Polyglycerol-Functionalized ß-Cyclodextrins as Crosslinkers in Thermoresponsive Nanogels for the Enhanced Dermal Penetration of Hydrophobic Drugs.

Thermoresponsive nanogels (tNGs) are promising candidates for dermal drug delivery. However, poor incorporation of hydrophobic drugs into hydrophilic tNGs limits the therapeutic efficiency. To address this challenge, ß-cyclodextrins (ß-CD) are functionalized by hyperbranched polyglycerol serving as crosslinkers (hPG-ßCD) to fabricate ßCD-tNGs. This novel construct exhibits augmented encapsulation of hydrophobic drugs, shows the appropriate thermal response to dermal administration, and enhances the dermal penetration of payloads. The structural influences on the encapsulation capacity of ßCD-tNGs for hydrophobic drugs are analyzed, while concurrently retaining their efficacy as skin penetration enhancers. Various synthetic parameters are considered, encompassing the acrylation degree and molecular weight of hPG-ßCD, as well as the monomer composition of ßCD-tNGs. The outcome reveals that ßCD-tNGs substantially enhance the aqueous solubility of Nile Red elevating to 120 µg mL-1 and augmenting its dermal penetration up to 3.33 µg cm-2. Notably, the acrylation degree of hPG-ßCD plays a significant role in dermal drug penetration, primarily attributed to the impact on the rigidity and hydrophilicity of ßCD-tNGs. Taken together, the introduction of the functionalized ß-CD as the crosslinker in tNGs presents a novel avenue to enhance the efficacy of hydrophobic drugs in dermatological applications, thereby offering promising opportunities for boosted therapeutic outcomes.

Delocalization Engineering of Heme-Mimetic Artificial Enzymes for Augmented Reactive Oxygen Catalysis.

Developing artificial enzymes based on organic molecules or polymers for reactive oxygen species (ROS)-related catalysis has broad applicability. Herein, inspired by porphyrin-based heme mimics, we report the synthesis of polyphthalocyanine-based conjugated polymers (Fe-PPc-AE) as a new porphyrin-evolving structure to serve as efficient and versatile artificial enzymes for augmented reactive oxygen catalysis. Owing to the structural advantages, such as enhanced π-conjugation networks and π-electron delocalization, promoted electron transfer, and unique Fe-N coordination centers, Fe-PPc-AE showed more efficient ROS-production activity in terms of Vmax and turnover numbers as compared with porphyrin-based conjugated polymers (Fe-PPor-AE), which also surpassed reported state-of-the-art artificial enzymes in their activity. More interestingly, by changing the reaction medium and substrates, Fe-PPc-AE also revealed significantly improved activity and environmental adaptivity in many other ROS-related biocatalytic processes, validating the potential of Fe-PPc-AE to replace conventional (poly)porphyrin-based heme mimics for ROS-related catalysis, biosensors, or biotherapeutics. It is suggested that this study will offer essential guidance for designing artificial enzymes based on organic molecules or polymers.

Thermoresponsive Amphiphilic Functionalization of Thermally Reduced Graphene Oxide to Study Graphene/Bacteria Hydrophobic Interactions.

An understanding of the interactions of 2D nanomaterials with pathogens is of vital importance to developing and controlling their antimicrobial properties. In this work, the interaction of functionalized graphene with tunable hydrophobicity and bacteria is investigated. Poly(ethylene glycol)- block-(poly- N-isopropylacrylamide) copolymer (PEG- b-PNIPAM) with the triazine joint point was attached to the graphene surface by a nitrene [2 + 1] cycloaddition reaction. By thermally switching between hydrophobic and hydrophilic states, functionalized graphene sheets were able to bind to bacteria. Bacteria were eventually disrupted when the functionality was switched to the hydrophobic state. On the basis of measuring the different microscopy methods and a live/dead viability assay, it was found that Escherichia coli ( E. coli) bacteria are more susceptible to hydrophobic interactions than B. cereus bacteria, under the same conditions. Our investigations confirm that hydrophobic interaction is one of the main driving forces at the presented graphene/bacteria interfaces and promotes the antibacterial activity of graphene derivatives significantly.

Interactions of Fullerene-Polyglycerol Sulfates at Viral and Cellular Interfaces.

Understanding the mechanism of interactions of nanomaterials at biointerfaces is a crucial issue to develop new antimicrobial vectors. In this work, a series of water-soluble fullerene-polyglycerol sulfates (FPS) with different fullerene/polymer weight ratios and varying numbers of polyglycerol sulfate branches are synthesized, characterized, and their interactions with two distinct surfaces displaying proteins involved in target cell recognition are investigated. The combination of polyanionic branches with a solvent exposed variable hydrophobic core in FPS proves to be superior to analogs possessing only one of these features in preventing interaction of vesicular stomatitis virus coat glycoprotein (VSV-G) with baby hamster kidney cells serving as a model of host cell. Interference with L-selectin-ligand binding is dominated by the negative charge, which is studied by two assays: a competitive surface plasmon resonance (SPR)-based inhibition assay and the leukocyte cell (NALM-6) rolling on ligands under flow conditions. Due to possible intrinsic hydrophobic and electrostatic effects of synthesized compounds, pico- to nanomolar half maximal inhibitory concentrations (IC50 ) are achieved. With their highly antiviral and anti-inflammatory properties, together with good biocompatibility, FPS are promising candidates for the future development towards biomedical applications.

Bioconjugated graphene oxide hydrogel as an effective adsorbent for cationic dyes removal.

In this study, graphene oxide - cellulose nanowhiskers nanocomposite hydrogel was easily synthesized through covalent functionalization of cellulose nanowhiskers with graphene oxide via a facile approach. The nitrene chemistry applied for covalent functionalization of graphene oxide sheets. The surface morphology and chemical structure of the nanocomposite hydrogel were characterized by FTIR, TGA, Raman, XRD, elemental analysis and SEM. The UV/Visible absorption spectrum revealed that the obtained porous nanocomposite hydrogel can efficiently remove cationic dyes such as methylene blue (MB) and Rhodamine B (RhB) from wastewater with high absorption power. The adsorption process showed that 100% of MB and 90% of RhB have been removed and the equilibrium state has been reached in 15min for low concentration solutions in accordance with the pseudo-second-order model. Moreover, the sample exhibited stable performance after being used several times. High adsorption capacity and easy recovery are the efficient factors making these materials as good adsorbent for water pollutants and wastewater treatment.

Preparation, characterization and efficiency of nanoencapsulated imidacloprid under laboratory conditions.

In this work, nano-imidacloprid was prepared by direct encapsulation with ABA triblock linear dendritic copolymers composed of poly(citric acid) (PCA) as A block and poly(ethylene glycol) (PEG) as B block. Nanocapsules of imidacloprid were characterized using spectroscopy, microscopy and thermal analysis. The encapsulation process was performed by self-assembly of PCA-PEG-PCA in the presence of imidacloprid in different solvents. Comparison of the TEM images of nano-imidacloprid prepared in ethanol and water showed that, during the first day, self-assemblies appeared as small particles with an average size of 10-20nm. Depending upon the type of solvent, the time and concentration, morphology and size of the nano-imidacloprid varied from fiber-like to globular to tubular from 10nm to several mm in size. Higher loading capacity and slower release rate of imidacloprid from nano-imidacloprid at optimum pH of Glyphodes pyloalis׳s gut (pH=10) compared to neutral pH confirmed the selective and controllable action of nano-imidacloprid. Results of bioassays on the model insect showed that by using the nanoform of imidacloprid, essential dosage of pesticide and environmental risk decreased significantly and indicated good performance for this formulation.

Carbon nanotubes in cancer therapy: a more precise look at the role of carbon nanotube-polymer interactions.

Despite the great potential of carbon nanotubes (CNTs) in various areas of biomedicine, concerns regarding their carcinogenicity, inefficient dispersion in aqueous solutions and biological activity in vivo still remain. One important and feasible route to overcome these barriers is modification of CNTs with polymers, which are widely studied and play a vital role in biological and biomedical fields, especially in drug delivery. This comprehensive review focuses on the achievements of our and other groups in currently used methods to functionalize the surface of CNTs with polymers to produce anticancer drug delivery systems. We have intensively studied covalent and noncovalent interactions between CNTs and linear, dendritic and hyperbranched biocompatible polymers as well as biomacromolecules interactions which are very crucial to diminish the toxicity of CNTs via changing their conformations.

Thermo- and pH-sensitive dendrosomes as bi-phase drug delivery systems.

Fully supramolecular dendrosomes (FSD) as bi-phase drug delivery systems are reported in this work. For preparation of FSD, amphiphilic linear-dendritic supramolecular systems (ALDSS) have been synthesized by host-guest interactions between hyperbranched polyglycerol having ß-cyclodextrin core and bi-chain polycaprolactone (BPCL) with a fluorescine focal point. Self-assembly of ALDSS in aqueous solutions led to FSD. They were able to encapsulate paclitaxel with a high loading capacity. The dendrosome-based drug delivery systems were highly sensitive to pH and temperature. They were stable at 20-37 °C and pH7-8, but dissociated and released drug at temperatures lower than 20 °C or higher than 37 °C and pH lower than 7 quickly. Dissociation of FSD building blocks by temperature or pH resulted in inclusion complexes between the released drugs and polyglycerol as the secondary drug delivery system. FROM THE CLINICAL EDITOR: This paper reports on the development of a pH- (below 7) and temperature- (below 20 °C or above 37 °C) sensitive delivery system using supramolecular dendrosomes for more specific delivery and release of drugs using paclitaxel as a model.

Ferrocene/ ß-cyclodextrin based supramolecular nanogels as theranostic systems.

A supramolecular redox responsive nanogel (NG) with the ability to sense cancer cells and loaded with a releasing therapeutic agent was synthesized using hostguest interactions between polyethylene glycol-grafted-ß-cyclodextrin and ferrocene boronic acid. Cyclic voltammetry matched with other spectroscopy and microscopy methods provided strong indications regarding host-guest interactions and formation of the NG. Moreover, the biological properties of the NG were evaluated using fluorescence silencing, confocal laser scanning microscopy, and cell toxicity assays. Nanogel with spherical core-shell architecture and 100-200 nm sized nanoparticles showed high encapsulation efficiency for doxorubicin (DOX) and luminol (LU) as therapeutic and sensing agents. High therapeutic and sensing efficiencies were manifested by complete release of DOX and dramatic quenching of LU fluorescence triggered by 0.05 mM H2O2 (as an ROS component). The NGs showed high ROS sensitivity. Taking advantage of a high loading capacity, redox sensitivity, and biocompatibility, the NGs can be used as strong theranostic systems in inflammation-associated diseases.

A review on the impacts of metal/metal nanoparticles on characteristics of hydrogels: Special focus on carbohydrate polymers.

Hydrogels with very interesting properties such as high water content, porosity, swelling, and mimicking the structure of the extracellular matrix (ECM) are promising candidates for a variety of applications. Recently, great efforts are being made to improve the shape and functionality of three-dimensional (3D) hydrogels. One of the most promising approaches is the incorporation of metal or metal nanoparticles (NPs) into hydrogels made of natural and synthetic polymers such as proteins, carbohydrates (i.e. chitosan, carboxymethyl cellulose, hyaluronic acid, etc), and the development of dynamic functional hydrogels that have been extensively studied. This review article focuses on the incorporation of metals or metal NPs into hydrogels to enhance their functionality and properties. In the first part, various metal-based hydrogels including metal- coordinated hydrogels, metal-nanocomposite hydrogels, and their synthesis methods are discussed. Subsequently, various properties of metal-containing hydrogels such as mechanical, self-healing, bioadhesion, antibacterial activity, and conductivity are explained. Finally, stimuli-responsive metal-based hydrogels are discussed with a special focus on carbohydrate polymers. This review article presents a new perspective on the development of hydrogels for various biomedical applications.

Synthesis of new hybrid nanomaterials: promising systems for cancer therapy.

Polyrotaxanes consisting of cyclodextrin rings, polyethylene glycol axes and quantum dot (QD) stoppers were synthesized and characterized. The molecular self-assembly of polyrotaxanes led to spindlelike nano-objects whose shape, size and position were dominated by QD stoppers. Due to their well-defined molecular self-assemblies, carbohydrate backbone, high functionality and several types of functional groups together with the high luminescence yield, synthesized hybrid nanostructures were recognized as promising candidates for biomedical applications. The potential applications of the molecular self-assemblies as drug-delivery systems was investigated by conjugation of doxorubicin (DOX) to their functional groups and then release the drug inside the cancer cells in mouse tissue connective fibroblast adhesive cell line L929. It was found that the molecular self-assemblies quickly transfer through the cell membrane and slowly release the drug into the intracellular environment. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and cell cycle assays showed that the molecular self-assemblies degrade back into individual molecules that can be broken down by the cell metabolically, confirming that they can be used as new drug-delivery systems with high treatment efficacy and minimum side effects for future cancer therapy, thus forming a firm foundation for further study and improvement. FROM THE CLINICAL EDITOR: This study investigates polyrotaxanes consisting of cyclodextrin rings, polyethylene glycol axes and quantum dot (QD) stoppers as promising candidates for biomedical applications, including cancer therapy.

Co-Delivery of Doxorubicin and Chloroquine by Polyglycerol Functionalized MoS2 Nanosheets for Efficient Multidrug-Resistant Cancer Therapy.

2D MoS2 has shown a great potential in biomedical applications, due to its superior loading capacity, photothermal property, and biodegradation. In this work, polyglycerol functionalized MoS2 nanosheets with photothermal and pH dual-stimuli responsive properties are used for the co-delivery of doxorubicin and chloroquine and treatment of multidrug-resistant HeLa (HeLa-R) cells. The polyglycerol functionalized MoS2 nanosheets with 80 nm average size show a high biocompatibility and loading efficiency (≈90%) for both drugs. The release of drugs from the nanosheets at pH 5.5 is significantly promoted by laser irradiation leading to efficient destruction of incubated HeLa-R cells. In vitro evaluation shows that the designed nanoplatform has a high ability to kill HeLa-R cells. Confocal experiments demonstrate that the synthesized drug delivery system enhances the cellular uptake of DOX via folic acid targeting ligand. Taking advantage of the combined properties including biocompatibility and targeting ability as well as high loading capacity and photothermal release, this multifunctional nanosystem is a promising candidate for anticancer therapy.

Poly(citric acid)-block-poly(ethylene glycol) copolymers--new biocompatible hybrid materials for nanomedicine.

Linear-dendritic ABA triblock copolymers containing poly(ethylene glycol) (PEG) as B block and hyperbranched poly(citric acid) (PCA) as A blocks were synthesized through polycondensation. The molecular self-assembly of synthesized PCA-PEG-PCA copolymers in water led to formation of nanoparticles and fibers in different sizes and shapes depending on the time and size of PCA blocks. Ten days after dissolving PCA-PEG-PCA copolymers in water, the size of fibers had reached several millimeters. Mixing a water solution of fluorescein as a small guest molecule and PCA-PEG-PCA copolymers led to the encapsulation of fluorescein by products of molecular self-assembly. To investigate their potential application in nanomedicine and to understand the limitations and capabilities of these materials as nanoexcipients in biological systems, different types of short-term in vitro cytotoxicity experiments on the HT1080 cell line (human fibrosarcoma) and hemocompatibility tests were performed. From the clinical editor: This manuscript investigates the potentials of linear-dendritic ABA triblock copolymers containing poly(ethylene glycol) (PEG) as B block and hyperbranched poly(citric acid) (PCA) as A blocks for future applications in nanomedicine.

The bio-interface between functionalized Au NR@GO nanoplatforms with protein corona and their impact on delivery and release system.

Interaction of nanoplatforms with biomolecules in biological fluids alters nanoplatforms approach to target tissue and deliver their cargo. Here in, three nanoplatforms were utilized as a carrier to detect the effects of subsequent biomolecules on gene delivery using NIR thermal therapy. Nanoplatforms included; graphene oxide coated gold nanorods (NR@GO), PEGylated NR@GO (NR@GO-PEG) and poly L arginine functionalized NR@GO-PEG (NR@GO-PEG-PLArg). Results indicated that incubation of nanoplatforms in different concentrations of human plasma induced the evolution of layer of proteins (corona) with different thickness on the surface of nanoplatforms. Protein corona decreased the surface charge and optical properties of nanoplatforms. Corona subunits of ITIH, HAS and APOs protein family were extracted from NR@GO-PEG-PLArg surface that play a major role in cellular internalization of nanoplatforms. Moreover, NR@GO-PEG-PLArg remarkably targeted the cancer cells due to uncovered long linear chains of targeting agent (PLArg). The process of gene release and activating apoptotic pathway were enhanced by NIR thermal therapy, which could disrupt the electrostatic interactions and release the protein corona and genes from the surface of nanoplatforms. In conclusion, modification of nanoplatforms with targeting agents could alter the composition of corona toward well interaction with cell and deliver the therapeutic agent.

Functionalized 2D nanomaterials with switchable binding to investigate graphene-bacteria interactions.

Graphene and its derivatives have recently attracted much attention for sensing and deactivating pathogens. However, the mechanism of multivalent interactions at the graphene-pathogen interface is not fully understood. Since different physicochemical parameters of graphene play a role at this interface, control over graphene's structure is necessary to study the mechanism of these interactions. In this work, different graphene derivatives and also zwitterionic graphene nanomaterials (ZGNMs) were synthesized with defined exposure, in terms of polymer coverage and functionality, and isoelectric points. Then, the switchable interactions of these nanomaterials with E. coli and Bacillus cereus were investigated to study the validity of the generally proposed "trapping" and "nano-knives" mechanisms for inactivating bacteria by graphene derivatives. It was found that the antibacterial activity of graphene derivatives strongly depends on the accessible area, i.e. edges and basal plane of sheets and tightness of their agglomerations. Our data clearly confirm the authenticity of "trapping" and "nano-knives" mechanisms for the antibacterial activity of graphene sheets.

Synthesis, self-assembly, and photocrosslinking of fullerene-polyglycerol amphiphiles as nanocarriers with controlled transport properties.

In this work, we report a new, simple, gram-scale method for synthesizing water-soluble fullerene-polyglycerol amphiphiles (FPAs) that self-assemble into partially and fully crosslinked nanoclusters with the ability to controllably transport hydrophobic and hydrophilic agents.

Advances in the biomedical application of polymer-functionalized carbon nanotubes.

Nowadays, carbon nanotubes (CNTs) have attracted the attention of scientists because of their unique electronic, magnetic, optical, mechanical, and chemical properties. However, their poor solubility in solvents, especially in water, limits their applications in several promising fields such as biomedicine, biomedical imaging, and cancer therapy. The attachment of hydrophilic segments to CNTs is a very efficient method for overcoming this problem. This review covers the latest advances in the synthesis of water-soluble CNTs with an emphasis on the molecular structure of various categories of hydrophilic molecules/macromolecules which have been grafted onto the surface of CNTs. Indeed, from the viewpoint of chemical synthesis, covalent bonding of several water-soluble molecules/macromolecules including small water-soluble organic molecules, linear, hyperbranched and dendritic polymers/biopolymers, glycoconjugate molecules/polymers as well as biomolecules onto the surface of CNTs has been deeply surveyed. Moreover, the most recent and interesting bio-applications of polymer-functionalized water-soluble CNTs have been properly reviewed.

Linear-dendritic copolymers/indoxacarb supramolecular systems: biodegradable and efficient nano-pesticides.

Photodegradable and biocompatible nano-indoxacarb was prepared successfully by encapsulation of indoxacarb with poly(citric acid)-poly(ethylene glycol)-poly(citric acid) (PCA-PEG-PCA) ABA type linear-dendritic copolymers both with (nano-IND/TiO2) and without (nano-IND) TiO2 nanoparticles via supramolecular interactions. Preparation of nano-indoxacarb by both formulae was confirmed using spectroscopy and microscopy analyses. TEM images showed small particles with average sizes of 10 nm for nano-IND and 12 nm for nano-IND/TiO2. Interestingly, the rate of degradation of indoxacarb in both nano-IND/TiO2 and nano-IND exposed to UV and natural light was higher than that for free indoxacarb in the presence of TiO2 nanoparticles. Furthermore, results of bioassay experiments on the model pest showed that the essential dosage of pesticide for pest control significantly decreased when nano-IND and nano-IND/TiO2 were used. Because of the higher loading capacity and slower release rate for indoxacarb from nano-IND than from nano-IND/TiO2, and because TiO2 nanoparticles show toxicity in bioassay experiments, nano-IND is introduced as a promising and eco-friendly pesticide system.

Synthesis of pseudopolyrotaxanes-coated Superparamagnetic Iron Oxide Nanoparticles as new MRI contrast agent.

Superparamagnetic Iron Oxide Nanoparticles (SPIONs) were synthesized and coated with pseudopolyrotaxanes (PPRs) and proposed as a novel hybrid nanostructure for medical imaging and drug delivery. PPRs were prepared by addition of α-cyclodextrin rings to functionalized polyethylene glycol (PEG) chain with hydrophobic triazine end-groups. Non-covalent interactions between SPIONs and PPRs led to the assembly of SPIONs@PRs hybrid nanomaterials. Measurements of the (1)H Nuclear Magnetic Resonance (NMR) relaxation times T(1) and T(2) allowed us to determine the NMR dispersion profiles. Comparison between our SPIONs@PRs hybrid nano-compound and the commercial SPION compound, Endorem, showed a higher transverse relaxivity for SPIONs@PRs. In vitro MRI experiments showed that our SPIONs@PRs produces better negative contrast compared to Endorem and can be considered as a novel MRI contrast agent.

Design and synthesis of novel polyglycerol hybrid nanomaterials for potential applications in drug delivery systems.

The synthesis of a new drug delivery system based on hybrid nanomaterials containing a ß-CD core and hyperbranched PG is described. Conjugating PG branches onto ß-CD not only increases its water solubility but also affects its host/guest properties deeply. It can form molecular inclusion complexes with small hydrophobic guest molecules such as ferrocene or FITC with reasonable release. In addition, the achievable payloads are significantly higher as for carriers such as hyperbranched PGs. Short-term in vitro cytotoxicity and hemocompatibility tests on L929 cell lines show that the hybrid nanomaterial is highly biocompatible. Due to their outstanding properties, ß-CD-g-PG hybrid nanomaterials are introduced as promising materials for nanomedicine, e.g., for drug delivery issues.