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1.
Bioorg Med Chem Lett ; 107: 129779, 2024 Jul 15.
Article En | MEDLINE | ID: mdl-38729317

Targeted protein degradation is mediated by small molecules that induce or stabilize protein-protein interactions between targets and the ubiquitin-proteasome machinery. Currently, there remains a need to expand the repertoire of viable E3 ligases available for hijacking. Notably, covalent chemistry has been employed to engage a handful of E3 ligases, including DCAF11. Here, we disclose a covalent PROTAC that enables DCAF11-dependent degradation, featuring a cyanoacrylamide warhead. Our findings underscore DCAF11 as an interesting candidate with a capacity to accommodate diverse electrophilic chemistries compatible with targeted protein degradation.


Acrylamides , Humans , Acrylamides/chemistry , Acrylamides/pharmacology , Acrylamides/chemical synthesis , Molecular Structure , Proteolysis/drug effects , Drug Discovery , Ubiquitin-Activating Enzymes/metabolism , Ubiquitin-Activating Enzymes/antagonists & inhibitors , Structure-Activity Relationship
2.
Biosensors (Basel) ; 14(5)2024 Apr 30.
Article En | MEDLINE | ID: mdl-38785696

This work presents a novel approach for tailoring molecularly imprinted polymers (MIPs) with a preliminary stage of atom transfer radical polymerization (ATRP), for a more precise definition of the imprinted cavity. A well-defined copolymer of acrylamide and N,N'-methylenebisacrylamide (PAAm-co-PMBAm) was synthesized by ATRP and applied to gold electrodes with the template, followed by a crosslinking reaction. The template was removed from the polymer matrix by enzymatic/chemical action. The surface modifications were monitored via electrochemical impedance spectroscopy (EIS), having the MIP polymer as a non-conducting film designed with affinity sites for CA15-3. The resulting biosensor exhibited a linear response to CA15-3 log concentrations from 0.001 to 100 U/mL in PBS or in diluted fetal bovine serum (1000×) in PBS. Compared to the polyacrylamide (PAAm) MIP from conventional free-radical polymerization, the ATRP-based MIP extended the biosensor's dynamic linear range 10-fold, improving low concentration detection, and enhanced the signal reproducibility across units. The biosensor demonstrated good sensitivity and selectivity. Overall, the work described confirmed that the process of radical polymerization to build an MIP material influences the detection capacity for the target substance and the reproducibility among different biosensor units. Extending this approach to other cancer biomarkers, the methodology presented could open doors to a new generation of MIP-based biosensors for point-of-care disease diagnosis.


Biosensing Techniques , Molecularly Imprinted Polymers , Polymerization , Molecularly Imprinted Polymers/chemistry , Molecular Imprinting , Humans , Dielectric Spectroscopy , Polymers/chemistry , Acrylamides/chemistry , Reproducibility of Results , Gold/chemistry , Acrylic Resins/chemistry
3.
J Med Chem ; 67(10): 8099-8121, 2024 May 23.
Article En | MEDLINE | ID: mdl-38722799

Nicotinamide phosphoribosyltransferase (NAMPT) is an attractive therapeutic target for treating select cancers. There are two forms of NAMPT: intracellular NAMPT (iNAMPT, the rate-limiting enzyme in the mammalian NAD+ main synthetic pathway) and extracellular NAMPT (eNAMPT, a cytokine with protumorigenic function). Reported NAMPT inhibitors only inhibit iNAMPT and show potent activities in preclinical studies. Unfortunately, they failed to show efficacy due to futility and toxicity. We developed a series of FK866-based NAMPT-targeting PROTACs and identified LYP-8 as a potent and effective NAMPT degrader that simultaneously diminished iNAMPT and eNAMPT. Importantly, LYP-8 demonstrated superior efficacy and safety in mice when compared to the clinical candidate, FK866. This study highlights the importance and feasibility of applying PROTACs as a superior strategy for interfering with both the enzymatic function of NAMPT (iNAMPT) and nonenzymatic function of NAMPT (eNAMPT), which is difficult to achieve with conventional NAMPT inhibitors.


Acrylamides , Drug Design , Nicotinamide Phosphoribosyltransferase , Piperidines , Nicotinamide Phosphoribosyltransferase/antagonists & inhibitors , Nicotinamide Phosphoribosyltransferase/metabolism , Acrylamides/pharmacology , Acrylamides/chemistry , Acrylamides/chemical synthesis , Animals , Humans , Piperidines/pharmacology , Piperidines/chemistry , Mice , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/chemistry , Cytokines/metabolism , Cell Line, Tumor , Structure-Activity Relationship , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry
4.
Bioorg Chem ; 147: 107394, 2024 Jun.
Article En | MEDLINE | ID: mdl-38691906

Epidermal growth factor receptor (EGFR) is one of the most studied drug targets for treating non-small-cell lung cancer (NSCLC). However, there are no approved inhibitors for the C797S resistance mutation caused by the third-generation EGFR inhibitor (Osimertinib). Therefore, the development of fourth-generation EGFR inhibitors is urgent. In this study, we clarified the structure-activity relationship of several synthesized compounds as fourth-generation inhibitors against human triple (Del19/T790M/C797S) mutation. Representative compound 52 showed potent inhibitory activity against EGFRL858R/T790M/C797S with an IC50 of 0.55 nM and significantly inhibited the proliferation of the Ba/F3 cell line harboring EGFRL858R/T790M/C797S with an IC50 of 43.28 nM. Moreover, 52 demonstrated good pharmacokinetic properties and excellent in vivo efficacy. Overall, the compound 52 can be considered a promising candidate for overcoming EGFR C797S-mediated mutations.


Acrylamides , Aniline Compounds , Antineoplastic Agents , Carcinoma, Non-Small-Cell Lung , Cell Proliferation , Dose-Response Relationship, Drug , Drug Design , Drug Resistance, Neoplasm , Drug Screening Assays, Antitumor , ErbB Receptors , Lung Neoplasms , Protein Kinase Inhibitors , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/metabolism , ErbB Receptors/genetics , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/pathology , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Acrylamides/pharmacology , Acrylamides/chemistry , Acrylamides/chemical synthesis , Structure-Activity Relationship , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/chemical synthesis , Aniline Compounds/pharmacology , Aniline Compounds/chemistry , Aniline Compounds/chemical synthesis , Aniline Compounds/therapeutic use , Cell Proliferation/drug effects , Drug Resistance, Neoplasm/drug effects , Molecular Structure , Animals , Mice , Cell Line, Tumor , Mutation , Indoles , Pyrimidines
5.
ACS Sens ; 9(4): 1735-1742, 2024 Apr 26.
Article En | MEDLINE | ID: mdl-38572917

Carbon dioxide (CO2) gas sensing and monitoring have gained prominence for applications such as smart food packaging, environmental monitoring of greenhouse gases, and medical diagnostic tests. Although CO2 sensors based on metal oxide semiconductors are readily available, they often suffer from limitations such as high operating temperatures (>250 °C), limited response at elevated humidity levels (>60% RH), bulkiness, and limited selectivity. In this study, we designed a chemiresistive sensor for CO2 detection to overcome these problems. The sensing material of this sensor consists of a CO2 switchable polymer based on N-3-(dimethylamino)propyl methacrylamide (DMAPMAm) and methoxyethyl methacrylate (MEMA) [P(D-co-M)], and diethylamine. The designed sensor has a detection range for CO2 between 103 and 106 ppm even at high humidity levels (>80% RH), and it is capable of differentiating ammonia at low concentrations (0.1-5 ppm) from CO2. The addition of diethylamine improved sensor performance such as selectivity, response/recovery time, and long-term stability. These data demonstrate the potential of using this sensor for the detection of food spoilage.


Carbon Dioxide , Carbon Dioxide/analysis , Humidity , Acrylamides/chemistry , Polymers/chemistry , Methacrylates/chemistry , Gases/analysis
6.
J Chromatogr A ; 1722: 464864, 2024 May 10.
Article En | MEDLINE | ID: mdl-38598890

In this study, a novel piperidinium-sulfonate based zwitterionic hydrophilic monolith was prepared through thermally initiated co-polymerization of a piperidinium-sulfonate monomer 3-(4-((methacryloyloxy)methyl)-1-methylpiperidin-1-ium-1-yl)propane-1-sulfonate (MAMMPS), and a hydrophilic crosslinker N,N'-methylenebisacrylamide (MBA) using n-propanol and H2O as porogenic system. Satisfactory mechanical and chemical stabilities, good repeatability and high column efficiency (120,000 N/m) were obtained on the optimal monolith. The resulting poly(MAMMPS-co-MBA) monolith showed a typical HILIC retention behavior over an ACN content range between 5 and 95 %. Furthermore, this column exhibited good separation performance for various polar compounds. Compared to quaternary ammonium-sulfonate based zwitterionic hydrophilic monolith, i.e. poly(N,N-dimethyl-N-methacryloxyethyl-N-(3-sulfopropyl)ammonium betaine-co-MBA), the poly(MAMMPS-co-MBA) monolith displayed stronger retention and better selectivity for the tested phenolic and amine compounds at different pH conditions. Finally, this column was applied for the separation of six sulfonamide antibiotics, and the analytical characteristics of the method were evaluated in terms of precision, repeatability, limits of detection (LOD) and quantitation (LOQ). Overall, this study not only developed a novel HILIC monolithic column, but also proved the potential of piperidinium-sulfonate based zwitterionic chemistry as stationary phase, which further increased the structure diversity of zwitterionic HILIC stationary phases.


Hydrophobic and Hydrophilic Interactions , Piperidines , Piperidines/isolation & purification , Piperidines/chemistry , Reproducibility of Results , Sulfonic Acids/chemistry , Chromatography, High Pressure Liquid/methods , Chromatography, Liquid/methods , Acrylamides/chemistry , Polymerization , Acetonitriles/chemistry
7.
Colloids Surf B Biointerfaces ; 238: 113881, 2024 Jun.
Article En | MEDLINE | ID: mdl-38608460

Hydrogels as wound dressing have attracted extensive attention in past decade because they can provide moist microenvironment to promote wound healing. Herein, this research designed a multifunctional hydrogel with antibacterial property and antioxidant activity fabricated from quaternary ammonium bearing light emitting quaternized TPE-P(DAA-co-DMAPMA) (QTPDD) and poly(aspartic hydrazide) (PAH). The protocatechuic aldehyde (PCA) grafted to the hydrogel through dynamic bond endowed the hydrogel with antioxidant activity and the tranexamic acid (TXA) was loaded to enhance the hemostatic performance. The hydrogel possesses preferable gelation time for injectable application, good antioxidant property and tissue adhesion, improved hemostatic performance fit for wound repairing. Furthermore, the hydrogel has excellent antimicrobial property to both E. coli and S. aureus based on quaternary ammonium structure. The hydrogel also showed good biocompatibility and the in vivo experiments proved this hydrogel can promote the wound repairing rate. This study suggests that TXA/hydrogel with quaternary ammonium structure and dynamic grafted PCA have great potential in wound healing applications.


Anti-Bacterial Agents , Antioxidants , Escherichia coli , Hydrogels , Staphylococcus aureus , Wound Healing , Wound Healing/drug effects , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Hydrogels/chemistry , Hydrogels/pharmacology , Antioxidants/pharmacology , Antioxidants/chemistry , Staphylococcus aureus/drug effects , Escherichia coli/drug effects , Animals , Hemostatics/chemistry , Hemostatics/pharmacology , Mice , Microbial Sensitivity Tests , Polymers/chemistry , Polymers/pharmacology , Acrylamides/chemistry , Acrylamides/pharmacology , Peptides/pharmacology , Peptides/chemistry
8.
J Med Chem ; 67(9): 7283-7300, 2024 May 09.
Article En | MEDLINE | ID: mdl-38676656

The epidermal growth factor receptor (EGFR) tertiary C797S mutation is an important cause of resistance to Osimertinib, which seriously hinders the clinical application of Osimertinib. Developing proteolysis-targeting chimeras (PROTACs) targeting EGFR mutants can offer a promising strategy to overcome drug resistance. In this study, some novel PROTACs targeting C797S mutation were designed and synthesized based on a new EGFR inhibitor and displayed a potent degradation effect in H1975-TM cells harboring EGFRL858R/T790M/C797S. The representative compound C6 exhibited a DC50 of 10.2 nM against EGFRL858R/T790M/C797S and an IC50 of 10.3 nM against H1975-TM. Furthermore, C6 also showed potent degradation activity against various main EGFR mutants, including EGFRDel19/T790M/C797S. Mechanistic studies revealed that the protein degradation was achieved through the ubiquitin-proteasome system. Finally, C6 inhibited tumor growth in the H1975-TM xenograft tumor model effectively and safely. This study identifies a novel and potent EGFR PROTAC to overcome Osimertinib resistance mediated by C797S mutation.


Antineoplastic Agents , Drug Design , ErbB Receptors , Mutation , Protein Kinase Inhibitors , Proteolysis , ErbB Receptors/metabolism , ErbB Receptors/genetics , ErbB Receptors/antagonists & inhibitors , Humans , Animals , Proteolysis/drug effects , Cell Line, Tumor , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Mice , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Mice, Nude , Acrylamides/pharmacology , Acrylamides/chemical synthesis , Acrylamides/chemistry , Drug Resistance, Neoplasm/drug effects , Xenograft Model Antitumor Assays , Cell Proliferation/drug effects , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Lung Neoplasms/metabolism , Lung Neoplasms/genetics , Aniline Compounds/pharmacology , Aniline Compounds/chemical synthesis , Aniline Compounds/chemistry , Mice, Inbred BALB C , Structure-Activity Relationship , Proteolysis Targeting Chimera , Indoles , Pyrimidines
9.
Int J Biol Macromol ; 268(Pt 1): 131617, 2024 May.
Article En | MEDLINE | ID: mdl-38631583

Hydrogels are a promising option for detecting food spoilage in humid conditions, but current indicators are prone to mechanical flaws, posing a concern for packaging systems that require strong mechanical properties. Herein, a double network hydrogel was prepared by polymerizing methacrylamide in a chitosan system with aluminum chloride and glycerol. The resulting hydrogel demonstrated high stretchability (strain >1500 %), notch insensitivity, excellent fatigue resistance, and exceptional anti-freezing capabilities even at -21 °C. When incorporating bromothymol blue (BB) or methyl red (MR), or mixtures of these dyes into the hydrogels as indicators, they exhibited sensitive colorimetric responses to pH and NH3 levels at different temperatures. Hydrogels immobilizing BB to MR ratios of 1:1 and 1:2 displayed clearer and more sensitive color responses when packed into chicken breast, with a sensitivity level of 1.5 ppm of total volatile basic nitrogen (TVB-N). This color response correlated positively with the accumulation of TVB-N on the packaging during storage at both 25 °C and 4 °C, providing sensitive indications of chicken breast deterioration. Overall, the developed hydrogels and indicators demonstrate enhanced performance characteristics, including excellent mechanical strength and highly NH3-sensitive color responses, making significant contributions to the food spoilage detection and intelligent packaging systems field.


Acrylamides , Ammonia , Chickens , Chitosan , Hydrogels , Hydrogels/chemistry , Animals , Ammonia/chemistry , Chitosan/chemistry , Acrylamides/chemistry , Food Packaging/methods , Freezing
10.
Int J Biol Macromol ; 268(Pt 1): 131652, 2024 May.
Article En | MEDLINE | ID: mdl-38649075

Vinylsulfonic acid (VSA), acrylamide (AM) and N, N methylene bis acrylamide(MBA) were copolymerized by radical polymerization in the presence of gum ghatti (GG) and treated water hyacianth (WH) in water. Several composite copolymers were prepared by varying the i) AM: VSA molar ratios ii) wt% of GG and iii) wt% of treated WH based on a Box-Behnken Design(BBD) of a response surface methodology (RSM) model with three input variables and the batch adsorption capacity (mg/g) of 100 mg/L Cd (II) from water as response. The composite polymer was characterized by Fourier transform Infrared spectroscopy (FTIR), X-ray diffraction (XRD), thermogravimetric analysis(TGA), X- ray photo electron spectroscopy (XPS), compressive strength, pH reversibility, pH at point zero charge (pHPZC), Brunauer-Emmett-Teller (BET) surface area and scanning electron microscopy (SEM). The network parameters of the composites were determined. The copolymer composite prepared with AM: VSA of 5:1 containing 10 wt% GG and 4 wt% treated WH showed an optimum batch adsorption capacity of 399.15 mg/g Cd (II) from water containing 100 mg/L Cd (II). The same composite showed an adsorption capacity of 170.1 mg/g and a removal% of 31.5 at a feed concentration/feed flow rate/bed height of 150 mgL-1/30mLmin-1/30 mm in a fixed bed column.


Cellulose , Plant Gums , Adsorption , Plant Gums/chemistry , Cellulose/chemistry , Cellulose/analogs & derivatives , Sulfonic Acids/chemistry , Water Purification/methods , Water/chemistry , Hydrogen-Ion Concentration , Acrylamide/chemistry , Water Pollutants, Chemical/chemistry , Water Pollutants, Chemical/isolation & purification , Polymerization , X-Ray Diffraction , Acrylamides/chemistry , Acrylic Resins/chemistry , Spectroscopy, Fourier Transform Infrared , Cadmium/chemistry , Polyvinyls/chemistry
11.
Int J Biol Macromol ; 268(Pt 2): 131735, 2024 May.
Article En | MEDLINE | ID: mdl-38653424

The CMC-PNIPAM hydrogel with semi-interpenetrating structure and temperature-sensitivity was prepared by in-situ polymerization of N-isopropylacrylamide (NIPAM) in sodium carboxymethylcellulose (CMC) solution at room temperature. The mass ratio of CMC to NIPAM was a key factor influencing the network structure and property of CMC-PNIPAM hydrogel. The low critical phase transition temperature (LCST) of CMC-PNIPAM hydrogels increased from 34.4 °C to 35.8 °C with the mass ratio of CMC to NIPAM rising from 0 to 1.2. The maximum compressive stress of CMC-PNIPAM hydrogel reached to 26.7 kPa and the relaxation elasticity was 52 % at strain of 60 %. The viscoelasticity of CMC-PNIPAM hydrogel was consistent with the generalized Maxwell model. The maximum swelling ratio in deionized water was 170.25 g·g-1 (dried hydrogel) with swelling rate of 2.57 g·g-1·min-1 at 25 °C. CMC-PNIPAM hydrogel hardly absorbed water above LCST, but the swollen hydrogel could release water at the rate of 0.36 g·g-1·min-1 once exceeding LCST. The test of water retention showed that soil mixed with 2 wt% dried CMC-PNIPAM hydrogel could retain 13.08 wt% water after 30 days at 25 °C that was 4.4 times than that of controlled soil without CMC-PNIPAM hydrogel. The semi-interpenetrating CMC-PNIPAM hydrogel showed a potential to conserve water responding to temperature.


Acrylic Resins , Carboxymethylcellulose Sodium , Hydrogels , Temperature , Water , Acrylic Resins/chemistry , Water/chemistry , Hydrogels/chemistry , Carboxymethylcellulose Sodium/chemistry , Phase Transition , Viscosity , Acrylamides/chemistry
12.
Macromol Rapid Commun ; 45(8): e2300643, 2024 Apr.
Article En | MEDLINE | ID: mdl-38225681

Smart hydrogels responsive to external stimuli are promising for various applications such as soft robotics and smart devices. High mechanical strength and fast response rate are particularly important for the construction of hydrogel actuators. Herein, tough hydrogels with rapid response rates are synthesized using vinyl-functionalized poly(N-isopropylacrylamide) (PNIPAM) microgels as macro-crosslinkers and N-isopropylacrylamide as monomers. The compression strength of the obtained PNIPAM hydrogels is up to 7.13 MPa. The response rate of the microgel-crosslinked hydrogels is significantly enhanced compared with conventional chemically crosslinked PNIPAM hydrogels. The mechanical strength and response rate of hydrogels can be adjusted by varying the proportion of monomers and crosslinkers. The lower critical solution temperature (LCST) of the PNIPAM hydrogels could be tuned by copolymerizing with ionic monomer sodium methacrylate. Thermo-responsive bilayer hydrogels are fabricated using PINPAM hydrogels with different LCSTs via a layer-by-layer method. The thermo-responsive fast swelling and shrinking properties of the two layers endow the bilayer hydrogel with anisotropic structures and asymmetric response characteristics, allowing the hydrogel to respond rapidly. The bilayer hydrogels are fabricated into clamps to grab small objects and flowers that mimicked the closure of petals, and it shows great application prospects in the field of actuators.


Acrylic Resins , Hydrogels , Temperature , Hydrogels/chemistry , Hydrogels/chemical synthesis , Acrylic Resins/chemistry , Microgels/chemistry , Cross-Linking Reagents/chemistry , Acrylamides/chemistry
13.
J Phys Chem Lett ; 15(3): 773-781, 2024 Jan 25.
Article En | MEDLINE | ID: mdl-38227953

The "lock-and-key" model that emphasizes the concept of chemical-structural complementary is the key mechanism for explaining the selectivity between small ligands and a larger adsorbent molecule. In this work, concerning the copolymer chain using only the combination of N-isopropylacrylamide (NIPAm) and hydrophobic N-tert-butylacrylamide (TBAm) monomers and by large-scale atomistic molecular dynamics simulations, our results show that the flexible copolymer chain may exhibit strong binding affinity for the biomarker protein epithelial cell adhesion molecule, in the absence of hydrophobic matching and strong structural complementarity. This surprising binding behavior, which cannot be anticipated by the "lock-and-key" model, can be attributed to the preferential interactions established by the copolymer with the protein's hydrophilic exterior. We observe that increasing the fraction of incorporated TBAm monomers leads to a prevalence of interactions with asparagine and glutamine amino acids due to the emerging hydrogen bonding with both NIPAm and TBAm monomers. Our findings suggest the appearance of highly specific and high-affinity binding sites on the protein created by engineering the copolymer composition, which motivates the applications of copolymers as protein affinity reagents.


Acrylamides , Polymers , Acrylamides/chemistry , Polymers/chemistry
14.
Int J Biol Macromol ; 260(Pt 2): 129546, 2024 Mar.
Article En | MEDLINE | ID: mdl-38246461

Present investigation deals with the synthesis of psyllium based copolymeric hydrogels and evaluation of their physiochemical and biomedical properties. These copolymers have been prepared by grafting of poly(vinyl phosphonic acid) (poly (VPA)) and poly(acrylamide) (poly(AAm)) onto psyllium in the presence of crosslinker N,N-methylene bis acrylamide (NNMBA). These copolymers [psyllium-poly(VPA-co-AAm)-cl-NNMBA] were characterized by field emission-scanning electron micrographs (FE-SEM), electron dispersion X-ray analysis (EDAX), Atomic force microscopy (AFM), Fourier transform infrared spectroscopy (FTIR), 13C-nuclear magnetic resonance (NMR), X-ray diffraction (XRD), and thermogravimetric analysis (TGA)- differential thermal analysis (DTG). FESEM, AFM and XRD demonstrated heterogeneous morphology with a rough surface and an amorphous nature. Diffusion of ornidazole occurred with a non-Fickian diffusion mechanism, and the release profile data was fitted in the Korsemeyer-Peppas kinetic model. Biochemical analysis of hydrogel properties confirmed the blood-compatible nature during blood-polymer interactions and revealed haemolysis value 3.95 ± 0.05 %. The hydrogels exhibited mucoadhesive character during biomembrane-polymer interactions and demonstrated detachment force = 99.0 ± 0.016 mN. During 2,2-diphenyl-1-picrylhydrazyl reagent (DPPH) assay, free radical scavenging was observed 37.83 ± 3.64 % which illustrated antioxidant properties of hydrogels. Physiological and biomedical properties revealed that these hydrogels could be explored for drug delivery uses.


Acrylamide , Phosphorous Acids , Psyllium , Acrylamide/chemistry , Psyllium/chemistry , Hydrogels/chemistry , Acrylamides/chemistry , Polymers/chemistry , Spectroscopy, Fourier Transform Infrared/methods , Hydrogen-Ion Concentration
15.
Small ; 20(22): e2308775, 2024 May.
Article En | MEDLINE | ID: mdl-38126895

RNA interference (RNAi) is an efficient strategy to post-transcriptionally silence gene expression. While all siRNA drugs on the market target the liver, the lung offers a variety of currently undruggable targets, which can potentially be treated with RNA therapeutics. To achieve this goal, the synthesis of poly(spermine acrylamides) (P(SpAA) is reported herein. Polymers are prepared via polymerization of N-acryloxysuccinimide (NAS) and afterward this active ester is converted into spermine-based pendant groups. Copolymerizations with decylacrylamide are employed to increase the hydrophobicity of the polymers. After deprotection, polymers show excellent siRNA encapsulation to obtain perfectly sized polyplexes at very low polymer/RNA ratios. In vitro 2D and 3D cell culture, ex vivo and in vivo experiments reveal superior properties of amphiphilic spermine-copolymers with respect to delivery of siRNA to lung cells in comparison to commonly used lipid-based transfection agents. In line with the in vitro results, siRNA delivery to human lung explants confirm more efficient gene silencing of protease-activated receptor 2 (PAR2), a G protein-coupled receptor involved in fibrosis. This study reveals the importance of the balance between efficient polyplex formation, cellular uptake, gene knockdown, and toxicity for efficient siRNA delivery in vitro, in vivo, and in fibrotic human lung tissue ex vivo.


Pulmonary Fibrosis , RNA, Small Interfering , Spermine , Spermine/chemistry , Spermine/pharmacology , Humans , Pulmonary Fibrosis/drug therapy , Pulmonary Fibrosis/pathology , Pulmonary Fibrosis/therapy , Animals , Lung/pathology , Lung/metabolism , Polymers/chemistry , Acrylamides/chemistry
16.
J Colloid Interface Sci ; 650(Pt B): 1881-1892, 2023 Nov 15.
Article En | MEDLINE | ID: mdl-37517188

Schizophrenic copolymers are one type of the popular smart polymers that show invertible colloidal structures in response to temperature stimulus. However, the lack of principles to predict the phase transition temperature of a schizophrenic copolymer from its corresponding parent thermo-responsive polymers limits their development. Additionally, studies on their applications remain scarce. Herein, a series of schizophrenic copolymers were synthesized by polymerization of a RAFT-made polymer precursor poly(acrylamide-co-N-acryloxysuccinimide-co-acrylic acid) (P(AAm-co-NAS-co-AAc)) with the mixture of N-isopropylmethacrylamide (NIPAm) and acrylamide (AAm) in varying molar ratios. In aqueous solution, the block P(AAm-co-NAS-co-AAc) and the block poly(NIPAm-co-AAm) exhibited upper and lower critical solution temperature (UCST and LCST) behavior, respectively. The schizophrenic copolymers featured either UCST-LCST, LCST-UCST, or only LCST thermo-responsive transition. A preliminary correlation of phase transition between the schizophrenic copolymers and their parent polymers was summarized. Furthermore, the co-assembly of the schizophrenic copolymers and proteins were conducted and the kinetics of protein loading and protein activity were investigated, which showed that the schizophrenic copolymers were efficient platforms for protein co-assembly with ultra-high protein loading while preserving the protein bioactivities. Additionally, all the materials were non-toxic towards NIH 3T3 and MCF-7 cells. This work offers the prospects of the schizophrenic polymers in soft colloidal and assembly systems, particularly in guiding the design of new materials and their use in biomedical applications.


Polymers , Schizophrenia , Humans , Polymers/chemistry , Proteins , Water , Temperature , Acrylamides/chemistry
17.
Int J Biol Macromol ; 229: 443-451, 2023 Feb 28.
Article En | MEDLINE | ID: mdl-36599382

A novel mussel-inspired adhesive hydrogel with enhanced adhesion based on methacrylated catechol-chitosan (MCCS) and dopamine methacrylate (DMA) was prepared via photopolymerization. The structure and morphology of the MCCS/DMA adhesive hydrogel were investigated by using FTIR, NMR, XRD, TG, and SEM. The rheological and texture properties, swelling and degradation characteristics, as well as the adhesion mechanism of the hydrogels were also examined. These results revealed that the MCCS/DMA hydrogels have a dense double cross-linking network structure with porous internal microstructures, and exhibited controllable swelling and degradation properties, good thermostability, and stable rheological characteristics. Furthermore, the adhesive mechanism of MCCS/DMA hydrogel has been confirmed by the FTIR and 2D correlation FTIR spectroscopy. Additionally, the results of in vitro cytotoxicity assessment indicated that the resulting hydrogels have good cytocompatibility. Overall, the MCCS/DMA adhesive hydrogel may have potential applications in medical bioadhesives.


Chitosan , Hydrogels , Hydrogels/chemistry , Chitosan/chemistry , Dopamine/chemistry , Acrylamides/chemistry , Adhesives/chemistry
18.
Carbohydr Polym ; 302: 120377, 2023 Feb 15.
Article En | MEDLINE | ID: mdl-36604055

In this study, a composite hydrogel with a low swelling ratio, excellent mechanical properties, and good U (VI) adsorption capacity was developed by incorporating a metal-organic framework (MOF) with a poly (acrylamide-co-acrylic acid)/chitosan (P(AM-co-AA)/CS) composite. The CS chain, which contains NH2, reduces the swelling ratio of the hydrogel to 4.17 after 5 h of immersion in water. The coordinate bond between the MOF and carboxyl group on the surface of P(AM-co-AA)/CS improves the mechanical properties and stability of P(AM-co-AA)/CS. The U(VI) adsorption capacity of P(AM-co-AA)/CS/MOF-808 is 159.56 mg g-1 at C0 = 99.47 mg L-1 and pH = 8.0. The adsorption process is well fitted by the Langmuir isotherm and pseudo-second-order model. The P(AM-co-AA)/CS/MOF-808 also exhibits good repeatability and stability after five adsorption-desorption cycles. The uranium adsorption capacity of the developed adsorbent after one month in natural seawater is 6.2 mg g-1, and the rate of uranium adsorption on the hydrogel is 0.21 mg g-1 day-1.


Chitosan , Metal-Organic Frameworks , Uranium , Uranium/chemistry , Chitosan/chemistry , Hydrogels/chemistry , Hydrogen-Ion Concentration , Kinetics , Seawater/chemistry , Acrylamides/chemistry , Adsorption
19.
Int J Biol Macromol ; 227: 241-251, 2023 Feb 01.
Article En | MEDLINE | ID: mdl-36539172

In this paper, a kind of superabsorbent resin (SAR) with superior quality for hygiene products was developed using Fructus Aurantii Immaturus pectin (FAIP) from Citrus aurantium L.. FAIP-g-AM/AMPS SAR was established by free radical graft co-polymerization with FAIP as skeleton structure, N, N'-Methylene-bis (acrylamide) (MBA) as the cross-linker. Meanwhile, the functional monomers of acrylamide (AM) and 2-acrylamido-2-methylpropane sulfonic acid (AMPS) were introduced. The structure and morphology of FAIP-g-AM/AMPS were characterized by FTIR, 13C NMR, XRD, SEM and TG-DSC analysis. The results confirmed that the AFIP-g-AM/AMPS SAR was successfully prepared, which exhibited a three-dimensional (3D) network structure and an excellent thermal stability. The absorption and retention capacity of FAIP-g-AM/AMPS was comparable to or even better than commercial diapers and sanitary napkins. Significantly, FAIP-g-AM/AMPS itself exhibited excellent antibacterial and safety. FAIP-g-AM/AMPS has an inhibition ratio of 97.1 % for Escherichia coli (E. coli) and 98.5 % for Staphylococcus aureus (S. aureus), and was non-irritating and non-allergic to the skin. In addition, FAIP-g-AM/AMPS presented amazing biodegradability and a weight loss reached 37.1 % after 30 days by soil burial test. The research provides a safe and high-performance SAR, which expected to be used in hygiene products such as baby diapers, adult incontinence pads and sanitary napkins.


Pectins , Staphylococcus aureus , Pectins/pharmacology , Escherichia coli , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Acrylamides/chemistry , Sodium Chloride , Acrylamide
20.
Adv Mater ; 35(10): e2209812, 2023 Mar.
Article En | MEDLINE | ID: mdl-36585849

While a majority of wireless microrobots have shown multi-responsiveness to implement complex biomedical functions, their functional executions are strongly dependent on the range of stimulus inputs, which curtails their functional diversity. Furthermore, their responsive functions are coupled to each other, which results in the overlap of the task operations. Here, a 3D-printed multifunctional microrobot inspired by pollen grains with three hydrogel components is demonstrated: iron platinum (FePt) nanoparticle-embedded pentaerythritol triacrylate (PETA), poly N-isopropylacrylamide (pNIPAM), and poly N-isopropylacrylamide acrylic acid (pNIPAM-AAc) structures. Each of these structures exhibits their respective targeted functions: responding to magnetic fields for torque-driven surface rolling and steering, exhibiting temperature responsiveness for on-demand surface attachment (anchoring), and pH-responsive cargo release. The versatile multifunctional pollen grain-inspired robots conceptualized here pave the way for various future medical microrobots to improve their projected performance and functional diversity.


Acrylamides , Hydrogels , Hydrogels/chemistry , Acrylamides/chemistry , Iron , Printing, Three-Dimensional
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