Polyethylene Glycol Derivatives Research Articles

Click Chemistry-Enabled Conjugation Strategy for Producing Dibenzodiazepinone-Type Fluorescent Probes To Target M2 Acetylcholine Receptors.

The development of fluorescently labeled receptor-targeting compounds represents a powerful pharmacological tool to study and characterize ligand-receptor interactions. Despite significant advances in developing sub-type-specific antagonists for muscarinic acetylcholine receptors (mAChRs), reports on antagonists feasible for click chemistry are less common. Here, we designed and synthesized an antagonist suitable for probe attachment through click chemistry, namely, dibenzodiazepinone (DIBA)-alkyne, based on a previously reported DIBA scaffold with a high binding affinity to type-2 mAChR (M2R). To demonstrate the versatility of DIBA-alkyne as a building block for bioconjugates, we assembled DIBA-alkyne with Cyanine5 fluorophores (Cy5) and polyethylene glycol (PEG) biomolecules to obtain fluorescent DIBA antagonist (DIBA-Cy5) and fluorescent DIBA PEG derivatives. Flow cytometric analysis showed that DIBA-Cy5 possessed a high binding affinity to M2R (Kd = 1.80 nM), a two-order magnitude higher binding affinity than M1R. Fluorescent DIBA PEG derivatives maintained a potent binding to the M2R (Kd ≤ 4 nM), confirmed by confocal microscopic imaging. Additionally, DIBA-Cy5 can serve as a fluorescent ligand in the receptor-ligand competitive binding assay for other mAChR ligands, an attractive alternative to the traditional radioligand-based assay. The competitive binding mode between DIBA-Cy5 and orthosteric antagonist atropine/allosteric modulator LY2119620 indicated a dualsteric binding mode of the DIBA-type antagonist to M2R. Lastly, we demonstrated the direct staining of DIBA-Cy5 to M2R receptors in the sinoatrial node of a mouse heart. The adaptability of the clickable DIBA antagonist to a wide range of fluorophores and biomolecules can facilitate its use in various biomedical applications such as binding assays that screen compounds for M2R as the receptor target.

Inhibition of Mitochondrial Biosynthesis Using a "Right-Side-Out" Membrane-Camouflaged Micelle to Facilitate the Therapeutic Effects of Shikonin on Triple-Negative Breast Cancer.

The mitochondria represent a potential target for the treatment of triple-negative breast cancer (TNBC) and shikonin (SK) has shown remarkable therapeutic effects on TNBC. Herein, it is found that SK possesses potent inhibitory effects on mitochondrial biogenesis via targeting polymerase gamma (POLG). However, its application is restricted by its poor aqueous solubility and stability, and therefore, a biomimetic micelle to aid with tumor lesion accumulation and mitochondria-targeted delivery of SK is designed. A folic acid (FA) conjugated polyethylene glycol derivative (FA-PEG-FA) is inserted onto the external membranes of red blood cells (FP-RBCm) to prepare a "right-side-out" RBCm-camouflaged cationic micelle (ThTM/SK@FP-RBCm). Both FP-RBCm coating and a triphenylphosphine (TPP) moiety on the periphery of micelles contribute to tumor lesion distribution, receptor-mediated cellular uptake, and electrostatic attraction-dependent mitochondrial targeting, thereby maximizing inhibitory effects on mitochondrial biosynthesis in TNBC cells. Intravenous administration of ThTM/SK@FP-RBCm leads to profound inhibition of tumor growth and lung metastasis in a TNBC mouse model with no obvious toxicity. This work highlights the mitochondria-targeted delivery of SK using a "right-side-out" membrane-camouflaged micelle for the inhibition of mitochondrial biogenesis and enhanced therapeutic effects on TNBC.

Dependence of Quantum Dot Toxicity In Vitro on Their Size, Chemical Composition, and Surface Charge.

Semiconductor nanocrystals known as quantum dots (QDs) are of great interest for researchers and have potential use in various applications in biomedicine, such as in vitro diagnostics, molecular tracking, in vivo imaging, and drug delivery. Systematic analysis of potential hazardous effects of QDs is necessary to ensure their safe use. In this study, we obtained water-soluble core/shell QDs differing in size, surface charge, and chemical composition of the core. All the synthesized QDs were modified with polyethylene glycol derivatives to obtain outer organic shells protecting them from degradation. The physical and chemical parameters were fully characterized. In vitro cytotoxicity of the QDs was estimated in both normal and tumor cell lines. We demonstrated that QDs with the smallest size had the highest in vitro cytotoxicity. The most toxic QDs were characterized by a low negative surface charge, while positively charged QDs were less cytotoxic, and QDs with a greater negative charge were the least toxic. In contrast, the chemical composition of the QD core did not noticeably affect the cytotoxicity in vitro. This study provides a better understanding of the influence of the QD parameters on their cytotoxicity and can be used to improve the design of QDs.

From Bench to Cell: A Roadmap for Assessing the Bioorthogonal "Click" Reactivity of Magnetic Nanoparticles for Cell Surface Engineering.

In this work, we report the use of bioorthogonal chemistry, specifically the strain-promoted click azide–alkyne cycloaddition (SPAAC) for the covalent attachment of magnetic nanoparticles (MNPs) on living cell membranes. Four types of MNPs were prepared, functionalized with two different stabilizing/passivation agents (a polyethylene glycol derivative and a glucopyranoside derivative, respectively) and two types of strained alkynes with different reactivities: a cyclooctyne (CO) derivative and a dibenzocyclooctyne (DBCO) derivative. The MNPs were extensively characterized in terms of physicochemical characteristics, colloidal stability, and click reactivity in suspension. Then, the reactivity of the MNPs toward azide-modified surfaces was evaluated as a closer approach to their final application in a living cell scenario. Finally, the DBCO-modified MNPs, showing superior reactivity in suspension and on surfaces, were selected for cell membrane immobilization via the SPAAC reaction on the membranes of cells engineered to express azide artificial reporters. Overall, our work provides useful insights into the appropriate surface engineering of nanoparticles to ensure a high performance in terms of bioorthogonal reactivity for biological applications.

Comparative analysis of aged documents by desorption electrospray ionization-Mass spectrometry (DESI-MS) imaging.

Document dating is an important and challenging task in the field of forensic science. With the development of analytical techniques, related methods are emerging for document dating studies. Desorption electrospray ionization-mass spectrometry (DESI-MS) is an ambient ionization-MS technique that has been applied in the forensic discrimination of inks. This study focused on utilizing DESI-MS to distinguish between ink entries of different ages. Blue ballpoint ink and black gel ink samples were artificially aged by heat and light exposure and then screened by DESI-MS in the positive ion mode, with a methanol-water-formic acid solution (90:10:0.1%, v/v/v) as the desorption solvent. As a result, the artificially aged ink samples were directly differentiated from the reference ones in the chemical images of age-dependent compounds such as basic dyes or polyethylene glycol derivatives. The amount of ethoxylated fatty amine surfactants in copy paper was also found to decrease after artificial aging. Moreover, this method enabled us to visualize the differences between the composition of naturally aged and fresh ink samples. It has been proven to cause no apparent destruction of the samples. The identification of chronological changes in document materials suggests that the DESI-MS method is a promising approach for relative document dating.

Tolerance of the mRNA COVID-19 vaccines in patients with reported taxane reactions

Tolerance of the mRNA COVID-19 vaccines in patients with reported taxane reactions

A ROS-Responsive Simvastatin Nano-Prodrug and its Fibronectin-Targeted Co-Delivery System for Atherosclerosis Treatment.

Nanoprodrugs with responsive release properties integrate the advantages of stimuli-responsive prodrugs and nanotechnology. They would provide ultimate opportunity in fighting atherosclerosis. In this study, we synthesized a redox-responsive nanoprodrug of simvastatin (TPTS) by conjugating α-tocopherol polyethylene glycol derivative to the pharmacophore of simvastatin with a thioketal linker. TPTS formed nanoparticles and released parent simvastatin in the presence of hydrogen peroxide. Moreover, by taking advantage of the self-assembly behavior of TPTS, we developed a fibronectin-targeted delivery system (TPTS/C/T) to codelivery simvastatin prodrug and ticagrelor. In vitro and in vivo experiments indicated that TPTS and TPTS/C/T had good stability, which could reduce off-target leakage of drugs. They greatly inhibited the M1-type polarization of macrophages; reduced intracellular reactive oxygen species level and inflammatory cytokine; and TNF-α, MCP-1, and IL-1β were secreted by macrophage cells, thus providing enhanced anti-inflammatory and antioxidant effects compared with free simvastatin. TPTS/C/T realized targeted drug release to plaques and synergistic therapeutic effects of simvastatin and ticagrelor on atherosclerosis treatment in an ApoE-/- mouse model, resulting in excellent atherosclerosis therapeutic efficacy and a promising biosafety profile. Therefore, this study provides a new method for manufacturing statin nanodrugs and a new design idea for related responsive drug release nanosystems for atherosclerosis.

Review on impact of pegylation on biopharmaceuticals

Covalent conjugation of polyethylene glycol (PEG) molecules to biopharmaceutical molecules is known to increase the pharmacological and medicinal characteristics of proteins and other big molecules and has been utilized effectively in 12 authorized medications. PEG reagents with straight and branched chains up to 40 kDa were utilized with a variety of PEG derivatives with varied linker chemistries. This article discusses the characteristics of PEG, the history and evolution of PEGylation chemistry, and examples of PEGylated pharmaceuticals with a proven track record. They prefer to employ bigger PEG polymers and complicated PEG structures, although they use extremely pure and well-characterized PEG reagents. The preclinical toxicity data for PEG in PEGylated biologics that have been authorized are summarised. Microscopically detected cell vacuolization in phagocytes, which is connected to the biological function of absorption and elimination of particles and macromolecules from blood and tissues. It's possible. Side effects in toxicity tests typically relate to the active moiety of the medicine, not the PEG moiety, according to experience with commercially available PEGylated pharmaceuticals.

Innovation in potentiometry: 3D-printed polylactic acid-based ion-selective bulk electrode membranes

Although ion-selective membrane-based potentiometric sensors have already proved their analytical performance in several fields of life, their applicability is still limited in practice. Biodegradable, ionic additive-free, polylactic acid-based bulk electrode membrane matrix containing various environmentally friendly polyethylene glycol derivatives as plasticizer was developed for the first time to replace the conventional PVC-based ones. Moreover, the first introduction of 3D printing in potentiometric chemosensing was also reported. It was demonstrated that a thoroughly optimized and generalizable procedure for filament extrusion combined with 3D printing technology provides a unique tool for series production of the redesigned ion-selective bulk electrochemical membranes. Finally, the potentiometric detection of Hg2+ in water was carried out as a proof-of-concept study on sensing. Results showed an unexpected improvement in electrochemical characteristics of the novel membranes compared to their conventional analogues. The present work expanded the practical applicability of conventional potentiometric cation-selective electrode membranes enabling their green, decentralized, and automated state-of-the-art manufacturing using a novel matrix composition.Graphical abstract

Superior CO2/N2 separation performance of highly branched Poly(1,3 dioxolane) plasticized by polyethylene glycol

With its high content of CO 2 -philic ether oxygen groups, poly(1,3-dioxolane) (PDXLA) has emerged as an attractive platform to achieve excellent CO 2 /N 2 separation properties for post-combustion carbon capture. Herein we demonstrate that the separation properties of PDXLA can be further enhanced by plasticizing with miscible polyethylene glycol (PEG)-based additives using an integrated experimentation and modeling approach. The effects of the chain end groups and loading level of the additives on the physical properties of the blends are thoroughly investigated, including glass transition temperature ( T g ), fractional free volume, and gas transport properties, and the effects can be satisfactorily described using models available for homogeneous blends. Notably, a T g -integrated free volume model is adapted to successfully interpret the unified effect of the blend composition and temperature on gas diffusivity and permeability. A sample containing 45 mass% PEG dimethyl ether (PEGDME with a molecular mass of 240 g/mol) displays stable mixed-gas CO 2 permeability of 1540 Barrer and CO 2 /N 2 selectivity of 40 when challenged with a model flue gas at 60 °C, outperforming Robeson's 2008 upper bound. Elucidating how small plasticizers impact gas transport in homogeneous blends may unravel a facile way to design high-performance membranes for gas separations. Enhancing CO 2 /N 2 separation performance of poly(1,3 dioxolane) by plasticizing with polyethylene glycol derivatives. • Homogeneous blends were prepared from poly(1,3 dioxolane) and polyethylene glycol. • Plasticization decreases T g and increases free volume and gas permeability. • Lower molecular weight PEG without OH groups show more plasticization impact. • Effect of temperature and composition on gas permeability is described using the free volume model. • Blends exhibit stable mixed-gas CO 2 /N 2 separation performance above the upper bound.

Comparative Investigation of Cellular Effects of Polyethylene Glycol (PEG) Derivatives.

Nowadays, polyethylene glycols referred to as PEGs are widely used in cosmetics, consumer care products, and the pharmaceutical industry. Their advantageous properties such as chemical stability, low immunogenicity, and high tolerability explain why PEGs are applied in many fields of pharmaceutical formulations including parenteral, topical, ophthalmic, oral, and rectal preparations and also in modern drug delivery systems. Given their extensive use, they are considered a well-known group of chemicals. However, the number of large-scale comparative studies involving multiple PEGs of wide molecular weight range is low, as in most cases biological effects are estimated upon molecular weight. The aim of this publication was to study the action of PEGs on Caco-2 cells and G. mellonella larvae and to calculate the correlation of these effects with molecular weight and osmolality. Eleven PEGs of different molecular weight were used in our experiments: PEG 200, PEG 300, PEG 400, PEG 600, PEG 1000, PEG 1500, PEG 4000, PEG 8000, PEG 10,000, 12,000, and PEG 20,000. The investigated cellular effects included cytotoxicity (MTT and Neutral Red assays, flow cytometry with propidium iodide and annexin V) and autophagy. The osmolality of different molecular weight PEGs with various concentrations was measured by a vapor pressure osmometer OSMOMAT 070 and G. mellonella larvae were injected with the solutions of PEGs. Sorbitol was used as controls of the same osmolality. Statistical correlation was calculated to describe the average molecular weight dependence of the different measured effects. Osmolality, the cytotoxicity assays, flow cytometry data, and larvae mortality had significant correlation with the structure of the PEGs, while autophagosome formation and the proportion of early apoptotic cells showed no statistical correlation. Overall, it must be noted that PEGs must be tested individually for biological effects as not all effects can be estimated by the average molecular weight.

A dye-andrographolide assembly as a turn-on sensor for detection of phthalate in both cells and fish

Phthalates can penetrate the environment and enrich various aquatic organisms through the food chain, which is involved in promoting the growth of breast cancer. It is of current interest to develop new sensors for phthalates. We herein reported a hydrogen-bond competing fluorescent sensor, BANP, for the detection of dibutyl phthalate (DBP). The BANP compound was synthesized by assembling andrographolide (Andro), nitro- and cyano-substituted BODIPY dye (BCN), and polyethylene glycol derivatives (DSPE-mPEG5000). BANP was found to be a turn-on fluorescent probe for DBP in water with a detection limit of 0.13 μg/g; the DBP-water system acts as a hydrogen bond switch to turn on the fluorescence. And BANP fluorescently detected DBP in contaminated fish meat. Moreover, BANP sensed the DBP-induced growth of human breast cancer MCF-7 cells, and the release of Andro in the DBP-cultivated cancer cells inhibited the proliferation of the MCF-7 cells. Taken together, BANP is a DBP-responsive probe for sensitive DBP detection in water, cells, and fish meats. The BANP sensor may be used in both in vitro fluorescence and cellular imaging analyses. Our results show that guest-induced reassembly brings forth significant fluorescence change, which is a promising way of designing new fluorescent probes for the analysis of phthalates in the environment and food.

Photo‐Controlled Reversible Multicolor Room‐Temperature Phosphorescent Solid Supramolecular Pseudopolyrotaxane

AbstractThe photoreversible switch persistent room‐temperature phosphorescent (p‐RTP) system is attractive but challenging in the field of smart luminescent materials. In particular, those p‐RTPs with the excitation‐wavelength‐responsive and time‐dependent multicolor emission are very important but underexplored. Herein an excitation‐wavelength‐responsive and time‐dependent multicolor p‐RTP emission pseudopolyrotaxanes supramolecular system based on host–guest interaction between α‐cyclodextrin (α‐CD) and two luminophores (benzene and naphthalene) modified polyethylene glycol (PEG) derivatives is reported. The excitation‐wavelength‐responsive and time‐dependent multicolor afterglows of the supramolecular system are derived from the diverse p‐RTP emission species with different lifetimes. More importantly, the p‐RTP can be reversibly adjusted by photoisomerization of diarylethylene (DAE), that is, it could be erased under ultraviolet light and recovered under visible‐light for several cycles. Taking advantage of the reversible photoencryption property, this intelligent luminescence supramolecular system has broad application prospects in information storage and treatment.

New Challenges in Drug Allergy: the Resurgence of Excipients.

Purpose of ReviewAllergy to excipients is a cause of multidrug allergy and if it is not taken into account, it can lead to unexpected severe reactions. If an excipient allergy is suspected, an accurate examination followed by algorithms is very important for a correct diagnosis and to give patients detailed information in order to avoid future reactions.Recent FindingsIn recent times, due to allergy COVID vaccine reactions, interest in excipients as polyethylene glycol derivatives (PEGs) has increased as a possible cause of drug and vaccine hypersensivity. In addition to PEGs many other excipients as gelatin, alpha-gal, protamine, benzalkonium chloride, and benzyl alcohol have been described as a cause of allergy to drugs and vaccines. For most excipients, the dilutions used for skin testing (ST) are not standardized and proper algorithms to reach a diagnosis are not available.SummaryThe purpose of this article is to review the excipients that may produce inmediate hypersensitivity drugs and vaccine reactions and update diagnostic procedures to reach an accurate diagnosis. We highlight the in vivo and in vitro diagnostic tests used in published reports and detail the dilution used for each excipient to perform ST in order to confirm this vital pathology and to prevent new reactions.

Solvent design for catalyst recycling of rhodium/amine catalysts via scCO2 extraction in the reductive hydroformylation of alpha olefins

Amine modified polyethylene glycol (PEG) derivatives are used as stationary phase to immobilize homogeneous rhodium catalysts during the extraction of alcohols with scCO2.

Complexation of Polyethyleneglycol Containing Small Molecules with Magnesium Chloride as a Purification and Isolation Strategy

Polyethyleneglycol (PEG) containing compounds are often non-crystalline, gel-like oils, which pose great challenges for handling, purification, and isolation, particularly on large scales. To overcome these isolation challenges, a new procedure has been established, which is based on the discovery that complexation with magnesium chloride (MgCl2) can transform these oily intermediates into solid complexes. This method significantly improves the handling of PEG compounds and leads a more process-friendly isolation for larger scale handling. Often, the resulting PEG–MgCl2 complexes could be used directly in subsequent transformations, such as a peptide coupling. Alternately, the inorganic Mg salt used in these weakly bonded complexes can be readily dissociated and removed from the desired PEG derivatives.

PEGylation of Guanidinium and Indole Bearing Poly(methacrylamide)s - Biocompatible Terpolymers for pDNA Delivery.

This study describes the first example for shielding of a high performing terpolymer that consists of N-(2-hydroxypropyl)methacrylamide (HPMA), N-(3-guanidinopropyl)methacrylamide (GPMA), and N-(2-indolethyl)methacrylamide monomers (IEMA) by block copolymerization of a polyethylene glycol derivative - poly(nona(ethylene glycol)methyl ether methacrylate) (P(MEO9 MA)) via reversible addition-fragmentation chain transfer (RAFT) polymerization. The molecular weight of P(MEO9 MA) is varied from 3 to 40 kg mol-1 while the comonomer content of HPMA, GPMA, and IEMA is kept comparable. The influence of P(MEO9 MA) block with various molecular weights is investigated over cytotoxicity, plasmid DNA (pDNA) binding, and transfection efficiency of the resulting polyplexes. Overall, the increase in molecular weight of P(MEO9 MA) block demonstrates excellent biocompatibility with higher cell viability in L-929 cells and an efficient binding to pDNA at N/P ratio of 2. The significant transfection efficiency in CHO-K1 cells at N/P ratio 20 is obtained for block copolymers with molecular weight of P(MEO9 MA) up to 10 kg mol-1 . Moreover, a fluorescently labeled analogue of P(MEO9 MA), bearing perylene monoimide methacrylamide (PMIM), is introduced as a comonomer in RAFT polymerization. Polyplexes consisting of labeled block copolymer with 20 kg mol-1 of P(MEO9 MA) and pDNA are incubated in Hela cells and investigated through structured illumination microscopy (SIM).

An academic hospital experience screening mRNA COVID-19 vaccine risk using patient allergy history

Higher than expected rates of anaphylaxis have been reported with the Pfizer-BioNTech and Moderna mRNA COVID-19 vaccines when compared with historical vaccine anaphylaxis trends.1 Although the mechanism for such reactions remains unclear, and current anaphylaxis classification schemes may be overly sensitive, early interest has been placed on polyethylene glycol (PEG) 2000 present in the lipid nanoparticle carrier system of these mRNA COVID-19 vaccines.2 In order to attempt to preempt allergic reactions, use of mRNA COVID-19 vaccines has been contraindicated in patients with known allergy to PEG and previously contraindicated in those with known allergy to PEG derivatives such as polysorbate where small studies have suggested cross-reactivity with PEG.

Morphologically Diverse Micro- and Macrostructures Created via Solvent Evaporation-Induced Assembly of Fluorescent Spherical Particles in the Presence of Polyethylene Glycol Derivatives.

The creation of fluorescent micro- and macrostructures with the desired morphologies and sizes is of considerable importance due to their intrinsic functions and performance. However, it is still challenging to modulate the morphology of fluorescent organic materials and to obtain insight into the factors governing the morphological evolution. We present a facile bottom-up approach to constructing diverse micro- and macrostructures by connecting fluorescent spherical particles (SPs), which are generated via the spherical assembly of photoisomerizable azobenzene-based propeller-shaped chromophores, only with the help of commercially available polyethylene glycol (PEG) derivatives. Without any extra additives, solvent evaporation created a slow morphological evolution of the SPs from short linear chains (with a length of a few micrometers) to larger, interconnected networks and sheet structures (ranging from tens to >100 µm) at the air–liquid interface. Their morphologies and sizes were significantly dependent on the fraction and length of the PEG. Our experimental results suggest that noncovalent interactions (such as hydrophobic forces and hydrogen bonding) between the amphiphilic PEG chains and the relatively hydrophobic SPs were weak in aqueous solutions, but play a crucial role in creating the morphologically diverse micro- and macrostructures. Moreover, short-term irradiation with visible light caused fast morphological crumpling and fluorescence switching of the obtained structures.

A novel polyethylene glycol (PEG)-drug conjugate of Venetoclax, a Bcl-2 inhibitor, for treatment of acute myeloid leukemia (AML).

BackgroundVenetoclax (VTX) is an anticancer drug. It is a selective Bcl‐2 inhibitor that is clinically used for the treatment of patients with lymphomas and leukemias. Treatment with VTX, however, is accompanied by severe adverse events such as tumor lysis syndrome and neutropenia, because VTX readily binds to serum proteins, which results in poor pharmacokinetics and poor tumor tissue concentration. To avoid such adverse events, VTX is administered using a daily or weekly ramp‐up schedule that is cumbersome in clinical situations.AimsTo overcome these shortcomings, we prepared a novel polyethylene glycol (PEG)‐drug conjugate of VTX (PEG‐VTX) and evaluated its cytotoxic effects on acute myeloid leukemia (AML) both in vitro and in vivo.Methods and resultsVTX and 4‐armed PEG derivatives were covalently attached through an amide bond linker. In a series of in vitro studies, PEG‐VTX selectively induced potent growth inhibition of MV4‐11 human AML cells via the inducement of Bcl‐2‐mediated apoptosis. PEG‐VTX had the effect of free VTX, presumably due to the protease‐mediated release of VTX from the conjugates. In in vivo studies with AML tumor‐xenograft mice models, intravenous PEG‐VTX promoted sufficient tumor growth suppression. Compared with a regimen of oral free VTX, the intravenous regimen in those studies used a VTX dosage that was 15–30 times smaller for an OCI‐AML‐2 xenograft model and a dosing regimen that was less frequent for an MV4‐11 xenograft model. The most important development, however, was the absence of weight loss related to severe side effects throughout the treatments. An increase in water solubility and the resultant hydrodynamic size of VTX via PEGylation improved the pharmacokinetics of VTX by avoiding protein interactions and lessening the extravasation from blood. The result was an increase in tumor accumulation and a decrease in the nonspecific distribution of VTX.ConclusionThe results of this study suggest that PEG‐VTX could be an alternative therapeutic option for the safe and effective treatment of patients with AML.