Chemoenzymatic Synthesis of D-Glucitol-Based Non-Ionic Amphiphilic Architectures as Nanocarriers

Newer non-ionic amphiphiles have been synthesized using biocompatible materials and by following a greener approach i.e., D-glucitol has been used as a template, and hydrophobic and hydrophilic segments were incorporated on it by using click chemistry. The hydrophilic segments in turn were prepared from glycerol using an immobilized Candida antarctica lipase (Novozym-435)-mediated chemoenzymatic approach. Surface tension measurements and dynamic light scattering studies reflect the self-assembling behavior of the synthesized amphiphilic architectures in the aqueous medium. The results from UV-Vis and fluorescence spectroscopy establish the encapsulation of guests in the hydrophobic core of self-assembled amphiphilic architectures. The results of 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay indicate that the amphiphiles are well tolerated by the used A549 cell lines at all tested concentrations

Fluorescent Polymer—Single‐Walled Carbon Nanotube Complexes with Charged and Noncharged Dendronized Perylene Bisimides for Bioimaging Studies

Fluorescent nanomaterials are expected to revolutionize medical diagnostic, imaging, and therapeutic tools due to their superior optical and structural properties. Their inefficient water solubility, cell permeability, biodistribution, and high toxicity, however, limit the full potential of their application. To overcome these obstacles, a water‐soluble, fluorescent, cytocompatible polymer—single‐walled carbon nanotube (SWNT) complex is introduced for bioimaging applications. The supramolecular complex consists of an alkylated polymer conjugated with neutral hydroxylated or charged sulfated dendronized perylene bisimides (PBIs) and SWNTs as a general immobilization platform. The polymer backbone solubilizes the SWNTs, decorates them with fluorescent PBIs, and strongly improves their cytocompatibility by wrapping around the SWNT scaffold. In photophysical measurements and biological in vitro studies, sulfated complexes exhibit superior optical properties, cellular uptake, and intracellular staining over their hydroxylated analogs. A toxicity assay confirms the highly improved cytocompatibility of the polymer‐wrapped SWNTs toward surfactant‐solubilized SWNTs. In microscopy studies the complexes allow for the direct imaging of the SWNTs' cellular uptake via the PBI and SWNT emission using the 1st and 2nd optical window for bioimaging. These findings render the polymer‐SWNT complexes with nanometer size, dual fluorescence, multiple charges, and high cytocompatibility as valuable systems for a broad range of fluorescence bioimaging studies

Esterase-Responsive Polyglycerol-Based Nanogels for Intracellular Drug Delivery in Rare Gastrointestinal Stromal Tumors

Rare gastrointestinal stromal tumors (GISTs) are caused by mutations in the KIT and PDGFRA genes. Avapritinib (BLU-285) is a targeted selective inhibitor for mutated KIT and PDGFRA receptors that can be used to treat these tumors. However, there are subtypes of GISTs that exhibit resistance against BLU-285 and thus require other treatment strategies. This can be addressed by employing a drug delivery system that transports a combination of drugs with distinct cell targets. In this work, we present the synthesis of esterase-responsive polyglycerol-based nanogels (NGs) to overcome drug resistance in rare GISTs. Using inverse nanoprecipitation mediated with inverse electron-demand Diels–Alder cyclizations (iEDDA) between dPG-methyl tetrazine and dPG-norbornene, multi-drug-loaded NGs were formed based on a surfactant-free encapsulation protocol. The obtained NGs displayed great stability in the presence of fetal bovine serum (FBS) and did not trigger hemolysis in red blood cells over a period of 24 h. Exposing the NGs to Candida Antarctica Lipase B (CALB) led to the degradation of the NG network, indicating the capability of targeted drug release. The bioactivity of the loaded NGs was tested in vitro on various cell lines of the GIST-T1 family, which exhibit different drug resistances. Cell internalization with comparable uptake kinetics of the NGs could be confirmed by confocal laser scanning microscopy (CLSM) and flow cytometry for all cell lines. Cell viability and live cell imaging studies revealed that the loaded NGs are capable of intracellular drug release by showing similar IC50 values to those of the free drugs. Furthermore, multi-drug-loaded NGs were capable of overcoming BLU-285 resistance in T1-α-D842V + G680R cells, demonstrating the utility of this carrier system

Wet deposition of hydrocarbons in the city of Tehran-Iran

Air pollution in the city of Tehran has been a major problem for the past three decades. The direct effects of hydrocarbon contaminants in the air are particularly important such as their carcinogenic, mutagenic, and teratogenic effects which can be transported to other environments via dry and wet deposition. In the present study, rainwater samples were collected and analyzed for 16 polycyclic aromatic hydrocarbons (PAHs), benzene, toluene, ethyl benzene, and xylene (BTEX) as well as fuel fingerprints in two ranges of gasoline (C5–C11) and diesel fuel (C12–C20) using a gas chromatograph equipped with a flame ionization detector (GC/FID). Mean concentrations of ∑16 PAHs varied between 372 and 527 µg/L and for BTEX was between 87 and 188 µg/L with maximum of 36 µg/L for toluene. Both gasoline range hydrocarbons (GRH) and diesel range hydrocarbons (DRH) were also present in the collected rainwater at concentrations of 190 and 950 µg/L, respectively. Hydrocarbon transports from air to soil were determined in this wet deposition. Average hydrocarbon transportation for ∑PAHs, BTEX, GRH, and DRH was 2,747, 627, 1,152, and 5,733 µg/m2, respectively

Polysulfates block SARS‐CoV‐2 uptake through electrostatic interactions

Here we report that negatively charged polysulfates can bind to the spike protein of SARS-CoV-2 via electrostatic interactions. Using a plaque reduction assay, we compare inhibition of SARS-CoV-2 by heparin, pentosan sulfate, linear polyglycerol sulfate (LPGS) and hyperbranched polyglycerol sulfate (HPGS). Highly sulfated LPGS is the optimal inhibitor, with a half-maximal inhibitory concentration (IC50) of 67 μg/mL (approx. 1.6 μM). This synthetic polysulfates exhibit more than 60-fold higher virus inhibitory activity than heparin (IC50: 4084 μg/mL), along with much lower anticoagulant activity. Furthermore, in molecular dynamics simulations, we verified that LPGS can bind stronger to the spike protein than heparin, and that LPGS can interact even more with the spike protein of the new N501Y and E484K variants. Our study demonstrates that the entry of SARS-CoV-2 into host cells can be blocked via electrostatic interaction, therefore LPGS can serve as a blueprint for the design of novel viral inhibitors of SARS-CoV-2

One-pot synthesis of poly(glycerol-co-succinic acid) nanogels for dermal delivery

Polyglycerol nanogels are three-dimensional polymeric networks with a few hundred nanometer sizes and the ability to encapsulate and deliver cargos for a wide range of biomedical applications. However, time-consuming and multistep synthetic routes as well as milligram-scale production have hindered further development of these nanomaterials. In this work, we report on a straightforward synthetic method for the production of polyglycerol nanoarchitectures. Enzymatic ring-opening copolymerization of a mixture of glycidol and succinic anhydride resulted in polyglycerol nanogels with succinic acid segments in their backbone. Novozyme 435 was used as a dual catalytic agent to support ring-opening polymerization of the above-mentioned cyclic monomers as well as esterification of the produced oligomers to obtain nanogels. While succinic acid segments improved the biodegradability and loading capacity of nanogels, polyglycerol caused water solubility, high functionality, and biocompatibility. Nanogels were loaded with tacrolimus and photosensitizer 5,10,15,20-tetrakis(3-hydroxyphenyl)porphyrin (mTHPP)-a close congener of the approved photosensitizer temoporfin (mTHPC)-and their ability to improve the skin penetration of these therapeutic agents was investigated. mTHPP delivery experiments on human skin, which were quantified by fluorescence microscopy, showed that these nanogels deposit in the stratum corneum and release the loaded drug to viable epidermis of skin efficiently in comparison with commercially available base cream. Taking advantage of the straightforward synthesis as well as biodegradability, biocompatibility, high loading capacity, and efficient skin penetration, the synthesized nanogels could be used as future topical delivery systems

Fabrication of nanostructures through selfassembly of non-ionic amphiphiles for biomedical applications

Fabrication of self-assembled nanostructures with defined size and morphology represents a formidable challenge and thus, has gained tremendous momentum in research because of their potential applications in various biological systems. Herein, we report on the synthesis of novel non-ionic amphiphiles using 2,2-di(prop-2-yn-1-yl)propane-1,3-diol as a core further functionalized with poly(ethylene glycol) monomethyl ether and alkyl chains employing a chemo-enzymatic approach. Surface tension and fluorescence measurements along with dynamic light scattering studies revealed that all of the amphiphilic systems spontaneously self-assemble in aqueous solution, which is further supplemented by cryogenic transmission electron microscopy. The solubilization behavior of these systems as evidenced from UV-Vis and fluorescence spectroscopy and high performance liquid chromatography suggested the effective encapsulation of hydrophobic entities like Nile red, nimodipine, curcumin and dexamethasone. A comparative study with a standard excipient, Cremophor® ELP demonstrated that our nanocarriers exhibited superior/equivalent solubilization behavior for curcumin. Confocal laser scanning microscopy revealed efficient uptake of encapsulated dye in the cytosol of lung cancer cells, thus suggesting, that the reported amphiphilic systems can transport drugs into cells. A study of cytotoxicity showed that the synthesized amphiphilic systems are non-cytotoxic at the concentrations studied. The release profile of encapsulated Nile red incubated with/without a hydrolase enzyme Candida antarctica lipase demonstrated that the dye is stable in the amphiphilic nanostructures in the absence of enzyme for up to 12 days, however, more than 90% release of the dye occurred in 12 days when incubated with lipase. The results advocate the potential of these nanostructures as prospective drug delivery vehicles

Gating the photochromism of an azobenzene by strong host–guest interactions in a divalent pseudo[2]rotaxane

The ability of an E-configured azobenzene guest to undergo photoisomerisation is controlled by the presence of a complementary host. Addition of base/acid allowed for a weakening/strengthening of the interactions in the divalent pseudo[2]rotaxane complex and hence could switch on/off photochromic activity.Peer Reviewe