapsulated drug. The other is the redox-responsive drug release behavior adaptable to the glutathione-rich atmosphere of tumor cell. All the hypothesis have been elucidated in this work through in vitro and in vivo studies. It was found that this drug delivery system may have a dual function, as they are preferentially toxic for tumor cells alone and are efficient and safe carriers for anticancer drugs.

Methemoglobin as a redox-responsive nanocarrier to trigger the in situ anticancer ability of artemisinin

Learning from the antimalarial mechanism of artemisinin (ART) in nature, we explored methemoglobin (MHb) as a smart nanocarrier of ART, in which anticancer abilities can be turned on in situ through the upregulated reducing capacity of tumor tissue. Ultra violet–visible, electron paramagnetic resonance spectrometry and in vitro cell assessment proved that a reducing agent such as glutathione can work as an excellent biogenic trigger to reduce ferric iron in MHb to the ferrous state, activating the ability of ART to generate free radicals and resulting in cytotoxicity and apoptosis. In vivo investigations showed that the MHb–ART complex had encouraging anticancer outcomes. The bioinspired nanocarrier may pave a new way to achieve targeted toxicity to cancer cells with extremely low side effects.

Redox-responsive nanocarriers for drug and gene co-delivery based on chitosan derivatives modified mesoporous silica nanoparticles

Stimuli-responsive nanocarriers for anticancer drug and gene co-delivery are promising strategy in cancer therapy. The ultimate goal is to deliver high local concentration of therapeutic agents with no premature release and result in synergistic effects for combination therapies. In this work, we developed a redox stimuli-responsive and synergistic co-delivery system for anticancer drug DOX and p53 gene for potential cancer therapy. A dendronized chitosan derivative (CP) as a “gatekeeper” to control release the drug was used to modify MSNs via a disulfide linker and improve the gene transfection efficiency. Stimulus-induced release of the DOX was studied in the presence of glutathione (GSH), which showed that polymer shell was shed and accelerated the release of embedded drugs inside the tumor cells under a GSH-rich environment. The obtained nanoparticles showed good gene delivery ability in vitro by inducing an obvious increase in p53 protein expression in Hela cells. Apoptosis analysis confirmed that DOX and p53 could be co-delivered to the Hela cells by MSN-SS-CP nanocarriers and induced significant cell apoptosis. These results demonstrated that the dual delivery system resulted in synergistic effects and lead to an effective cancer cell apoptosis, which may be promising for cancer therapeutic application.