Redox-responsive Poly Research Articles

PH-sensitive and redox-responsive poly(tetraethylene glycol) nanoparticle-based platform for cancer treatment

Effective drug delivery with precise tumour targeting is crucial for cancer treatment. To address the challenges posed by the specificity and complexity of the tumour microenvironment, we developed a poly(tetraethylene glycol)-based disulfide nanoparticle (NP) platform and explored its potential in cancer treatment, focusing on drug loading and controlled release performance. Poly(tetraethylene glycol) NPs were characterised using nuclear magnetic resonance spectroscopy, mass spectrometry, and ultraviolet-visible spectroscopy. Additionally, we evaluated physicochemical properties, including dynamic light scattering, zeta potential analysis, drug loading capacity (DLC), and drug loading efficiency (DLE). The impact of NPs on the mouse colorectal cancer cell line (CT26) and NIH3T3 cells was assessed using a cytotoxicity assay, live/dead staining assay, flow cytometry, and confocal fluorescence microscopy. The experimental results align with the expected chemical structure and physicochemical properties of poly(tetraethylene glycol) NPs. These NPs exhibit high DLE (78.7%) and DLC (12%), with minimal changes in particle size over time in different media.In vitroexperiments revealed that the NPs can induce significant cytotoxicity and apoptosis in CT26 cells. Cellular uptake notably increases with increasing concentration and exposure time. The confocal microscopic analysis confirmed the effective distribution and accumulation of NPs within cells. In conclusion, poly(tetraethylene glycol) NPs hold promise for improving drug-delivery efficiency, offering potential advancements in cancer treatment.

Biomimetic copper-containing nanogels for imaging-guided tumor chemo-chemodynamic-immunotherapy

Developing multifunctional nanoplatforms to comprehensively modulate the tumor microenvironment and enhance diagnostic and therapeutic outcomes still remains a great challenge. Here, we report the facile construction of a multivariate nanoplatform based on cancer cell membrane (CM)-encapsulated redox-responsive poly(N-vinylcaprolactam) (PVCL) nanogels (NGs) co-loaded with Cu(II) and chemotherapeutic drug toyocamycin (Toy) for magnetic resonance (MR) imaging-guided combination tumor chemodynamic therapy/chemoimmunotherapy. We show that redox-responsive PVCL NGs formed through precipitation polymerization can be aminated, conjugated with 3,4-dihydroxyhydrocinnamic acid for Cu(II) complexation, physically loaded with Toy, and finally camouflaged with CMs. The created ADCT@CM NGs with an average size of 113.0 nm are stable under physiological conditions and can efficiently release Cu(II) and Toy under tumor microenvironment with a high level of glutathione. Meanwhile, the developed NGs are able to enhance cancer cell oxidative stress and endoplasmic reticulum stress by synergizing the effects of chemodynamic therapy mediated by Cu-based Fenton-like reaction and Toy-mediated chemotherapy, thereby triggering significant immunogenic cell death (ICD). In a melanoma mouse model, the NGs show potent immune activation effects to reinforce tumor therapeutic efficacy through ICD induction and immune modulation including high levels of immune cytokine secretion, increased tumor infiltration of CD8+ cytotoxic T cells, and reduced tumor infiltration of regulatory T cells. With the CM coating and Cu(II) loading, the developed NG platform demonstrates homologous tumor targeting and T1-weighted MR imaging, hence providing a general biomimetic NG platform for ICD-facilitated tumor theranostic nanoplatform. Statement of significanceDeveloping multifunctional nanoplatforms to comprehensively modulate the tumor microenvironment (TME) and enhance theranostic outcomes remains a challenge. Here, a cancer cell membrane (CM)-camouflaged nanoplatform based on aminated poly(N-vinylcaprolactam) nanogels (NGs) co-loaded with Cu(II) and toyocamycin (Toy) was prepared for magnetic resonance (MR) imaging-guided combination tumor chemodynamic therapy/chemoimmunotherapy. The tumor targeting specificity and efficient TME-triggered release of Cu(II) and Toy could enhance tumor cell oxidative stress and endoplasmic reticulum stress by synergizing the effects of chemodynamic therapy mediated by Cu-based Fenton-like reaction and Toy-mediated chemotherapy, respectively, thereby leading to significant immunogenic cell death (ICD) and immune response. With the CM coating and Cu(II) loading, the developed NG platform also demonstrates good T1-weighted tumor MR imaging performance. Hence, this study provides a general biomimetic NG platform for ICD-facilitated tumor theranostics.

Construction of biomimetic camouflaged neutrophil membrane nanoparticles for precise delivery and augmented glioma cancer treatment

Developing novel nanomedicine formulations that successfully penetrate the blood-brain barrier (BBB) to treat and diagnose glioma effectively is still a significant obstacle. This study presents the development of polymer nanogels camouflaged with macrophage membranes. The nanogels are loaded with manganese dioxide (MnO2) and carboplatin. They are designed for the treatment of glioma using a combination of chemotherapy and chemodynamic therapy (CDT). The precipitation polymerization process was used to create redox-responsive poly(caprolactone) (PCL) nanogels (NGs). These NGs were then loaded with MnO2 and physically encapsulated with carboplatin. The resulting nanogels had an average diameter of 102.52 nm and were covered with macrophage membranes to provide excellent stability. The developed NGs exhibit redox and pH responsiveness, releasing carboplatin and Mn(II) in a controlled manner. NGs may effectively deplete glutathione (GSH) in the tumour milieu. The Mn(II) generated in this process enhances the effectiveness of the loaded carboplatin by exerting its chemotherapeutic action and promoting the formation of reactive oxygen species to improve the efficiency of CDT. The results of our study show a very efficient and promising nanomedicine platform for the treatment and diagnosis of glioma, a type of cancer. This platform is self-adaptive, cooperative, and based on NG technology. Furthermore, this platform can potentially be used for other challenging types of cancer.

Iron-chelated and GSH-responsive polymersome nanoreactors facilitating therapeutic cascade reactions in cooperative starvation-ferroptosis therapy

A combination of starvation therapy and ferroptosis offers a potent therapeutic strategy to treat triple-negative breast cancer (TNBC). Herein, a polymersome-based nanoreactor containing ferric ions and glucose oxidase (GOx) activates cascade reactions for multifaced and cooperative cancer treatments. The nanoreactor is constructed from a redox-responsive poly(methacrylic acid)–SS–poly(ε-caprolactone) copolymer (PCL–SS–PMAA) with a disulfide linkage located between the hydrophobic and hydrophilic junctions. The hydrophilic core of the polymersome (namely PSP) is loaded with oxidoreductase enzyme to induce starvation, and the outer shell of carboxylic groups is chelated with Fe3+ ions to activate ferroptosis. The nanoreactor, FePSP@GOx, demonstrates the activation of a chain reaction that produces reactive oxygen species (ROS), thereby accelerating ferroptosis. The TNBC cell line MDA-MB-231 exposed to FePSP@GOx exhibits efficient glutathione (GSH) and glutathione peroxidase 4 (GPX4) depletion. Furthermore, the level of lipid peroxidation in MDA-MB-231 cells is significantly enhanced following the treatment with FePSP@GOx. In cytotoxicity assays, MDA-MB-231 cells treated with FePSP@GOx show pronounced enhancement in cell death. The integrated results imply that while starvation therapy coincides with the occurrence of a defensive autophagic response, the predominance of the ferroptosis mechanism over autophagy ultimately leads to cell death. FePSP@GOx, constructed from a GSH-responsive copolymer as a cascade nanoreactor, is a safe and promising nanomedicine for cooperative starvation-ferroptosis cancer therapy.

Facile synthesis of poly(disulfide)s through one-step oxidation polymerization for redox-responsive drug delivery.

Poly(disulfide)s-based systems with repetitive disulfide bonds in their backbones are emerging as promising tumor microenvironment responsive platforms for drug delivery. However, complicated synthesis and purification processes have restricted their further application. Herein, we developed redox-responsive poly(disulfide)s (PBDBM) by one-step oxidation polymerization of a commercially available monomer, 1,4-butanediol bis(thioglycolate) (BDBM). PBDBM can self-assemble with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-poly(ethylene glycol)3400 (DSPE-PEG3.4k) by the nanoprecipitation method and be formulated into PBDBM NPs (sub 100 nm). It can also be loaded with docetaxel (DTX), a first-line chemotherapy agent for breast cancer, to form DTX@PBDBM NPs with a loading capacity of 6.13%. DTX@PBDBM NPs with favorable size stability and redox-responsive capability exhibit superior antitumor activity in vitro. In addition, owing to the different glutathione (GSH) levels in normal and tumor cells, PBDBM NPs with disulfide bonds could synergistically increase intracellular ROS levels, further inducing apoptosis and cell cycle arrest in the G2/M phase. Moreover, in vivo studies revealed that PBDBM NPs could accumulate in tumors, suppress 4T1 tumor growth, and significantly attenuate the systemic toxicity of DTX. Thus, a novel redox-responsive poly(disulfide)s nanocarrier was successfully and facilely developed for cancer drug delivery and effective breast cancer therapy.

Redox responsive poly(allylamine)/eudragit S-100 nanoparticles for dual drug delivery in colorectal cancer

Herein, we report redox responsive, colon cancer targeting poly(allylamine) (PA)/eudragit S-100 (EU) nanoparticles (PAEU NPs) (≈59 nm). These disulfide crosslinked PAEU NPs are developed via air oxidation of thiolated PA and thiolated EU, eliminating the need of any external crosslinking agent for dual drug delivery. PAEU NPs can effectively encapsulate both hydrophilic doxorubicin (DOX) and hydrophobic curcumin (Cur) drug with ≈85 % and ≈97 % encapsulation efficiency respectively. Here, the combination of drugs having different anticancer mechanism offers the possibility of developing nanosystem with enhanced anticancer efficacy. The developed PAEU NPs show good colloidal stability and low drug release under physiological conditions, while high DOX (≈98 %) and Cur (≈93 %) release is observed in reducing environment (10 mM GSH). Further, DOX and Cur loaded PAEU NPs exhibit higher cancer cell killing efficiency as compared to individual free drugs. In vivo biodistribution studies with Balb/C mice display the retention of PAEU NPs in the colon region up to 24 h presenting the developed approach as an efficient way for colorectal cancer therapy.

Preparation and evaluation of paclitaxel-loaded reactive oxygen species and glutathione redox-responsive poly(lactic-co-glycolic acid) nanoparticles for controlled release in tumor cells.

Aim: To formulate and assess the anticancer effect of the poly(lactic-co-glycolic acid) (PLGA) copolymer with the thioether groups (diethyl sulfide [Des]) and disulfide bond (cystamine containing disulfide [Cys]), which encapsulated the anticancer drug paclitaxel (PTX) and triggered PTX release in cancer cell H2O2-rich or glutathione-rich surroundings. Methods: PLGA-b-P (Des@Cys) and PLGA-b-P nanoparticles loaded with PTX were prepared and characterized in vitro. The delivery ability of the PLGA-b-P nanoparticles and PLGA-b-P-PTX nanoparticles was assessed on a CT26 (mouse colon cancer cell line) and mouse lung cancer LLC model. Results: The nanoparticles were successfully prepared. Compared with free PTX, the formulated PLGA-b-P nanoparticles loaded with PTX exhibited greater accumulation at the tumor site in the mouse model. Conclusion: PLGA-b-P nanoparticles promote drug accumulation at tumor sites, providing an effective strategy for an intelligent, responsive drug-delivery system.

Macrophage Membrane-Camouflaged Responsive Polymer Nanogels Enable Magnetic Resonance Imaging-Guided Chemotherapy/Chemodynamic Therapy of Orthotopic Glioma.

Development of innovative nanomedicine formulations to traverse the blood-brain barrier (BBB) for effective theranostics of glioma remains a great challenge. Herein, we report the creation of macrophage membrane-camouflaged multifunctional polymer nanogels coloaded with manganese dioxide (MnO2) and cisplatin for magnetic resonance (MR) imaging-guided chemotherapy/chemodynamic therapy (CDT) of orthotopic glioma. Redox-responsive poly(N-vinylcaprolactam) (PVCL) nanogels (NGs) formed via precipitation polymerization were in situ loaded with MnO2 and physically encapsulated with cisplatin to have a mean size of 106.3 nm and coated with macrophage membranes to have a good colloidal stability. The generated hybrid NGs display dual pH- and redox-responsive cisplatin and Mn(II) release profiles and can deplete glutathione (GSH) rich in tumor microenvironment through reaction with disulfide-containing cross-linkers within the NGs and MnO2. The thus created Mn(II) enables enhanced CDT through a Fenton-like reaction and T1-weighted MR imaging, while the loaded cisplatin not only exerts its chemotherapy effect but also promotes the reactive oxygen species generation to enhance the CDT efficacy. Importantly, the macrophage membrane coating rendered the hybrid NGs with prolonged blood circulation time and ability to traverse BBB for specific targeted chemotherapy/CDT of orthotopic glioma. Our study demonstrates a promising self-adaptive and cooperative NG-based nanomedicine platform for highly efficient theranostics of glioma, which may be extended to tackle other difficult cancer types.

Redox-responsive poly(ionic liquid) microgels explored as the building blocks for supramolecular assembly

In this study, poly(ionic liquid) (PIL) microgel functionalized by ferrocene (Fc) was fabricated via a facile one-step cross-linking copolymerization in selective solvent. The results demonstrated that the sizes of PIL microgels could be well-tuned through the feeding ratio of IL monomers to the cross-linker. The presence of Fc groups in PIL microgel was confirmed through ultraviolet–visible (UV–vis), inductively coupled plasma optical emission spectrometer (ICP-OES) and Fourier transform infrared (FT-IR) measurements, as well as cyclic voltammetry (CV) technique. In addition, Fc-anchored PIL microgels were found to be electrochemically active and could respond reversibly to the redox stimulus. As a prototype application, Fc-anchored PIL microgels were explored as the building blocks for the supramolecular self-assembly. Through the host-guest inclusion complexation interaction of Fc group with β-cyclodextrin (β-CD) dimer, PIL microgels could undergo a reversible association and dissociation. Importantly, an enhanced peak current could be achieved when PIL microgel-supported Fc groups were complexed with β-CD dimer. The founding thus pave a way toward fabricating supramolecular systems using nanoparticles as the building blocks, which will find wide applications in smart material, drug delivery and electrochemistry.

Ferrocene containing redox-responsive poly(2-oxazoline)s

A new monomer, 2-ferrocene-ethyl-2-oxazoline, was copolymerized with 2-alkyl-2-oxazolines. The cationic ring opening polymerization (CROP) of 2-oxazolines allows the synthesis of well-defined copolymers with adjustable molar masses as well as end-group control, which was also evident from kinetic studies. The utilization of this new comonomer led to redox-active polymers as proven by UV-VIS-measurements and cyclic-voltammetry.

A versatile reactive oxygen species‐responsive gels sensor for analysis of metabolic species

AbstractWe report a flexible redox responsive polymer‐based sensor for detection of reactive oxygen species (ROS). The sensor comprises multilayers of silver nanoparticles (AgNPs), carbon nanotube/cellulose nanocrystal (CNT/CNC) and a redox responsive poly (glycidyl methacrylate‐co‐ethylene glycol dimethacrylate‐co‐vinyl ferrocene), herewith called poly (GMA‐co‐EGDMA‐co Fc) nanoferrogels. These sensor layers were printed on a micropillared polydimethylsiloxane (PDMS) substrate. The nanoferrogel sensor versatility has been demonstrated in its effective detection of ROS species, specifically H2O2, peroxylipids, and oxidative deriving species such as cholesterol and unsaturated triglycerides. The nanoferrogel ROS sensor rapidly (~1 min) responds to both H2O2 and peroxylipids with a limit of detection (LOD) of ~0.060 ± 0.001 µg/ml) and 0.012 ± 0.001 µg/ml, respectively. The cholesterol oxidase and lipoxygenase‐based nanoferrogel sensor were successfully evaluated for the detection of cholesterol (LOD of 0.12 ± 0.02 µg/ml) and glyceryltrilinoeate (LOD of 1.8 ± 0.2 ng/ml) standards, respectively. These enzyme‐loaded ROS nanoferrogel sensors were also evaluated for quantification of cholesterol and glyceryltrilinoeate in bacon lard and olive oils. The fabricated flexible ROS sensors are versatile for quantitation of oxidative stress biomarkers, useful in myriad applications including clinical, environmental, food, and plant physiology.

Three-Step Synthesis of a Redox-Responsive Blend of PEG-block-PLA and PLA and Application to the Nanoencapsulation of Retinol.

Smart polymeric nanocarriers have been developed to deliver therapeutic agents directly to the intended site of action, with superior efficacy. Herein, a mixture of poly(lactide) (PLA) and redox-responsive poly(ethylene glycol)–block–poly(lactide) (PEG–block–PLA) containing a disulfide bond was synthesized in three steps. The nanoprecipitation method was used to prepare an aqueous suspension of polymeric nanocarriers with a hydrodynamic diameter close to 100 nm. Retinol, an anti-aging agent very common in cosmetics, was loaded into these smart nanocarriers as a model to measure their capacity to encapsulate and to protect a lipophilic active molecule. Retinol was encapsulated with a high efficiency with final loading close to 10% w/w. The stimuli-responsive behavior of these nanocarriers was demonstrated in vitro, in the presence of l-Glutathione, susceptible to break of disulfide bond. The toxicity was low on human keratinocytes in vitro and was mainly related to the active molecule. Those results show that it is not necessary to use 100% of smart copolymer in a nanosystem to obtain a triggered release of their content.

CRGD mediated redox and pH dual responsive poly(amidoamine) dendrimer-poly(ethylene glycol) conjugates for efficiently intracellular antitumor drug delivery

To improve antitumor efficiency of chemotherapy and reduce side effect, according to the physiological characteristics of tumor tissues and tumor intracellular microenvironment, a multifunctional drug delivery system with properties of long circulation, active targeting, redox and pH triggered drug release was established based on the Generation 4 polyamidoamine dendrimer (PAMAM). First, the redox cleavable disulfide bonds (SS) were introduced for linking polyethylene glycol (PEG) with PAMAM to form PAMAM-S-S-PEG (PSSP). Then cRGD peptide was applied to the PEG end of PSSP to construct RGD-PSSP conjugates. Finally, encapsulating the antitumor chemotherapy drug doxorubicin (DOX) into the hydrophobic cavity of RGD-PSSP conjugates constructed the RGD-PSSP/DOX drug delivery system. The in vitro experiments displayed that RGD-PSSP/DOX NPs showed obviously redox and pH dual sensitive drug release profile. MTT and cell uptake observation elucidated cRGD modification could increase the cytotoxicity, and promote the uptake of B16 cells and HUVEC cells both overexpressing integrin ανβ3on cell membrane. Cell uptake mechanism investigation further revealed that RGD-PSSP/DOX interacted with plasma membrane via specific recognition of cRGD peptide with integrin ανβ3, and was subsequently internalized mainly through clathrin- and caveolin-mediated endocytosis. Remarkably, RGD-PSSP/DOX presented superior anticancer activity and lower heart and kidney toxicity in vivo, which could be regarded as a potential candidate for efficient antitumor chemotherapy drug delivery.

Transferrin Conjugated pH- and Redox-Responsive Poly(Amidoamine) Dendrimer Conjugate as an Efficient Drug Delivery Carrier for Cancer Therapy.

IntroductionA multifunctional redox- and pH-responsive polymeric drug delivery system is designed and investigated for targeted anticancer drug delivery to liver cancer.MethodsThe nanocarrier (His-PAMAM-ss-PEG-Tf, HP-ss-PEG-Tf) is constructed based on generation 4 polyamidoamine dendrimer (G4 PAMAM). Optimized amount of histidine (His) residues is grafted on the surface of PAMAM to obtain enhanced pH-sensitivity and proton-buffering capacity. Disulfide bonds (ss) are introduced between PAMAM and PEG to reach accelerated intracellular drug release. Transferrin (Tf) was applied to achieve active tumor targeting. Doxorubicin (DOX) is loaded in the hydrophobic cavity of the nanocarrier to exert its anti-tumor effect.ResultsThe results obtained from in vitro and in vivo evaluation indicate that HP-ss-PEG-Tf/DOX complex has pH and redox dual-sensitive properties, and exhibit higher cellular uptake and cytotoxicity than the other control groups. Flow cytometry and confocal microscopy display internalization of HP-ss-PEG-Tf/DOX via clathrin mediated endocytosis and effective endosomal escape in HepG2 cancer cells. Additionally, cyanine 7 labeled HP-ss-PEG-Tf conjugate could quickly accumulate in the HepG2 tumor. Remarkably, HP-ss-PEG-Tf/DOX present superior anticancer activity, enhanced apoptotic activity and lower heart and kidney toxicity in vivo.DiscussionThus, HP-ss-PEG-Tf is proved to be a promising candidate for effective targeting delivery of DOX into the tumor.

Stimuli-responsive poly(hydroxyethyl methacrylate) hydrogels from carboxylic acid-functionalized crosslinkers.

Tailoring hydrogel properties by modifications of the crosslinker structure is a good method for the design of hydrogels with a wide range of properties. In this study, two novel carboxylic acid-functionalized dimethacrylate crosslinkers (1a and 2a) are synthesized by the reaction of poly(ethylene glycol) or 2-hydroxyethyl disulfide with tert-butyl α-bromomethacrylate followed by cleavage of tert-butyl groups using trifluoroacetic acid. Their copolymerization reactivity with 2-hydroxyethyl methacrylate (HEMA) investigated by photopolymerization studies performed on photo-differential scanning calorimetry shows higher reactivity of 2a compared to 1a. These crosslinkers are then used at different ratios for fabrication of pH- and redox-responsive poly(2-hydroxyethyl methacrylate)-based hydrogels. The swelling behavior of the hydrogels is found to be dependent on the structure of the crosslinker, degree of crosslinking, pH, and CaCl2 concentration. The redox-responsive behavior is demonstrated by degradation of the hydrogel upon exposure to 1,4-dithiothreitol. The dye Rhodamine 6G and the drug resorcinol are used as models to demonstrate the pH and redox dependent release of loaded compounds from the hydrogels. The electrostatic interactions between the carboxylate groups and the positively charged R6G are found to govern the release profile in DTT and counteract the diffusion of dye molecules and significant amount of release (79% in 120 hr) occurs only at highly acidic conditions. The degradation mediated release in DTT is observed better in case of resorcinol (around 88% in 5 hr). Overall, these hydrogels can be regarded as good candidates for several applications, such as matrices for controlled release, tissue repair, and regeneration.

Fluorinated Redox-Responsive Poly(amidoamine) as a Vaccine Delivery System for Antitumor Immunotherapy.

As a potential method for tumor treatment, tumor vaccine immunization induces a tumor-specific cellular immune response via immunization with tumor antigens. The delivery of exogenous antigen proteins into the cytoplasm of antigen-presenting cells is well known to induce an intensive cellular immune response for tumor treatment. In this work, we fluorinated a redox-responsive hyperbranched poly(amidoamine) (HPAA) with heptafluorobutyric anhydride to prepare a fluorinated HPAA (HPAA-F7) for use as a vaccine delivery system for antitumor therapy. The immunization results show that HPAA-F7 as a vaccine carrier could effectively promote the intracellular uptake and cytoplasmatic delivery of antigen proteins and induce potent antitumor cellular immunity. The novel vaccine carrier HPAA-F7 could be further developed for antitumor immunotherapy.

A Versatile Redox Responsive Nanoferrogels Based Sensor for Metabolics Analytics

Developed is an inexpensive label free redox responsive nanoferrogel molecular receptor integrated in a chemoresisistive sensor for rapid detection of Reactive Oxygen Species (ROS) such as H2O2 and H2O2 deriving metabolites, species are of interest in myriad applications including clinical, environmental, food, and plant physiology. Inexpensively fashioned by contact printing of redox responsive poly(N-isopropylacrylamide hydrogels herewith called ‘nanoferrogel’ on a conductive nanocellulose paper aerogel, the sensor is designed for specimen surface attachment as wearables, non-invasive transdermal sensors, and can be configured as microneedle sensor for in vivo analysis. Operating via ROS oxidation of the nanoferrogel trapped in the conductive aerogel film, the oxidized nanoferrogel volume change results in an overall change in conductivity, linearly proportional to ROS/ROS deriving metabolite concentration. In the presentation, the responsivity of the nanoferrogel to different ROS species such as H2O2, oxylipin, antioxidants will be demonstrated. The nanoferrogel based H2O2 sensor figures of merit, featuring, rapid (≤ 1min) H2O2 response, high selectivity, low limits of detection (≤ 0.01 µM),and broad linear dynamic range of (≤ 0.03 µM to ≥ 1.5M) will be highlighted. The nanoferrogel is perfectly recyclable, by electrochemical regeneration, affording ≥ 15 multiple usable cycles. Also showcased will be the adaptability of nanoferrogel for different sensor design configurations (e.g. micro/nanoelectrode systems), with some preliminary data attesting to the sensors utility for fundamental studies and detection of efflux of endogenous and exogenous H2O2 in single cells and other redox biomolecules, (e.g. glucose, choline). Preliminarily the sensor can be used for detection of bacterial (model used in our study Escherichia coli) autoinducers and metabolites, of importance in bacterial communication-quorum sensing. This would be a useful platform for understanding bacterial biofilm formation. Further, the nanoferrogel sensor fashioned for utility as a wearable device for detection of redox potential and inherent sweat metabolites will be demonstrated.

Tumor-Penetrating Peptide-Functionalized Redox-Responsive Hyperbranched Poly(amido amine) Delivering siRNA for Lung Cancer Therapy.

Biosafety and the targeting ability of gene delivery systems are critical aspects for gene therapy of cancer. In this study, we report the synthesis and use of redox-responsive poly(amido amine) (PAA) with good biocompatibility and biodegradation as a gene carrier material. A tumor-specific tissue penetration peptide, internalizing-RGD (iRGD) was then conjugated to PAA with an amidation reaction. In experiments using H1299 cells, PAA-iRGD was found to have a lower cytotoxicity and higher cellular uptake efficiency compared to PAA. An siRNA, specific to epidermal growth factor receptor (EGFR) that is overexpressed on the lung cancer cell surface and often targeted in lung cancer treatment, was designed to silence EGFR (i.e., siEGFR) for delivery by the gene carrier PAA-iRGD. EGFR gene silencing, apoptosis, antiproliferation, and antitumor effects of PAA-iRGD/siEGFR were evaluated in vitro and in vivo. PAA-iRGD/siEGFR displayed a much higher gene silencing ability compared to PAA and polyethylenimine (25 kDa), significantly inhibited the proliferation and migration of H1299 cells, and elicited significant cell apoptosis. Moreover, intravenously injected PAA-iRGD/siEGFR inhibited lung tumor growth in vivo. These results suggest that PAA-iRGD with good biocompatibility, biodegradation, and targeting ability could be a promising gene delivery system for gene therapy of cancers.

Disulfide and β -sheet stabilized poly(amino acid) nanovesicles for intracellular drug delivery

Abstract We report the fabrication of redox-responsive poly(amino acid) vesicles containing bilayers highly stabilized by disulfide cross-links, β-sheets, and hydrophobic interactions. Tailor-made amphiphilic poly(amino acid)s, specifically poly(2-hydroxyethyl aspartamide)-g-oligo( l -cysteine) (P-g-OC), were used as building blocks for the formation of vesicles. The stable bilayer prematurely released hardly any of an encapsulated anticancer drug, doxorubicin, and the drug release was triggered only by millimolar concentrations of reducing agent, which mimic intracellular conditions. The vesicles demonstrated successful delivery of the drug to the inside of cells, triggered release of the drug after cellular uptake, and translocation of the drug to nuclei in cancer cells.

Effect of topology structure on the electrochemical behavior of hydrogen-bonded self-assembled Poly(4-vinylpyridine) -ferrocenyl dendron complexes

In this report, two new redox-responsive complexes with different dendritic tail chain number (P4VP- nFc, n = 1, 2) were prepared via the hydrogen-bonded self-assembly of poly(4-vinylpyridine) and ferrocenyl-modified percec-type dendrons. These complexes exhibited a crystalline phase for P4VP-1Fc and liquid crystalline for P4VP-2Fc at room temperature. The cyclic voltammetry measurement shows that the electrode process of P4VP-nFc (n = 1, 2) films was diffusion controlled and the reversibility of the electrode process for the P4VP-2Fc films became better than that for the P4VP-1Fc. Moreover, the redox peak current |ip| increased with increasing dendritic tail chain number n in the complex, because the complex film formed with 2Fc-COOH has the looser stacking of alkyl chains, which was favorable for the electrolyte diffusion and charge transfer. The present results demonstrate that the electrochemical activity of the redox-responsive poly(4-vinylpyridine) -ferrocenyl dendron complex can be easily tuned using the dendritic tail chain with different numbers. These complexes may be used as new kinds of modified electrodes.