Publications by authors named "Pradip Dey"

22 Publications

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Functional Surfactants for Molecular Fishing, Capsule Creation, and Single-Cell Gene Expression.

Nanomicro Lett 2021 Jun 19;13(1):147. Epub 2021 Jun 19.

Institut Für Chemie Und Biochemie, Freie Universität Berlin, Takustrasse 3, 14195, Berlin, Germany.

Creating a single surfactant that is open to manipulation, while maintaining its surface activity, robustness, and compatibility, to expand the landscape of surfactant-dependent assays is extremely challenging. We report an oxidation-responsive precursor with thioethers and multiple 1,2-diols for creating a variety of functional surfactants from one parent surfactant. Using these multifunctional surfactants, we stabilize microfluidics-generated aqueous droplets. The droplets encapsulate different components and immerse in a bioinert oil with distinct interfaces where an azide-bearing surfactant allow fishing of biomolecules from the droplets, aldehyde-bearing surfactant allow fabrication of microcapsules, and hydroxyl-bearing surfactants, with/without oxidized thioethers, allow monitoring of single-cell gene expression. Creating multifunctional surfactants poses opportunities for broad applications, including adsorption, bioanalytics, catalysis, formulations, coatings, and programmable subset of emulsions.
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http://dx.doi.org/10.1007/s40820-021-00663-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8214653PMC
June 2021

Molecular Recognition Driven Bioinspired Directional Supramolecular Assembly of Amphiphilic (Macro)molecules and Proteins.

Acc Chem Res 2021 06 20;54(11):2670-2682. Epub 2021 May 20.

School of Applied and Interdisciplinary Sciences, Indian Association for the Cultivation of Science, 2A and 2B Raja S. C. Mullick Road, Kolkata 700032, India.

Bioinspired self-assembly has been explored with diverse synthetic scaffolds, among which amphiphiles are perhaps the most extensively studied systems. Classical surfactants or amphiphilic block copolymers, depending on the hydrophobic-hydrophilic balance, produce distinct nanostructures, which hold promise for applications ranging from biology to materials sciences. Nevertheless, their immiscibility-driven aggregation does not provide the opportunity to precisely regulate the internal order, morphology, or functional group display, which is highly desirable, especially in the context of biological applications.A new class of amphiphiles have emerged in the recent past in which the hydrophilic segment(s) is appended with a hydrophobic supramolecular-structure-directing-unit (SSDU), consisting of a π-conjugated chromophore and a H-bonding group. Self-recognition of the SSDU by attractive directional interactions governs the supramolecular assembly, which is fundamentally different than the repulsive solvent-immiscibility driven aggregation of traditional amphiphiles. Such SSDU-appended hydrophilic polymers exhibit entropy-driven highly stable self-assembly producing distinct nanostructures depending on the H-bonding functional group. For example, polymers with the hydrazide-functionalized SSDU attached form a polymersome, while in a sharp contrast, the same polymers when connected to an amide containing SSDU produce a cylindrical micelle via a spherical-micelle intermediate. This relationship holds true for a series of SSDU-attached hydrophilic polymers irrespective of the hydrophobic/hydrophilic balance or chemical structure, indicating that the supramolecular-assembly is primarily controlled by the specific molecular-recognition motif of the SSDU, instead of the packing parameter-based norms. Beyond synthetic polymers, SSDU-attached proteins also exhibit similar molecular-recognition driven self-assembly as well as coassembly with SSDU-attached polymers or hydrophilic wedges, producing multi-stimuli-responsive nanostructures in which the protein gains remarkable protection from thermal denaturation or enzymatic hydrolysis and exhibits redox-responsive enzymatic activity.Furthermore, SSDU-derived bola-shape π-amphiphiles have been recognized as a useful scaffold for the synthesis of unsymmetric polymersomes, rarely reported in the literature. The building block consists of a hydrophobic naphthalene-diimide (NDI) π-system attached to a hydrophilic functional group (ionic or nonionic) and a nonionic wedge on its two opposite arms. Extended H-bonding among the hydrazide groups, placed only on one side of the central chromophore by design, ensures stacking of the NDIs with parallel orientation and induces a preferred direction of curvature so that the H-bonded chain and consequently the functional groups attached to the same side remain at the inner-wall of the supramolecular polymersome. Automatically, the functional groups, located on the other side, are displayed at the outer surface. This design works for different amphiphiles, which by virtue of efficient and predictable functional group display, strongly influences the multivalent binding with different biological targets resulting in efficient enzyme inhibition, glycocluster effect, or antibacterial activity, depending on the nature of the functional group. By taking advantage of the electron accepting nature of the NDI, electron rich pyrene-containing amphiphiles can be costacked in alternating sequence, producing temperature and redox-responsive supramolecular polymers with NDI/pyrene stoichiometry-dependent morphology, lower critical solution temperature (LCST), functional group display, and antibacterial activity.
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http://dx.doi.org/10.1021/acs.accounts.1c00195DOI Listing
June 2021

Meet me halfway: Are in vitro 3D cancer models on the way to replace in vivo models for nanomedicine development?

Adv Drug Deliv Rev 2021 08 7;175:113760. Epub 2021 Apr 7.

Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 69978, Israel. Electronic address:

The complexity and diversity of the biochemical processes that occur during tumorigenesis and metastasis are frequently over-simplified in the traditional in vitro cell cultures. Two-dimensional cultures limit researchers' experimental observations and frequently give rise to misleading and contradictory results. Therefore, in order to overcome the limitations of in vitro studies and bridge the translational gap to in vivo applications, 3D models of cancer were developed in the last decades. The three dimensions of the tumor, including its cellular and extracellular microenvironment, are recreated by combining co-cultures of cancer and stromal cells in 3D hydrogel-based growth factors-inclusive scaffolds. More complex 3D cultures, containing functional blood vasculature, can integrate in the system external stimuli (e.g. oxygen and nutrient deprivation, cytokines, growth factors) along with drugs, or other therapeutic compounds. In this scenario, cell signaling pathways, metastatic cascade steps, cell differentiation and self-renewal, tumor-microenvironment interactions, and precision and personalized medicine, are among the wide range of biological applications that can be studied. Here, we discuss a broad variety of strategies exploited by scientists to create in vitro 3D cancer models that resemble as much as possible the biology and patho-physiology of in vivo tumors and predict faithfully the treatment outcome.
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http://dx.doi.org/10.1016/j.addr.2021.04.001DOI Listing
August 2021

Potential of cotton for remediation of Cd-contaminated soils.

Environ Monit Assess 2021 Mar 13;193(4):186. Epub 2021 Mar 13.

ICAR-Indian Institute of Soil Science, Nabi Bagh, Berasia Road, Bhopal, India.

The present research was conducted to study the potential of cotton for the remediation of soils contaminated with Cd, to understand the biochemical basis of its tolerance to, and to investigate the plant-microbe interaction in the rhizosphere for enhancement of phytoextraction of Cd. Cotton (Bt RCH-2) was exposed to four Cd levels (0, 50, 100, and 200 mg/kg soil) in a completely randomised design and found that the plant could tolerate up to 200 mg/kg soil. Cd stress increased the total phenol, proline, and free amino acid contents in the plant leaf tissue compared with control but inhibited basal soil respiration, fluorescein diacetate hydrolysis, and activities of several enzymes viz. dehydrogenase, phosphatases, and β-glucosidase in the soil over control. The concentration of Cd in the shoot was less than the critical concentration of 100 µg/g dry weight, and bioconcentration and translocation factors were < 1 to classify the plant as a hyperaccumulator of Cd. This was further confirmed by another experiment in which the cotton plant was exposed various higher levels of Cd (200, 400, 600, 800, and 1000 mg/kg soil). Though the concentration of Cd in the shoot was > 100 µg g dw beyond 600 mg Cd/kg soil, the bioconcentration and translocation factors were < 1. The study on plant-microbe (Aspergillus awamori) interaction revealed that the fungus did not affect the absorption of Cd by cotton. It was concluded that the cotton was classified as an excluder of Cd and therefore could be suitable for the phytostabilization of Cd-contaminated soils.
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http://dx.doi.org/10.1007/s10661-021-08976-5DOI Listing
March 2021

Tolerance of cotton to elevated levels of Pb and its potential for phytoremediation.

Environ Sci Pollut Res Int 2021 Feb 23. Epub 2021 Feb 23.

ICAR-Indian Institute of Soil Science, Nabi Bagh, Berasia Road, Bhopal, India.

Two experiments were conducted to determine the cotton plant's tolerance to Pb and its remediation potential. In the first experiment, the phytoremediation potential was determined by exposing the plant to four levels of Pb (0, 500, 750, and 1000 mg kg). The cotton plant exhibited an excellent tolerance index at Pb 1000 mg kg (root 78.65% and shoot 93.08%) and lower grade of growth inhibition (root 21.35% and shoot 6.92%). Pb stress resulted in higher leakage of electrolytes and increased the synthesis of higher proline, total phenol, and free amino acid contents to mitigate stress. The plant could not meet the criteria of a hyperaccumulator of Pb. The concentration of Pb in the shoot was a mere 96 μg g dry wt (< the critical judging concentration of 1000 μg g dry wt), and bioconcentration and translocation factors were <1. The study established that cotton exhibited an exclusion mechanism of Pb. Further, the translocation efficiency (TE %) was very low, i.e., <50% (ranged from 49% at 500 mg kg to 42% at 1000 mg kg ), and the % of Pb removed by the crop was too little (on an average 0.1%). Pb inhibited the dehydrogenase activity (DHA) by 76%, fluorescein diacetate (FDA) hydrolysis by 60%, and β-glucosidase activity by 20%. However, applied Pb increased the population of actinomycetes by 3.21 times, but significantly decreased heterotrophic bacteria by 3.40 times and N fixers by over 53% over control. In the second experiment, the plant was exposed to very high Pb (0, 1000, 1500, 2000, 2500, and 3000 mg kg ) to determine the concentration up to which the plant will survive. The investigation revealed that plants could survive up to Pb 3000 mg kg. It confirmed the first experiment in the tolerance index, grade of growth inhibition, bioconcentration factor, translocation factor, and partitioning of Pb. Therefore, it was concluded that the cotton plant was an excluder of Pb and could be effectively cultivated for the phytostabilization of soils polluted with Pb.
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http://dx.doi.org/10.1007/s11356-021-13067-6DOI Listing
February 2021

Evaluation of Furcraea foetida (L.)Haw. for phytoremediation of cadmium contaminated soils.

Environ Sci Pollut Res Int 2021 Mar 25;28(11):14177-14181. Epub 2021 Jan 25.

ICAR-Indian Institute of Soil Science, NabiBagh, Berasia Road, Bhopal, 462038, India.

In the present study, we evaluated Furcraea foetida for the phytoremediation of cadmium (Cd)-contaminated soils. We selected F. foetida because it is a drought-resistant plant, produces high biomass, and needs minimum maintenance. It belongs to the leaf fiber group of plants and therefore has economic importance. Since it is a non-edible crop, there is no danger of food chain contamination. Despite possessing these ideal characteristics, surprisingly, to date, the plant is underutilized for phytoremediation purposes. Therefore, to evaluate the phytoremediation potential of the plant, we exposed it to five levels of cadmium (0, 25, 50, 100, and 200 mg Cd kg soil) and studied its influence on growth, dry matter production, uptake, and translocation efficiency. The plant showed good tolerance to Cd 200 mg kg soil without exhibiting any visible toxicity symptoms. The metal mainly accumulated in the roots (233 μg gdw), followed by leaf (51 μg g dw). The bioconcentration factor was > 1, but the translocation factor was < 1. The plant was not classified as a hyperaccumulator of Cd; however, because of its high uptake (897 μ g plant) and translocation efficiency (78%), we concluded that the plant could be utilized for phytoextraction of Cd from soils with low to moderately contaminated soils.
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http://dx.doi.org/10.1007/s11356-021-12534-4DOI Listing
March 2021

Controlled supramolecular polymerization of π-systems.

Chem Commun (Camb) 2020 Jun;56(50):6757-6769

School of Applied and Interdisciplinary Sciences, Indian Association for the Cultivation Science, 2A and 2B Raja S. C. Mullick Road, Kolkata, 700032, India.

Supramolecular polymers, albeit having precise internal order, largely lack precision in the mesoscopic scale because in most examples supramolecular polymerization occurs under thermodynamic control through spontaneous self-assembly. Recent reports have exemplified that by varying experimental parameters including cooling rate, solvent composition, interplay of intra- vs. inter-molecular H-bonding and others, it is possible to retard the spontaneous nucleation, and isolate a dormant kinetically controlled monomeric/aggregated state which in turn can serve as the monomer pool to undergo controlled supramolecular polymerization (CSP) through a chain-growth mechanism in the presence of an aggregated/molecular initiator (seed) or by an external stimuli like light. Supramolecular polymers with narrow dispersity, predictable length or stereo-selectivity have been achieved by CSP. Chain extension (similar to "living" polymerization) in such seed initiated CSP is now possible by batch wise addition of monomers, allowing synthesis of supramolecular block copolymers. This feature article describes recent developments in CSP (primarily under kinetic control) of various π-conjugated building blocks.
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http://dx.doi.org/10.1039/d0cc02787aDOI Listing
June 2020

Disulfide chemistry in responsive aggregation of amphiphilic systems.

Soft Matter 2020 Jan 28;16(1):11-26. Epub 2019 Nov 28.

School of Applied and Interdisciplinary Sciences, Indian Association for the Cultivation of Science, 2A and 2B Raja S. C. Mullick Road, Kolkata, 700032, India.

The dynamic nature of the disulfide bond has enhanced the potential for disulfide based amphiphiles in the emerging biomedical field. Disulfide containing amphiphiles have extensively been used for constructing wide ranging soft nanostructures as potential candidates for delivery of drugs, proteins and genes owing to their degradable nature in the presence of intracellular glutathione (present in a many fold excess compared to the extracellular milieu). This degradable nature of amphiphiles is not only useful to deliver therapeutics but it also eliminates the toxicity issues associated with the carrier after delivery of such therapeutics. Therefore, these bioreducible and biocompatible nano-aggregates inspired researchers to use them as vehicles for therapeutic delivery and as a result the literature of disulfide containing amphiphiles has been intensified. This review article highlights the structural diversity in disulfide containing amphiphilic small molecule and polymeric systems, structural effects on their aqueous aggregation, redox-responsive disassembly and biological applications. Furthermore, the use of disulfide chemistry towards the design of cell penetrating polymers has also been discussed. Finally a brief perspective on some future opportunities of these systems is provided.
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http://dx.doi.org/10.1039/c9sm01960jDOI Listing
January 2020

Dendronized fluorosurfactant for highly stable water-in-fluorinated oil emulsions with minimal inter-droplet transfer of small molecules.

Nat Commun 2019 10 4;10(1):4546. Epub 2019 Oct 4.

Institut für Chemie und Biochemie, Freie Universität Berlin, Takustrasse 3, 14195, Berlin, Germany.

Fluorosurfactant-stabilized microfluidic droplets are widely used as pico- to nanoliter volume reactors in chemistry and biology. However, current surfactants cannot completely prevent inter-droplet transfer of small organic molecules encapsulated or produced inside the droplets. In addition, the microdroplets typically coalesce at temperatures higher than 80 °C. Therefore, the use of droplet-based platforms for ultrahigh-throughput combination drug screening and polymerase chain reaction (PCR)-based rare mutation detection has been limited. Here, we provide insights into designing surfactants that form robust microdroplets with improved stability and resistance to inter-droplet transfer. We used a panel of dendritic oligo-glycerol-based surfactants to demonstrate that a high degree of inter- and intramolecular hydrogen bonding, as well as the dendritic architecture, contribute to high droplet stability in PCR thermal cycling and minimize inter-droplet transfer of the water-soluble fluorescent dye sodium fluorescein salt and the drug doxycycline.
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http://dx.doi.org/10.1038/s41467-019-12462-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6778136PMC
October 2019

Synthesis and Self-assembly of a Helical Polymer Grafted from a Foldable Polyurethane Scaffold.

Chem Asian J 2019 Dec 14;14(24):4741-4747. Epub 2019 Oct 14.

School of Applied and Interdisciplinary Sciences, Indian Association for the Cultivation of Science, 2A & 2B Raja S. C. Mullick Road, Jadavpur Kolkata, 700032, India.

Herein a polyurethane graft poly-l-glutamate amphiphilic copolymer was synthesized from a polyurethane (PU)-based macro-initiator (containing pendant primary amine groups) through the ring opening polymerization of N-carboxy anhydride of γ-benzyl-l-glutamate (BLG-NCA). On average, twenty two l-glutamic acids were grafted from each amino group which was pendant on the polyurethane chain with 10 repeating units. The grafted polymer (PU-PP-1) exhibits self-assembly to produce a hydrogel in a wide pH window ranging from pH 5.0 to 8.0 with a critical gelation concentration (CGC) of 5.0 wt % (w/v) at pH 7.4. Furthermore, circular dichroism study revealed the transition of the α-helix to a random coil upon increasing the pH. Due to the protonation of side chains at pH 4.0, PU-PP-1 adopted an α-helical conformation whereas at pH >8.0 the side-chain carboxylic acid groups of the PLGAs were ionized, leading to the formation of an extended random coil conformation as a result of charge repulsion. Conformational switching was also supported by FTIR spectroscopy.
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http://dx.doi.org/10.1002/asia.201901119DOI Listing
December 2019

Design and Synthesis of PEG-Oligoglycerol Sulfates as Multivalent Inhibitors for the Scavenger Receptor LOX-1.

Biomacromolecules 2019 03 4;20(3):1157-1166. Epub 2019 Feb 4.

Institute of Laboratory Medicine, Clinical Chemistry and Pathobiochemistry, Charité-Universitätsmedizin Berlin , Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Augustenburger Platz 1 , 13353 Berlin , Germany.

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a cell surface scavenger receptor. The protein is involved in binding and internalization of oxidized low-density lipoprotein (oxLDL), which leads under pathophysiological circumstances to plaque formation in arteries and initiation of atherosclerosis. A structural feature of LOX-1 relevant to oxLDL binding is the "basic spine" motif consisting of linearly aligned arginine residues stretched over the dimer surface. Inhibition of LOX-1 can be done by blocking these positively charged motifs. Here we report on the design, synthesis, and evaluation of a series of novel LOX-1 inhibitors having different numbers of sulfates and polyethylene glycerol (PEG) spacer. Two molecules, compounds 6b and 6d, showed binding affinity in the low nM range, i.e. 45.8 and 47.4 nM, respectively. The in vitro biological studies reveal that these molecules were also able to block the interaction of LOX-1 with its cognate ligands oxLDL, aged RBC, and bacteria.
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http://dx.doi.org/10.1021/acs.biomac.8b01416DOI Listing
March 2019

Interaction of human serum albumin with dendritic polyglycerol sulfate: Rationalizing the thermodynamics of binding.

J Chem Phys 2018 Oct;149(16):163324

Institute of Soft Matter and Functional Materials, Helmholtz-Zentrum Berlin, Hahn-Meitner-Platz 1, 14109 Berlin, Germany.

We study the thermodynamics of the interaction between human serum albumin (HSA) and dendritic polyglycerol sulfate (dPGS) of different sizes (generations) by isothermal titration calorimetry (ITC) and computer simulations. The analysis by ITC revealed the formation of a 1:1 complex for the dPGS-G2 of second generation. The secondary structure of HSA remained unchanged in the presence of dPGS-G2, as shown by circular dichroism. For higher generations, several HSA are bound to one polymer (dPGS-G4: 2; dPGS-G5.5: 4). The Gibbs free energy Δ was determined at different temperatures and salt concentrations. The binding constant exhibited a logarithmic dependence on the salt concentration thus indicating a marked contribution of counterion-release entropy to Δ . The number of released counterions (∼4) was found to be independent of temperature. In addition, the temperature dependence of Δ was small, whereas the enthalpy Δ was found to vary strongly with temperature. The corresponding heat capacity change Δ for different generations was of similar values [8 kJ/(mol K)]. The nonlinear van't Hoff analysis of Δ revealed a significant heat capacity change Δ of similar magnitude [6 kJ/(mol K)] accompanied by a strong enthalpy-entropy compensation. Δ obtained by molecular dynamics simulation with implicit water and explicit ions coincided with experimental results. The agreement indicates that the enthalpy-entropy compensation assigned to hydration effects is practically total and the binding affinity is fully governed by electrostatic interactions.
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http://dx.doi.org/10.1063/1.5030601DOI Listing
October 2018

Enhanced Permeability and Retention-like Extravasation of Nanoparticles from the Vasculature into Tuberculosis Granulomas in Zebrafish and Mouse Models.

ACS Nano 2018 08 15;12(8):8646-8661. Epub 2018 Aug 15.

Department of Biosciences , University of Oslo , Blindernveien 31 , 0371 Oslo , Norway.

The enhanced permeability and retention (EPR) effect is the only described mechanism enabling nanoparticles (NPs) flowing in blood to reach tumors by a passive targeting mechanism. Here, using the transparent zebrafish model infected with Mycobacterium marinum we show that an EPR-like process also occurs allowing different types of NPs to extravasate from the vasculature to reach granulomas that assemble during tuberculosis (TB) infection. PEGylated liposomes and other NP types cross endothelial barriers near infection sites within minutes after injection and accumulate close to granulomas. Although ∼100 and 190 nm NPs concentrated most in granulomas, even ∼700 nm liposomes reached these infection sites in significant numbers. We show by confocal microscopy that NPs can concentrate in small aggregates in foci on the luminal side of the endothelium adjacent to the granulomas. These spots are connected to larger foci of NPs on the ablumenal side of these blood vessels. EM analysis suggests that NPs cross the endothelium via the paracellular route. PEGylated NPs also accumulated efficiently in granulomas in a mouse model of TB infection with Mycobacterium tuberculosis, arguing that the zebrafish embryo model can be used to predict NP behavior in mammalian hosts. In earlier studies we and others showed that uptake of NPs by macrophages that are attracted to infection foci is one pathway for NPs to reach TB granulomas. This study reveals that when NPs are designed to avoid macrophage uptake, they can also efficiently target granulomas via an alternative mechanism that resembles EPR.
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http://dx.doi.org/10.1021/acsnano.8b04433DOI Listing
August 2018

Multivalent Flexible Nanogels Exhibit Broad-Spectrum Antiviral Activity by Blocking Virus Entry.

ACS Nano 2018 07 19;12(7):6429-6442. Epub 2018 Jun 19.

Institut für Virologie, Robert von Ostertag-Haus, Zentrum für Infektionsmedizin , Freie Universität Berlin , Robert-von-Ostertag-Str. 7-13 , 14163 Berlin , Germany.

The entry process of viruses into host cells is complex and involves stable but transient multivalent interactions with different cell surface receptors. The initial contact of several viruses begins with attachment to heparan sulfate (HS) proteoglycans on the cell surface, which results in a cascade of events that end up with virus entry. The development of antiviral agents based on multivalent interactions to shield virus particles and block initial interactions with cellular receptors has attracted attention in antiviral research. Here, we designed nanogels with different degrees of flexibility based on dendritic polyglycerol sulfate to mimic cellular HS. The designed nanogels are nontoxic and broad-spectrum, can multivalently interact with viral glycoproteins, shield virus surfaces, and efficiently block infection. We also visualized virus-nanogel interactions as well as the uptake of nanogels by the cells through clathrin-mediated endocytosis using confocal microscopy. As many human viruses attach to the cells through HS moieties, we introduce our flexible nanogels as robust inhibitors for these viruses.
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http://dx.doi.org/10.1021/acsnano.8b01616DOI Listing
July 2018

Biomimetic sulfated polyethylene glycol hydrogel inhibits proteoglycan loss and tumor necrosis factor-α-induced expression pattern in an osteoarthritis in vitro model.

J Biomed Mater Res B Appl Biomater 2019 04 16;107(3):490-500. Epub 2018 Apr 16.

Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Tissue Engineering Laboratory, Berlin-Brandenburg Center for Regenerative Therapies & Department of Rheumatology and Clinical Immunology, Berlin, Germany.

This study aimed to evaluate the potential of an anti-inflammatory polyethylene glycol (PEG) hydrogel for osteoarthritis (OA) management in an OA in vitro model. Freshly isolated porcine chondrocytes were maintained in high-density cultures to form cartilage-like three-dimensional micromasses. Recombinant porcine tumor necrosis factor-alpha (TNF-α) was used to induce OA-like changes. Normal and OA-like micromasses were treated with dendritic polyglycerol sulfate-based PEG hydrogel. Live/dead staining showed that all micromasses remained vital and presented similar morphological characteristics. Safranin-O staining demonstrated a typical depletion of glycosaminoglycans in TNF-α-treated micromasses but not in the presence of the hydrogel. There was no distinct difference in immunohistochemical detection of type II collagen. Microarray data showed that rheumatoid arthritis and TNF signaling pathways were down regulated in hydrogel-treated OA-like micromasses compared to nontreated OA-like micromasses. The hydrogel alone did not affect genes related to OA such as ANPEP, COMP, CXCL12, PTGS2, and TNFSF10, but it prevented their regulation caused by TNF-α. This study provides valuable insights toward a fully synthetic hydrogel for the intra-articular treatment of OA. The findings proved the potential of this hydrogel to prevent the development of TNF-α-induced OA with regard to proteoglycan loss and TNF-α-induced expression pattern without additional signs of differentiation and inflammation. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2018. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 490-500, 2019.
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http://dx.doi.org/10.1002/jbm.b.34139DOI Listing
April 2019

Bioorthogonal in Situ Hydrogels Based on Polyether Polyols for New Biosensor Materials with High Sensitivity.

ACS Appl Mater Interfaces 2018 Apr 21;10(13):11382-11390. Epub 2018 Mar 21.

Institut für Chemie und Biochemie, Freie Universität Berlin , Takustraße 3 , 14195 Berlin , Germany.

Both noncovalent and covalent encapsulations of active biomolecules, for example, proteins and oligonucleotides, for a new biosensor matrix in an in situ bioorthogonal hydrogel formation via a strain-promoted azide-alkyne cycloaddition reaction were investigated. Unspecific interaction between the gel and the biomolecules as well as protein denaturation was prevented by the bioorthogonal gel components, which ensure a uniform aqueous environment in the hydrogel network. No leaching of the active biomolecules was observed. Additionally, a much higher and also adjustable loading of biomolecules in the hydrogel matrix was achieved compared to conventional biosensor surfaces, where the sensor molecules are immobilized on monolayers (2D surfaces) or brushlike structures (3D surfaces). Spotting experiments of the hydrogel confirm the possibility to use this new surface for microarray-based multiplex applications which require very high signal-to-noise ratios.
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http://dx.doi.org/10.1021/acsami.8b01860DOI Listing
April 2018

Counterion-Release Entropy Governs the Inhibition of Serum Proteins by Polyelectrolyte Drugs.

Biomacromolecules 2018 02 10;19(2):409-416. Epub 2018 Jan 10.

Institut für Weiche Materie und Funktionale Materialien, Helmholtz-Zentrum Berlin , Hahn-Meitner-Platz 1, 14109 Berlin, Germany.

Dendritic polyelectrolytes constitute high potential drugs and carrier systems for biomedical purposes. Still, their biomolecular interaction modes, in particular those determining the binding affinity to proteins, have not been rationalized. We study the interaction of the drug candidate dendritic polyglycerol sulfate (dPGS) with serum proteins using isothermal titration calorimetry (ITC) interpreted and complemented with molecular computer simulations. Lysozyme is first studied as a well-defined model protein to verify theoretical concepts, which are then applied to the important cell adhesion protein family of selectins. We demonstrate that the driving force of the strong complexation, leading to a distinct protein corona, originates mainly from the release of only a few condensed counterions from the dPGS upon binding. The binding constant shows a surprisingly weak dependence on dPGS size (and bare charge) which can be understood by colloidal charge-renormalization effects and by the fact that the magnitude of the dominating counterion-release mechanism almost exclusively depends on the interfacial charge structure of the protein-specific binding patch. Our findings explain the high selectivity of P- and L-selectins over E-selectin for dPGS to act as a highly anti-inflammatory drug. The entire analysis demonstrates that the interaction of proteins with charged polymeric drugs can be predicted by simulations with unprecedented accuracy. Thus, our results open new perspectives for the rational design of charged polymeric drugs and carrier systems.
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http://dx.doi.org/10.1021/acs.biomac.7b01499DOI Listing
February 2018

Injectable hydrogels for treatment of osteoarthritis - A rheological study.

Colloids Surf B Biointerfaces 2017 Nov 5;159:477-483. Epub 2017 Aug 5.

Stranski-Laboratorium für Physikalische und Theoretische Chemie, Institut für Chemie, Technische Universität Berlin, Straße des 17. Juni 124, Sekr. TC 7, 10623 Berlin, Germany. Electronic address:

Osteoarthritis (OA) is a disabling condition especially in the elderly population. The current therapeutic approaches do not halt the OA progression or reverse joint damage. In order to overcome the problem of rapid clearance of hyaluronic acid (HA), a standard viscosupplement for OA, we investigated the rheological properties of a relatively non-degradable dendritic polyglycerol sulfate (dPGS) hydrogel to determine a suitable concentration for intra articular injections that mimics HA in terms of its viscoelastic and mechanical properties. To do so, the concentration range from 3.6 to 4.8wt% of dPGS and, as a reference, blends of commercially available HAs (Ostenil, GO-ON, Synocrom Forte and Synvisc), were investigated by means of oscillating and flow rheology, thereby yielding storage (G') and loss modulus (G"), as well as yield stress and shear viscosity. In our rheological experiments we observe a pronounced coupling of the molecular weight and the rheological properties for the HAs. Furthermore, we find the dPGS hydrogel to form more compact networks with increasing concentration. From a broader comparison the current findings suggest that an overall polymer concentration of 4.0wt% dPGS has viscoelastic properties that are comparable to hyaluronic acid in the medically relevant frequency range, where for medical application the dPGS hydrogel has the advantage of being much less easily displaced from its injection place than HA.
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http://dx.doi.org/10.1016/j.colsurfb.2017.07.073DOI Listing
November 2017

Mimicking of Chondrocyte Microenvironment Using In Situ Forming Dendritic Polyglycerol Sulfate-Based Synthetic Polyanionic Hydrogels.

Macromol Biosci 2016 Apr 11;16(4):580-90. Epub 2016 Jan 11.

Institut für Chemie und Biochemie, Freie Universität Berlin, Takustr. 3, 14195, Berlin, Germany.

A stable polymeric network that mimics the highly polyanionic extracellular cartilage matrix still remains a great challenge. The main aim of this study is to present the synthesis of dendritic polyglycerol sulfate (dPGS)-based in situ forming hydrogels using strain promoted azide-alkyne cycloaddition reactions. A real time rheological study has been used to characterize the hydrogel properties. The viability of encapsulated human chondrocytes in the different hydrogels are monitored using live-dead staining. Furthermore, type I and II collagen gene have been analyzed. Hydrogels with elastic moduli ranging from 1 to 5 kPa have been prepared by varying the dPGS amount. The chondrocyte viability in dPGS hydrogels is found to be higher than in pure PEG and alginate-based hydrogels after 21 d. The higher cell viability in the dPGS engineered hydrogels can be explained by the fact that dPGS can interact with different proteins responsible for cell growth and proliferation.
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http://dx.doi.org/10.1002/mabi.201500377DOI Listing
April 2016

Dendritic polyglycerol-poly(ethylene glycol)-based polymer networks for biosensing application.

ACS Appl Mater Interfaces 2014 Jun 5;6(12):8937-41. Epub 2014 Jun 5.

Institut für Chemie and Biochemie, Freie Universität Berlin , Takustrasse 3, 14195 Berlin, Germany.

This work describes the formation of a new dendritic polyglycerol-poly(ethylene glycol)-based 3D polymer network as a matrix for immobilization of the redox enzyme periplasmatic aldehyde oxidoreductase to create an electrochemical biosensor. The novel network is built directly on the gold surface, where it simultaneously stabilizes the enzyme for up to 4 days. The prepared biosensors can be used for amperometric detection of benzaldehyde in the range of 0.8-400 μM.
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http://dx.doi.org/10.1021/am502018xDOI Listing
June 2014

Mitochondrial DNA copy number and risk of oral cancer: a report from Northeast India.

PLoS One 2013 4;8(3):e57771. Epub 2013 Mar 4.

Department of Biotechnology, Assam University, Silchar, Assam, India.

Background: Oral squamous cell carcinoma (OSCC) is the sixth most common cancer globally. Tobacco consumption and HPV infection, both are the major risk factor for the development of oral cancer and causes mitochondrial dysfunction. Genetic polymorphisms in xenobiotic-metabolizing enzymes modify the effect of environmental exposures, thereby playing a significant role in gene-environment interactions and hence contributing to the individual susceptibility to cancer. Here, we have investigated the association of tobacco - betel quid chewing, HPV infection, GSTM1-GSTT1 null genotypes, and tumour stages with mitochondrial DNA (mtDNA) content variation in oral cancer patients.

Methodology/principal Findings: The study comprised of 124 cases of OSCC and 140 control subjects to PCR based detection was done for high-risk HPV using a consensus primer and multiplex PCR was done for detection of GSTM1-GSTT1 polymorphism. A comparative ΔCt method was used for determination of mtDNA content. The risk of OSCC increased with the ceased mtDNA copy number (Ptrend  = 0.003). The association between mtDNA copy number and OSCC risk was evident among tobacco - betel quid chewers rather than tobacco - betel quid non chewers; the interaction between mtDNA copy number and tobacco - betel quid was significant (P = 0.0005). Significant difference was observed between GSTM1 - GSTT1 null genotypes (P = 0.04, P = 0.001 respectively) and HPV infection (P<0.001) with mtDNA content variation in cases and controls. Positive correlation was found with decrease in mtDNA content with the increase in tumour stages (P<0.001). We are reporting for the first time the association of HPV infection and GSTM1-GSTT1 null genotypes with mtDNA content in OSCC.

Conclusion: Our results indicate that the mtDNA content in tumour tissues changes with tumour stage and tobacco-betel quid chewing habits while low levels of mtDNA content suggests invasive thereby serving as a biomarker in detection of OSCC.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0057771PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3587625PMC
August 2013

Computational validation of 3-ammonio-3-(4-oxido- 1H-imidazol-1-ium-5-yl) propane-1, 1-bis (olate) as a potent anti-tubercular drug against mt-MetAP.

Bioinformation 2012 21;8(18):875-80. Epub 2012 Sep 21.

Bioinformatics Centre (DBT-BIF), Assam University Silchar, Assam, India-788011.

The advent of Multi Drug Resistant (MDR) strain of Mycobacterium tuberculosis (TB) necessitated search for new drug targets for the bacterium. It is reported that 3.3% of all new tuberculosis cases had multidrug resistance (MDR-TB) in 2009 and each year, about 0.44 million MDR-TB cases are estimated to emerge and 0.15 million people with MDR-TB die. Keeping such an alarming situation under consideration we wanted to design suitable anti tubercular molecules for new target using computational tools. In the work Methionine aminopeptidase (MetAP) of Mycobacterium tuberculosis was considered as target and three non-toxic phenolic=ketonic compounds were considered as ligands. Docking was done with Flex X and AutoDock 4.2 separately. Ten proven inhibitors of MetAP were collected from literature with their IC50 and were correlated using EasyQSAR to generate QSAR model. Activity of ligands in question was predicted from QSAR. Pharmacophore for each docking was generated using Ligandscout 3.0. Toxicity of the ligands in question was predicted on [email protected] portal and Actelion property explorer. Molecular docking with target showed that of all three ligands, 3-ammonio-3-(4-oxido-1H-imidazol-1-ium-5-yl) propane-1, 1-bis (olate) has highest affinity (- 37.5096) and lowest IC50 (4.46 µM). We therefore, propose that -3-ammonio-3-(4-oxido-1H-imidazol-1-ium-5-yl) propane-1,1- bis(olate) as a potent MetAP inhibitor may be a new anti-tubercular drug particularly in the context of Multi Drug Resistant Tuberculosis (MDR-TB).
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http://dx.doi.org/10.6026/97320630008875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3489093PMC
November 2012
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