Redox-sensitive Nanoparticles Research Articles

EGFR Targeted Redox Sensitive Chitosan Nanoparticles of Cabazitaxel: Dual-Targeted Cancer Therapy, Lung Distribution, and Targeting Studies by Photoacoustic and Optical Imaging.

In this research, we have modified tocopheryl polyethylene glycol succinate (TPGS) to a redox-sensitive material, denoted as TPGS-SH, and employed the same to develop dual-receptor-targeted nanoparticles of chitosan loaded with cabazitaxel (CZT). The physicochemical properties and morphological characteristics of all nanoparticle formulations were assessed. Dual-receptor targeting redox-sensitive nanoparticles of CZT (F-CTX-CZT-CS-SH-NPs) were developed by a combination of pre- and postconjugation techniques by incorporating synthesized chitosan-folate (F) and TPGS-SH during nanoparticle synthesis and further postconjugated with cetuximab (CTX) for epidermal growth factor receptor (EGFR) targeting. The in vitro release of the drug was seemingly higher in the redox-sensitive buffer media (GSH, 20 mM) compared to that in physiological buffer. However, the extent of cellular uptake of dual-targeted nanoparticles was significantly higher in A549 cells than other control nanoparticles. The IC50 values of F-CTX-CZT-CS-SH-NPs against A549 cells was 0.26 ± 0.12 μg/mL, indicating a 6.3-fold and 60-fold enhancement in cytotoxicity relative to that of dual-receptor targeted, nonredox sensitive nanoparticles and CZT clinical injection, respectively. Furthermore, F-CTX-CZT-CS-SH-NPs demonstrated improved anticancer activity in the benzo(a)pyrene lung cancer model with a higher survival rate. Due to the synergistic combination of enhanced permeability and retention (EPR) effect of small-sized nanoparticles, the innovative and redox sensitive TPGS-SH moiety and the dual folate and EGFR mediated augmented endocytosis have all together significantly enhanced their biodistribution and targeting exclusively to the lung which is evident from their ultrasound/photoacoustic and in vivo imaging system (IVIS) studies.

Varying growth behavior of redox-sensitive nanoparticles on 1:1 and 2:1 clay surfaces: Mechanistic insights on preferential toxic ions removal in mono, co, and multi-metal contaminated waters

In the current study, contrasting growth behaviour of redox sensitive Fe0 nanoparticles (nZVI) was observed on different clay surfaces i.e., 1:1 non-swelling kaolinite (K-nZVI) and 2:1 swelling bentonite (B-nZVI). Osmotic swelling of bentonite led to Fe0 nucleation and growth of 5–7 nm size particles in the broadened interlayer spaces. B-nZVI had negative zeta potential due to the domination of the surface charge of bentonite clay. In contrast, kaolinite has shown dominant surface growth of nZVI particles (>24.8 ± 7.4 nm) and positive zeta potential, suggesting domination of Fe0 nanoparticles (nZVI) characteristics. This surface-dependent variation led to higher and faster removal of oxy-anions with K-nZVI, i.e., chromium and arsenic (87.5 and 157.35 mg/g) than B-nZVI (18.4 and 86.9 mg/g). In comparison, B-nZVI has shown higher sorption of cations i.e., nickel and cadmium (36 mg/g and 46 mg/g) than K-nZVI (25 and 27 mg/g). XPS and pXRD analysis of reaction precipitates confirmed reductive sorption of chromium, co-precipitation/ complexation of arsenic, electrostatic attraction and complexation of nickel and cadmium as major removal mechanisms. Drastically higher total contaminant sorption capacities of B-nZVI (327 mg/g) and K-nZVI (372 mg/g) in multi-contaminant (Cr + As + Ni + Cd) solutions than individual capacities in mono-ionic solutions was due to co-operative effects and newer sites induced via sorption and redox-transformation of other ionic species. K-nZVI removed chromium and arsenic to below drinking water permissible limits whereas B-nZVI succeeded in separating nickel and cadmium to drinkable levels in groundwater, freshwater, river water, and wastewater samples, emphasizing their applicability in high cationic—low anionic and low cationic-higher anionic species contaminated waters, respectively.

Dextran/eudragit S-100 based redox sensitive nanoparticles for colorectal cancer therapy.

Herein, we present disulfide crosslinked dextran/eudragit S-100 nanoparticles (DEEU NPs) (≈55 nm) for colorectal cancer treatment. These redox environment sensitive DEEU NPs are synthesized by simple oxidation of thiolated polymers in air. This approach allows avoiding the use of any additional chemical crosslinker. These DEEU NPs have high encapsulation efficiency for the doxorubicin (DOX) model drug (≈95%). The prepared DEEU NPs are redox sensitive owing to disulfide units and exhibit ≈80% DOX release in the reducing environment of GSH. Additionally, DOX-DEEU NPs display enhanced cytotoxicity for HCT116 cancer cells as compared to free DOX. Annexin V staining results also support the higher anticancer efficiency of DOX-DEEU NPs via induction of apoptosis. In vivo biodistribution results demonstrate that DEEU NPs can remain in the colon region for up to 24 hours. These results indicate that DEEU NPs can act as a promising platform for colorectal cancer treatment.

Effective Sonosensitizer Delivery by Redox Sensitive Nanoparticles for Prostate Cancer Sonodynamic Therapy via Amplifying Oxidative Stress and Peroxidation.

Sonodynamic therapy (SDT), a novel noninvasive therapeutic modality, provides many noteworthy benefits by generating reactive oxygen species (ROS). However, water-insoluble sonosensitizer delivery strategies have continuously underperformed because of unavoidable toxicity and a short circulation time. In this study, l-cystine derivative-based biocompatible nanoparticles (NPs) that can be used in SDT and induce limited cytotoxicity are designed and synthesized. After ultrasonic (US) irradiation, these sonosensitizer-loaded NPs show highly efficient sonodynamic performance that leads to cytotoxic ROS production. The ability to stop and start ROS generation induced by US irradiation enables accurate temporal and spatial control. In vivo and in vitro experiments are systematically performed to investigate the effects of this system on tumors, and the results indicate remarkable tumor suppression via markedly high persistent oxidative stress that induces peroxidation and endoplasmic reticulum stress. Thus, this novel temporally and spatially controllable ROS generation platform offers a safe and effective theranostic strategy for prostate cancer treatment.

Docetaxel-loaded redox-sensitive nanoparticles self-assembling from poly(caprolactone) conjugates with disulfide-linked poly(ethylene glycol)

In this study, novel redox-sensitive nanoparticles (NPs) were fabricated from the poly(caprolactone) conjugates with disulfide-linked poly(ethylene glycol) (DDMAT- mPEG-S-S-PCL, DPSP). The DPSP polymer was synthesized by ring-opening polymerization (ROP) and reversible addition-fragmentation chain transfer (RAFT) polymerization. The obtaining of the DPSP polymer was confirmed by the 1H nuclear magnetic resonance (1H NMR) and Fourier transform infrared spectroscopy (FTIR) spectra. The DPSP NPs were fabricated with the solvent-evaporation method. Docetaxel (DTX) was employed as a model drug and encapsulated into the DPSP NPs. The in vitro anti-tumor activity of the DTX-loaded DPSP NPs and free DTX against the breast cancer cells (4T1) were evaluated by MTT assay. The cargo-free DPSP NPs were in circular shapes with an average diameter of 107.8 ± 0.4 nm. These NPs displayed redox-responsive behavior in the presence of glutathione. Animal experiments indicated that the DPSP NPs showed excellent blood compatibility and good bio-security. Cell tests suggested that the DPSP NPs could be taken in by 4T1 cells, smoothly, which improved the anti-tumor activity of free DTX.

PH and Redox-Dual Sensitive Chitosan Nanoparticles Having Methyl Ester and Disulfide Linkages for Drug Targeting against Cholangiocarcinoma Cells.

The aim of this study is to prepare pH- and redox-sensitive nanoparticles for doxorubicin (DOX) delivery against DOX-resistant HuCC-T1 human cholangiocarcinoma (CCA) cells. For this purpose, L-histidine methyl ester (HIS) was attached to chitosan oligosaccharide (COS) via dithiodipropionic acid (abbreviated as ChitoHISss). DOX-incorporated nanoparticles of ChitoHISss conjugates were fabricated by a dialysis procedure. DOX-resistant HuCC-T1 cells were prepared by repetitive exposure of HuCC-T1 cells to DOX. ChitoHISss nanoparticles showed spherical morphology with a small diameter of less than 200 nm. The acid pH and glutathione (GSH) addition induced changes in the size distribution pattern of ChitoHISss nanoparticles from a narrow/monomodal distribution pattern to a wide/multimodal pattern and increased the fluorescence intensity of the nanoparticle solution. These results indicate that a physicochemical transition of nanoparticles can occur in an acidic pH or redox state. The more acidic the pH or the higher the GSH concentration the higher the drug release rate was, indicating that an acidic environment or higher redox states accelerated drug release from ChitoHISss nanoparticles. Whereas free DOX showed decreased anticancer activity at DOX-resistant HuCC-T1 cells, DOX-incorporated ChitoHISss nanoparticles showed dose-dependent anticancer activity. Intracellular delivery of DOX-incorporated ChitoHISss nanoparticles was relatively increased at an acidic pH and in the presence of GSH, indicating that DOX-incorporated ChitoHISss nanoparticles have superior acidic pH- and redox-sensitive behavior. In an in vivo tumor xenograft model, DOX-incorporated ChitoHISss nanoparticles were specifically delivered to tumor tissues and then efficiently inhibited tumor growth. We suggest that ChitoHISss nanoparticles are a promising candidate for treatment of CCA.

Quantification of doping state of redox sensitive nanoparticles for probing the invasiveness of cancer cells using surface enhanced Raman scattering.

Redox activity is known to regulate migration, invasion, metastasis, proliferation, and vascularization of cancer. Because cancer is heterogeneous, the role of redox activity in different cancers and cancer-related processes vary widely. In this study, water soluble, Tween 80-coated polyaniline (TPAni) nanoparticles were synthesized and used as nano-agents for sensing the redox activities of various cancer cells. To identify the relationship between the redox activity and the aggressiveness of cancer cells, two different cancer cell lines, derived from the same tissue but different with regards to aggressiveness, were selected for study. First, the cancer cell lines were incubated with TPAni nanoparticles, and an absorbance ratio obtained from the cell culture media was used as a colorimetric indicator of the redox activities of the cells. Simultaneously, hydrophobically modified filter papers coated with silver nanosnowflakes (SNSF) were used as sensing substrates for surface enhanced Raman scattering (SERS). SERS spectra obtained from varying concentrations of rhodamine 6G were used to confirm the detection limit of the SNSF-based SERS substrate. Cell culture media containing TPAni nanoparticles were treated with the SNSF-containing SERS substrates to examine the redox activities of the various cancer cell lines.The redox activities of cancer cell lines were confirmed by absorbance spectral analysis, and these redox activities were better identified via an SERS analysis method. A SNSF-containing SERS substrate, fabricated from SNSF and filter paper, was used to sense redox activity in cancer cell lines and to further identify correlations between redox activity and cancer cell line aggressiveness, as indicated by the use of EpCAM as a biomarker. Finally, potential of ​in vivo ​redox activity sensing was also confirmed.

A Unique Core-Shell Structured, Glycol Chitosan-Based Nanoparticle Achieves Cancer-Selective Gene Delivery with Reduced Off-Target Effects.

The inherent instability of nucleic acids within serum and the tumor microenvironment necessitates a suitable vehicle for non-viral gene delivery to malignant lesions. A specificity-conferring mechanism is also often needed to mitigate off-target toxicity. In the present study, we report a stable and efficient redox-sensitive nanoparticle system with a unique core–shell structure as a DNA carrier for cancer theranostics. Thiolated polyethylenimine (PEI-SH) is complexed with DNA through electrostatic interactions to form the core, and glycol chitosan-modified with succinimidyl 3-(2-pyridyldithio)propionate (GCS-PDP) is grafted on the surface through a thiolate-disulfide interchange reaction to form the shell. The resulting nanoparticles, GCS-PDP/PEI-SH/DNA nanoparticles (GNPs), exhibit high colloid stability in a simulated physiological environment and redox-responsive DNA release. GNPs not only show a high and redox-responsive cellular uptake, high transfection efficiency, and low cytotoxicity in vitro, but also exhibit selective tumor targeting, with minimal toxicity, in vivo, upon systemic administration. Such a performance positions GNPs as viable candidates for molecular-genetic imaging and theranostic applications.

Glycogen-based pH and redox sensitive nanoparticles with ginsenoside Rh2 for effective treatment of ulcerative colitis

The purpose of this study is to construct a pH and redox sensitive nanoparticle to effectively deliver ginsenoside Rh2 for the treatment of ulcerative colitis (UC). Herein, glycogen was modified by urocanic acid and α-lipoic acid (α-LA) to obtain an amphiphilic polymer (LA-UaGly). Such polymer LA-UaGly could self-assemble to form nanoparticles (Blank NPs) in water with excellent stability, which could also successfully encapsulated ginsenoside Rh2 to form Rh2 nanoparticles (Rh2 NPs) with encapsulation efficiency of 74.36 ± 0.34%. DLS analysis indicated Rh2 NPs were spherical with a particle size of 128.9 ± 0.3 nm. As expected, Rh2 NPs exhibited typical pH and redox dual response release behaviour as well as the excellent in vivo safety. In vitro tests showed that Rh2 NPs could effectively internalize and release Rh2 into RAW264.7 cells, and protect cells from apoptosis (p < 0.05). More interestingly, Rh2 NPs exhibited strong anti-inflammatory activity via significantly inhibiting the overproduction of nitric oxide (NO) and inflammatory cytokines (TNF-α, IL-1β and IL-6) (p < 0.05). In vivo experiments suggested that Rh2 NPs significantly ameliorated the weight loss, colon length, disease activity index (DAI) score, and myeloperoxidase (MPO) activity in mice caused by dextran sulfate sodium salt (DSS) (p < 0.05). Simultaneously, pathological analysis proved that Rh2 NPs could significantly reduce histological damage and inflammatory infiltration in mice. Rh2 NPs could also effectively regulate the intestinal flora of mice by improving the species uniformity and abundance of the intestinal flora of mice and restoring the species diversity of the intestinal flora. In addition, both in vivo and in vitro experiments proved that Rh2 NPs had stronger anti-inflammatory activity than Rh2. This study provides a promising strategy for the effective treatment of UC.

Heterogeneously Porous Multiadsorbent Clay–Biochar Surface to Support Redox-Sensitive Nanoparticles: Applications of Novel Clay–Biochar–Nanoscale Zerovalent Iron Nanotrident (C-BC-nZVI) in Continuous Water Filtration

An eco-friendly layered-porous C-BC surface was prepared by intercalating properties of layered bentonite clay (C) having high cation-exchange capacity, with biochar (BC), containing pores and vast...

Combined antioxidant capped and surface supported redox-sensitive nanoparticles for continuous elimination of multi-metallic species.

A strategic modification involving (i) a multi-functional almond shell biochar surface support and (ii) capping with almond skin extracted antioxidants was performed to preserve redox-sensitive Fe0 nanoparticles (NPs). pXRD data showed generation of an iron-carbonyl shell on the supported Fe0 NPs (SA-Fe0), justifying successful antioxidant capping. The total metal removal capacity of 695 mg g-1i.e. AsO2- (300.2 mg g-1) > Cd2+ (224.2 mg g-1) > CrO42- (125.2 mg g-1) > Ni2+ (44.5 mg g-1) in batch mode, and 102 mg g-1 in continuous column setup confirms the excellent reactivity of the SA-Fe0 nanocomposite. Loss of the iron-carbonyl shell and iron oxidation during interaction with contaminants confirm no hindrance in electron transfer due to antioxidant capping.

Reduction-Sensitive Polymeric Micelles for Intracellular Doxorubicin Delivery

The hazard of cancer is continuously increasing with age, Doxorubicin (DOX) encapsulated by liposomes as an effective formulation is widely used to treat malignancies. To avoid the cardiotoxicity of DOX and increase the half-life and targeting of liposomal drugs, redox-sensitive nanoparticle that improve the delivery of therapeutics to target tissue have become an extensive choice of medical treatment. In this work, we synthesised a kind of redox-sensitive product, PEG-redox-DOX micelles which were made of PEG-SS-COOH coupled with DOX by a reduction-sensitive disulfide bond. This micellar system has a mean diameter of 60nm with acceptable distribution (PDI=0.81) and remained unchanged in phate buffered saline (PBS, pH=7.4) for 24 hours. However, the disulfide bond between DOX and hydrophilic PEG broke readily in the presence of 10 mM DTT imitating intracellular condition. The micelle released more than 75% DOX within 48h at 10 mM DTT, whereas only 12% DOX were released from prodrug at 0 mM DTT. These results suggest that PEG-redox-DOX has expectable efficiency of drug-loading and release. Nowadays, redox-sensitive micelles are more and more taken into considered, demonstrating its developmental potential in cancer therapy categories by providing a new search direction.

Redox-sensitive nanoparticles based on xylan-lipoic acid conjugate for tumor targeted drug delivery of niclosamide in cancer therapy

In this study, novel redox-sensitive nanoparticles based on xylan-lipoic acid (Xyl-LA) conjugate were developed for tumor targeted delivery of niclosamide (Nic) in cancer therapy. The niclosamide loaded xylan-lipoic acid conjugate nanoparticles (Xyl-LA/Nic NPs) showed redox responsive behaviour in presence of reductive glutathione (GSH), which indicate their suitability for intracellular drug release. The obtained Xyl-LA/Nic NPs exhibited uniform particle size (196 ± 1.64 nm), high loading capacity (~28.6 wt %) and excellent blood compatibility. The anticancer activity of the Niclosamide and the Xyl-LA/Nic NPs against the colon carcinoma cell lines (HCT-15, Colo-320) were evaluated by MTT assay and the overall results indicate that the Xyl-LA/Nic NPs significantly enhanced the therapeutic efficiency of niclosamide in cancer therapy.

Enhanced Anti-Glioma Efficacy by Borneol Combined With CGKRK-Modified Paclitaxel Self-Assembled Redox-Sensitive Nanoparticles.

The serious therapeutic obstacles to glioma treatment include poor penetration across the blood-brain barrier (BBB) and low accumulation of therapeutic drugs at tumor sites. In this study, borneol combined with CGKRK peptide (a ligand of the heparan sulfate which overexpress on the glioma cells) modified paclitaxel prodrug self-assembled redox-responsive nanoparticles (CGKRK-PSNPs) were hypothesized to enhance the BBB penetration ability and active tumor targeting efficiency, respectively. The resulting CGKRK-PSNPs possessed a spherical shape with a small particle size (105.61 ± 1.53 nm) and high drug loading for PTX (54.18 ± 1.13%). The drug release behavior proved that CGKRK-PSNPs were highly sensitive to glutathione (GSH) redox environment. The in vitro cell experiments suggested that CGKRK-PSNPs significantly increased the cellular uptake and cytotoxicity of U87MG cells, meanwhile CGKRK-PSNPs showed the low cytotoxicity against BCEC cells. Combined with borneol, CGKRK-PSNPs exhibited enhanced transportation across in vitro BBB model. In intracranial U87MG glioma-bearing nude mice, the higher accumulation of CGKRK-PSNPs combined with borneol was observed through real-time fluorescence image. Moreover, the in vivo anti-glioma results confirmed that CGKRK-PSNPs combined with borneol could improve the anti-glioma efficacy with the prolonged medium survival time (39 days). In conclusion, the collaborative strategy of CGKRK-PSNPs combined with borneol provided a promising drug delivery routine for glioblastoma therapy.

TAT-modified redox-sensitive nanoparticles for triggered drug delivery and effective breast cancer therapy

Tumor cell internalization and controlling drug release are two major biological barriers, which limit the clinical application of chemotherapeutic drugs. To address these obstacles, an effective redox-responsive TAT-DSPE-PEG/PEI-SS-PLA/DOX (shorten as TPSPD) nanoparticle was designed in this paper. Doxorubicin (DOX) was incorporated with polyethylenemine-disulfide bond-polylactic acid (PEI-SS-PLA/DOX) to form the core of nanoparticles, while the TAT peptide modifided-1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[maleimide-(polyethylene glycol)5000 (TAT-PEG-DSPE) was as the shell. Nanoparticles presented proper particle size and suitable serum stability as well as the long circulation time. Moreover, TPSPD nanoparticles enhanced the cellular uptake rate and realized the controlled drug release at the tumor site. In vivo experiments showed that TPSPD possessed favorable antitumor activity and reduced the systemic toxicity. Altogether, the prepared TPSPD nanoparticle was expected to be a promising strategy in cancer therapy.

Influence of the method of preparation on the characteristics and performance of cholesterol-based polymeric nanoparticles for redox-triggered release of doxorubicin in tumor cells.

Immature manufacturing and sub-optimal control of quality attributes hinder the effective translation of nanoformulations for cancer treatment, being partially responsible for the scarce number of products on the market. The effect of the method of preparation on the performance of complex formulations such as bio-responsive nanomedicines needs further understanding. In this study, we investigated the the influence of the method of preparation on the characteristics and bio-responsiveness of doxorubicin-loaded redox-sensitive nanoparticles (DOX-SS-NPs), formed by a biocompatible cholesterol-based amphiphilic block copolymer (PC5MA-SS-PEO). Two commonly used preparation techniques: (1) cosolvent removal and (2) an O/W emulsion method were compared and the in vitro and in vivo performance of promising formulations was assessed. Besides particle size distribution and drug loading, the response of the nanoparticles to reducing environments and subsequent release kinetics and cytotoxicity were also affected by the method of preparation. The investigation and understanding of this extensive influence, led to a DOX-SS-NPs formulation with significant in vivo efficacy and an improved safety profile when evaluated against free doxorubicin (DOX-HCl) and the commercial pegylated liposomal form (Doxil®). Our findings highlight the importance of formulation optimization and support the use of systematic approaches like Quality by Design to the development of bio-responsive nanomedicines for cancer treatment.

Paclitaxel-loaded redox-sensitive nanoparticles based on hyaluronic acid-vitamin E succinate conjugates for improved lung cancer treatment.

BackgroundLung cancer is the primary cause of cancer-related death worldwide. A redox-sensitive nanocarrier system was developed for tumor-targeted drug delivery and sufficient drug release of the chemotherapeutic agent paclitaxel (PTX) for improved lung cancer treatment.MethodsThe redox-sensitive nanocarrier system constructed from a hyaluronic acid-disulfide-vitamin E succinate (HA-SS-VES, HSV) conjugate was synthesized and PTX was loaded in the delivery system. The physicochemical properties of the HSV nanoparticles were characterized. The redox-sensitivity, tumor-targeting and intracellular drug release capability of the HSV nanoparticles were evaluated. Furthermore, in vitro and in vivo antitumor activity of the PTX-loaded HSV nanoparticles was investigated in a CD44 over-expressed A549 tumor model.ResultsThis HSV conjugate was successfully synthesized and self-assembled to form nanoparticles in aqueous condition with a low critical micelle concentration of 36.3 μg mL−1. Free PTX was successfully entrapped into the HSV nanoparticles with a high drug loading of 33.5% (w/w) and an entrapment efficiency of 90.6%. Moreover, the redox-sensitivity of the HSV nanoparticles was confirmed by particle size change of the nanoparticles along with in vitro release profiles in different reducing environment. In addition, the HA-receptor mediated endocytosis and the potency of redox-sensitivity for intracellular drug delivery were further verified by flow cytometry and confocal laser scanning microscopic analysis. The antitumor activity results showed that compared to redox-insensitive nanoparticles and Taxol®, PTX-loaded redox-sensitive nanoparticles exhibited much greater in vitro cytotoxicity and apoptosis-inducing ability against CD44 over-expressed A549 tumor cells. In vivo, the PTX-loaded HSV nanoparticles possessed much higher antitumor efficacy in an A549 mouse xenograft model and demonstrated improved safety profile. In summary, our PTX-loaded redox-sensitive HSV nanoparticles demonstrated enhanced antitumor efficacy and improved safety of PTX.ConclusionThe results of our study indicated the redox-sensitive HSV nanoparticle was a promising nanocarrier for lung cancer therapy.

Redox-sensitive nanoparticles based on 4-aminothiophenol-carboxymethyl inulin conjugate for budesonide delivery in inflammatory bowel diseases

The purpose of this study was to develop an oral nanocarrier as budesonide delivery system and to evaluate its therapeutic potential for inflammatory bowel disease (IBD). The nanoparticles (NPs) based on an amphiphilic inulin polymer with 4-aminothiophenol (ATP) grafted onto carboxymethyl inulin (CMI) were prepared. The particle sizes were about 210.18 nm and had the obvious pH/redox sensitive swelling transitions. The drug-release study of NPs <-- >in vitro showed a low release rate (about 45 wt%) in GSH-free media, whereas high release rate (about 80 wt%) in the media containing 20 mM GSH, exhibiting a redox-responsive property. Further in vivo experiments found the NPs tended to accumulate in inflamed sites, and exerted excellent therapeutic efficacy in comparison to drug suspension in colitis mice model. All the results demonstrated that the redox-sensitive NPs, based on amphiphilic inulin, may be used as colon-targeted drug delivery for the treatment of IBD.

Redox-sensitive self-assembled nanoparticles based on alpha-tocopherol succinate-modified heparin for intracellular delivery of paclitaxel

To remedy the problems riddled in cancer chemotherapy, such as poor solubility, low selectivity, and insufficient intra-cellular release of drugs, novel heparin-based redox-sensitive polymeric nanoparticles were developed. The amphiphilic polymer, heparin-alpha-tocopherol succinate (Hep-cys-TOS) was synthesized by grafting hydrophobic TOS to heparin using cystamine as the redox-sensitive linker, which could self-assemble into nanoparticles in phosphate buffer saline (PBS) with low critical aggregation concentration (CAC) values ranging from 0.026 to 0.093mg/mL. Paclitaxel (PTX)-loaded Hep-cys-TOS nanoparticles were prepared via a dialysis method, exhibiting a high drug-loading efficiency of 18.99%. Physicochemical properties of the optimized formulation were characterized by dynamic light scattering (DLS), transmission electron microscope (TEM) and differential scanning calorimetry (DSC). Subsequently, the redox-sensitivity of Hep-cys-TOS nanoparticles was confirmed by the changes in size distribution, morphology and appearance after dithiothreitol (DTT) treatment. Besides, the in vitro release of PTX from Hep-cys-TOS nanoparticles also exhibited a redox-triggered profile. Also, the uptake behavior and pathways of coumarin 6-loaded Hep-cys-TOS nanoparticles were investigated, suggesting the nanoparticles could be taken into MCF-7 cells in energy-dependent, caveolae-mediated and cholesterol-dependent endocytosis manners. Later, MTT assays of different PTX-free and PTX-loaded formulations revealed the desirable safety of PTX-free nanoparticles and the enhanced anti-cancer activity of PTX-loaded Hep-cys-TOS nanoparticles (IC50=0.79μg/mL). Apoptosis study indicated the redox-sensitive formulation could induce more apoptosis of MCF-7 cells than insensitive one (55.2% vs. 41.7%), showing the importance of intracellular burst release of PTX. Subsequently, the hemolytic toxicity confirmed the safety of the nanoparticles for intravenous administration. The results indicated the developed redox-sensitive nanoparticles were promising as intracellular drug delivery vehicles for cancer treatment.

Redox-sensitive nanoparticles from amphiphilic cholesterol-based block copolymers for enhanced tumor intracellular release of doxorubicin

A novel amphiphilic cholesterol-based block copolymer comprised of a polymethacrylate bearing cholesterol block and a polyethylene glycol block with reducible disulfide bonds (PC5MA-SS-PEO) was synthesized and evaluated as a redox-sensitive nanoparticulate delivery system. The self-assembled PC5MA-SS-PEO nanoparticles (SS-NPs) encapsulated the anticancer drug doxorubicin (DOX) with high drug loading (18.2% w/w) and high encapsulation efficiency (94.9%). DOX-encapsulated PC5MA-SS-PEO self-assembled nanoparticles (DOX-encapsulated SS-NPs) showed excellent stability and exhibited a rapid DOX release in response to dithiothreitol reductive condition. Importantly, following internalization by lung cancer cells, the reducible DOX-encapsulated SS-NPs achieved higher cytotoxicity than the non-reducible thioester NPs whereas blank nanoparticles were non-cytotoxic. Furthermore, in vivo imaging studies in tumor-bearing severe combined immunodeficiency (SCID) mice showed that the nanoparticles preferentially accumulated in tumor tissue with remarkably reduced accumulation in the healthy non-target organs. The results indicated that the SS-NPs may be a promising platform for cancer-cell specific delivery of hydrophobic anticancer drugs. From the Clinical EditorThe use of nanocarriers for drug delivery against tumors has been under intense research. One problem of using carrier system is the drug release kinetics at tumor site. In this article, the authors continued their previous study in the development of an amphiphilic cholesterol-based block copolymer with redox-sensitive modification, so that the payload drug could be released in response to the microenvironment. The interesting results should provide a new direction for designing future novel nanocarrier systems.