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Dendritic hydrogels based on carbosilane crosslinkers are promising drug delivery systems, as their amphiphilic nature improves the compatibility with poorly water-soluble drugs. In this work, we explored the impact of the complementary polymer on the amphiphilic properties of the dendritic network. Different polymers were selected as precursors, from the highly lipophilic propylene glycol (PPG) to the hydrophilic polyethylene glycol (PEG), including amphiphilic Pluronics L31, L35 and L61. The dithiol polymers reacted with carbosilane crosslinkers through UV-initiated thiol-ene coupling (TEC), and the resultant materials were classified as non-swelling networks (for PPG, PLU L31 and PLU L61 ) and high-swelling hydrogels (for PEG and PLU L35 ). The hydrogels exhibited thermo-responsive properties, shrinking at higher temperatures, and exhibited an intriguing drug release pattern due to internal nanostructuring. Furthermore, we fine-tuned the dendritic crosslinker, including hydroxyl and azide pendant groups in the focal point, generating functional networks that can be modified through degradable (ester) and non-degradable (triazol) bonds. Overall, this work highlighted the crucial role of the amphiphilic balance in the design of dendritic hydrogels with thermo-responsive behavior and confirmed their potential as functional networks for biomedical applications.

Cationic dendritic amphiphiles were prepared through the linkage of interesting hydrophobic molecules such as cholesterol or vitamin E to the focal point of carbosilane dendrons. These new dendritic systems self-assembled in saline, producing micellar aggregates with hydrodynamic diameters ranging from 6.5 to 9.2 nm, and critical micelle concentrations of approximately 5 and 10 μM for second- and third-generation systems, respectively. The assemblies were able to encapsulate drugs of different charges (anionic, neutral, and cationic). Surprisingly, a 92% encapsulation efficiency for diclofenac was achieved in micelles prepared from second-generation dendrons. Toxicity measurements on peripheral blood mononuclear cells indicated different behavior depending on the generation, corresponding to the micellar regime. In contrast to the third-generation system, the second-generation system was non-toxic up to 20 μM, opening a window for its use in a micellar regimen, thereby operating as a drug delivery system for different biomedical applications.

Separation of PEGylated protein mixtures into individual species is a challenging procedure, and many efforts have been focused on creating novel chromatographic supports for this purpose. In this study, a new monolithic stationary phase with hyperbranched nanostructures was chemically synthesized. For this, monoliths with a support matrix of poly (glycidyl methacrylate-co-ethylene dimethacrylate) and ethylenediamine chemistry were modified with third-generation dendrons with butyl-end groups. The new monolith was analyzed by infrared spectroscopy, confirming the dendron with butyl ligands and exhibited low mass transfer resistance as observed by breakthrough frontal analysis. This support was able to separate mono-PEG ribonuclease A from the PEGylation mixture, indicated by a single band (∼30 kDa) in the electrophoretic analysis. Moreover, the separation of mono-PEGylated positional isomers was probably observed, as the protein with ∼30 kDa was found in two separate peaks. Interestingly, the dendronized monolith allowed the separation of the reaction mixture into individual PEGylated species when using high ammonium sulfate concentrations (2 M). A correlation between the PEGylation degree and the strength of the hydrophobic interactions on the monolith was observed. This chromatographic approach combines the natural branched architecture of dendrons and the higher capabilities of the monoliths enhancing the hydrophobic surface area, and therefore the interaction between the PEGylated proteins and ligands. Thus, the novel support represents a novel platform for the purification of PEGylated from non-PEGylated proteins with biotechnological applications., (© 2023 Wiley-VCH GmbH.)

Two families of phosphorhydrazone dendrons having either an azide or an alkyne linked to the core and diverse types of pyridine derivatives as terminal functions have been synthesized and characterized. These dendrons were grafted via click reaction to graphene oxide (GO) functionalized with either alkyne or azide functions, respectively. The resulting modified-GO and GO-dendrons materials have been characterized by Fourier Transform Infrared (FTIR), Raman spectroscopy (RS), and Magic Angle Spinning Nuclear Magnetic Resonance (MAS NMR) analyses. In addition, the free dendrons and the dendrons grafted to GO were tested toward cancerous (HCT116) and non-cancerous (RPE1) cell lines., (© 2023 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

The Staudinger reaction between a phosphine and an azide, applied to phosphorus azides, has been used for the synthesis of a large variety of dendritic structures, incorporating P=N-P=X moieties (X = mainly S, but also O and N-R). Conjugation of the P=N bond with the P=X bond greatly stabilizes the P=N bond. Highly branched structures such as dendrons, dendrimers, Janus dendrimers, layered dendrimers, surface-block dendrimers, and diverse other dendritic structures incorporating such linkage have been elaborated. Accelerated methods of synthesis of dendrimers are also based on the Staudinger reaction. A versatile reactivity was observed exclusively on the sulfur atom of P=N-P=S linkages, such as alkylation or complexation. Alkylation on S induces a weakening of the strength of the P=S bond, which can be easily cleaved to generate phosphines able to react in Staudinger reactions inside the structure of dendrimers, thus affording highly sophisticated dendritic structures., (© 2023 Wiley-VCH GmbH.)

DNA origami has emerged as a common technique to create custom two- (2D) and three-dimensional (3D) structures at the nanoscale. These DNA nanostructures have already proven useful in development of many biotechnological tools; however, there are still challenges that cast a shadow over the otherwise bright future of biomedical uses of these DNA objects. The rather obvious obstacles in harnessing DNA origami as drug-delivery vehicles and/or smart biodevices are related to their debatable stability in biologically relevant media, especially in physiological low-cation and endonuclease-rich conditions, relatively poor transfection rates, and, although biocompatible by nature, their unpredictable compatibility with the immune system. Here we demonstrate a technique for coating DNA origami with albumin proteins for enhancing their pharmacokinetic properties. To facilitate protective coating, a synthesized positively charged dendron was linked to bovine serum albumin (BSA) through a covalent maleimide-cysteine bonding, and then the purified dendron-protein conjugates were let to assemble on the negatively charged surface of DNA origami via electrostatic interaction. The resulted BSA-dendron conjugate-coated DNA origami showed improved transfection, high resistance against endonuclease digestion, and significantly enhanced immunocompatibility compared to bare DNA origami. Furthermore, our proposed coating strategy can be considered highly versatile as a maleimide-modified dendron serving as a synthetic DNA-binding domain can be linked to any protein with an available cysteine site., (© 2023. Springer Science+Business Media, LLC, part of Springer Nature.)

Precision antisense antibacterial agents may be developed into novel antibiotics in the fight against multidrug-resistant Gram-negative bacteria. In this study, a series of diaminobutanoic acid (DAB) dendrons are presented as novel carriers for the delivery of antisense antibacterial peptide nucleic acids (PNAs). The dendron-PNA conjugates targeting the essential acpP gene exhibit specific antisense antimicrobial bactericidal activity against Escherichia coli and Klebsiella pneumoniae at one-digit micromolar concentrations, while showing low toxicity to human cells. One compound selected from a structure-activity relationship series showed high stability in mouse and human serum ( t 1/2 ≫ 24 h) as well as in vivo activity against a multidrug-resistant, extended spectrum beta-lactamase-producing E. coli in a murine peritonitis model. The compound was also well tolerated in mice upon i.v. administration up to a dose of 20 mg/kg, and in vivo fluorescence imaging indicated clearance via renal excretion with slight accumulation in the kidneys and liver. Thus, DAB-based dendrons constitute a promising new chemistry platform for development of effective delivery agents for antibacterial drugs with possible in vivo use.

Three new amino- s -triazine-based dendrons, 1a , 1b , and 1c , containing an aryl-CN moiety in the dendritic skeleton were prepared in 72-81% yields ( 1a : R 1 = - N( n -C 8 H 17 ) 2 , R 2 = n -OC 8 H 17 , 1b : R 1 = R 2 = - N( n -C 8 H 17 ) 2 , 1c : R 1 = - N( n -C 8 H 17 ) 2 , R 2 = - N( n -C 4 H 9 ) 2 ). Dendrons 1a with N( n -C 8 H 17 ) 2 and n -OC 8 H 17 peripheral substituents, surprisingly, did not show any mesogenic phase during the thermal process. However, non-mesogenic 1a can be converted to mesogenic 1b or 1c by eliminating the peripheral dipole arising from the alkoxy substituent; dendron 1b only comprising the same N( n -C 8 H 17 ) 2 peripheral groups showed a ~25 °C mesogenic range on heating and ~108 °C mesogenic range on cooling. In contrast, dendron 1c possessing different N( n -C m H 2m+1 ) 2 (m = 8 versus m = 4) peripheral units, having similar stacking as 1b , exhibited a columnar phase on thermal treatment, but its mesogenic range (~9 and ~66 °C on heating and cooling, respectively) was much narrower than that of 1b, attributed to 1c 's less flexible alkyl chains in the peripheral part of dendron. Dendron 1a with the alkoxy substituent in the peripheral skeleton, creating additional dipole correspondingly, thus, leads to the dendritic molecules having a non-mesogenic stacking. Without the peripheral dipole for intermolecular side-by-side interaction, dendrons 1b and 1c exhibit a columnar phase on thermal treatment because of the vibration from the peripheral alkyl chain.

Functional supramolecular gel materials have potential applications in sensors, optical switches, artificial antennae, drug delivery and so on. In this paper, quinoline-cored poly(aryl ether) dendritic organogelators were designed, synthesized and fully characterized. The gelation behaviour of the dendritic organogelator was tested in organic solvents, mixed solvents and ionic liquids. The dendron Q-G1 was found to be an efficient and versatile organogelator toward various apolar and polar organic solvents with the critical gelation concentrations (CGCs) approaching 1.2×10 -2  mol/L, indicating one dendritic organogelator could immobilize 1.2×10 3 solvent molecules in the organogel network. Interestingly, these dendrons exhibited excellent gel formation in ionic liquids. Notably, these dendritic organogels were found to display multiple stimuli-responsive properties toward external stimuli including heat, ultrasound and shear stress, with a reversible sol-gel phase transition. In addition, the dendritic organogel could effectively adsorb heavy metals and organic dyes. The removal rate of Pb 2+ was up to 20% and the adsorption rate for Rhodamine B was as high as 89%., (© 2021 Wiley-VCH GmbH.)

Carbon-carbon cross-coupling reactions are among the most important synthetic tools for the preparation of pharmaceuticals and bioactive compounds. However, these reactions are normally carried out using copper, phosphines, and/or amines, which are poisonous for pharmaceuticals. The use of nanocomposite catalysts holds promise for facilitating these reactions and making them more environmentally friendly. In the present work, the PEGylated (PEG stands for poly(ethylene glycol) pyridylphenylene dendrons immobilized on silica loaded with magnetic nanoparticles have been successfully employed for the stabilization of Pd 2+ complexes and Pd nanoparticles. The catalyst developed showed excellent catalytic activity in copper-free Sonogashira and Heck cross-coupling reactions. The reactions proceeded smoothly in green solvents at low palladium loading, resulting in high yields of cross-coupling products (from 80% to 97%) within short reaction times. The presence of magnetic nanoparticles allows easy magnetic separation for repeated use without a noticeable decrease of catalytic activity due to the strong stabilization of Pd species by rigid and bulky dendritic ligands. The PEG dendron periphery makes the catalyst hydrophilic and better suited for green solvents. The minor drop in activity upon the catalyst reuse is explained by the formation of Pd nanoparticles from the Pd 2+ species during the catalytic reaction. The magnetic separation and reuse of the nanocomposite catalyst reduces the cost of target products as well as energy and material consumption and diminishes residual contamination by the catalyst. These factors as well as the absence of copper in the catalyst makeup pave the way for future applications of such catalysts in cross-coupling reactions.

AB 5 compounds issued from the reactivity of hexachlorocyclotriphosphazene are relatively easy to obtain using two ways: either first the reaction of one chloride with one reagent, followed by the reaction of the five remaining Cl with another reagent, or first the reaction of five chlorides with one reagent, followed by the reaction of the single remaining Cl with another reagent. This particular property led to the use of such compounds as core for the synthesis of dendrons (dendritic wedges), using the five functions for growing the dendritic branches. The single function can be used for the synthesis of diverse types of dendrimers (onion peel, dumbbell-shape, Janus), for covalent or non-covalent grafting to solid surfaces, providing nanomaterials, for grafting a fluorophore, especially for studying biological mechanisms, or for self-associations to get micelles. All these properties are reviewed in this paper.

Antibiotic resistance and biofilm-related infections, persistent in conventional antimicrobial treatment, are continuously increasing and represent a major health problem worldwide. Therefore, the development of new effective treatments to prevent and treat biofilm-related infections represents a crucial challenge. Unfortunately, the extensive use of antibiotics has led to an increase of resistant bacteria with the subsequent loss of effectivity of commercial antibiotics, mainly due to antibiotic resistance and the ability of some bacteria to form microbial communities in biotic or abiotic surfaces (biofilms). In some cases, these biofilms are resistant to high concentrations of antibiotics that lead to treatment failure and recurrence of the associated infections. In the fight against microbial resistance, the combination of traditional antibiotics with new compounds (combination therapy) is an alternative that is becoming more extensive in the medical field. In this work, we studied the cooperative effects between levofloxacin, an approved antibiotic, and peptides or cationic dendritic molecules, compounds that are emerging as a feasible solution to overcome the problem of microbial resistance caused by pathogenic biofilms. We studied a new therapeutic approach that involves the use of levofloxacin in combination with a cationic carbosilane dendron, called MalG 2 (SNHMe 2 Cl) 4 , or a synthetic cell-penetrating peptide, called gH625, conjugated to the aforementioned dendron. To carry out the study, we used two combinations (1) levofloxacin/dendron and (2) levofloxacin/dendron-peptide nanoconjugate. The results showed the synergistic effect of the combination therapy to treat Staphylococcus aureus biofilms. In addition, we generated a fluorescein labeled peptide that allowed us to observe the conjugate (dendron-peptide) localization throughout the bacterial biofilm by confocal laser scanning microscopy.

Combination treatment through the co-delivery of drugs and genes by nanoformulations may achieve a synergistic effect. In our previous study, poly(amidoamine) dendronized chitosan derivative (PAMAM-Cs) showed good gene transfection efficiency and low cytotoxicity. Here, we incorporated hydrophobic deoxycholic acid (DCA) onto the chitosan backbone of PAMAM-Cs to obtain an amphiphilic derivative-PAMAM-Cs-DCA, which could self-assemble into cationic nanoparticles (NPs). The resulting NPs with diameters of 140-220 nm can encapsulate the hydrophobic anticancer drug doxorubicin (DOX) in the core while bind pDNA via the positively charged PAMAM shell. PAMAM-Cs-DCA NPs could completely complex with pDNA at a ratio of nitrogen to phosphorous (N/P) low as 1 and the complexes achieved a transfection efficiency up to 74 % at N/P 20. Moreover, low-dose co-delivered DOX could enhance the transgene expression, showing a synergistic effect. These results suggest that PAMAM-Cs-DCA NPs hold great promise to co-deliver chemotherapeutics and nucleic acid drugs., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The interaction of nanoparticles (NP) with proteins (the so-called 'protein corona') is a huge challenge in attempting to apply them in personalized nanomedicine. We have analyzed the interaction between A) two 'soft' NPs (a cationic phosphorus dendrimer of generation 3; a cationic phosphorus amphiphilic dendron of generation 2), and B) one 'hard' nanoparticle (silver NP covered with cationic carbosilane dendritic moieties); and membrane-bound protein phospholipase A2 from bovine pancreas. The hard and soft NPs have differences in the nature of their interactions with phospholipase A2. This enzyme surrounds hard AgNP, whereas dendrimer and amphiphilic dendron form aggregates/micelles with phospholipase A2. There is a difference in action of phospholipase A2 bound to the core of dendrimer, and of micelles formed from non-covalent interactions between the amphiphilic dendron. These data are important in understanding the nature of interaction between different kinds of nanoparticles and proteins., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Acute stress is a potent suppressor of pulsatile luteinizing hormone (LH) secretion, but the mechanisms through which corticotrophin-releasing hormone (CRH) neurons inhibit gonadotropin-releasing hormone (GnRH) release remain unclear. The activation of paraventricular nucleus (PVN) CRH neurons with Cre-dependent hM3Dq in Crh-Cre female mice resulted in the robust suppression of pulsatile LH secretion. Channelrhodopsin (ChR2)-assisted circuit mapping revealed that PVN CRH neuron projections existed around kisspeptin neurons in the arcuate nucleus (ARN) although many more fibers made close appositions with GnRH neuron distal dendrons in the ventral ARN. Acutely prepared brain slice electrophysiology experiments in GnRH- green fluorescent protein (GFP) mice showed a dose-dependent (30 and 300 nM CRH) activation of firing in ~20% of GnRH neurons in both intact diestrus and ovariectomized mice with inhibitory effects being uncommon (<8%). Confocal GCaMP6 imaging of GnRH neuron distal dendrons in acute para-horizontal brain slices from GnRH-Cre mice injected with Cre-dependent GCaMP6s adeno-associated viruses demonstrated no effects of 30 to 300 nM CRH on GnRH neuron dendron calcium concentrations. Electrophysiological recordings of ARN kisspeptin neurons in Crh-Cre,Kiss1-GFP mice revealed no effects of 30 -300 nM CRH on basal or neurokinin B-stimulated firing rate. Similarly, the optogenetic activation (2-20 Hz) of CRH nerve terminals in the ARN of Crh-Cre,Kiss1-GFP mice injected with Cre-dependent ChR2 had no effect on kisspeptin neuron firing. Together, these studies demonstrate that PVN CRH neurons potently suppress LH pulsatility but do not exert direct inhibitory control over GnRH neurons, at their cell body or dendron, or the ARN kisspeptin neuron pulse generator in the female mouse., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The neural mechanisms generating pulsatile GnRH release from the median eminence (ME) remain unclear. Studies undertaken in the mouse demonstrate that GnRH neurons extend projections to the ME that have properties of both dendrites and axons, termed "dendrons," and that the kisspeptin neuron pulse generator targets these distal dendrons to drive pulsatile GnRH secretion. It presently remains unknown whether the GnRH neuron dendron exists in other species. We report here the generation of a knock-in Gnrh1-Ires-Cre rat line with near-perfect targeting of Cre recombinase to the GnRH neuronal phenotype. More than 90% of adult male and female GnRH neurons express Cre with no ectopic expression. Adeno-associated viruses were used in adult female Gnrh1-Ires-Cre rats to target mCherry or GCAMP6 to rostral preoptic area GnRH neurons. The mCherry tracer revealed the known unipolar and bipolar morphology of GnRH neurons and their principal projection pathways to the external zone of the ME. Synaptophysin-labeling of presynaptic nerve terminals revealed that GnRH neuron distal projections received numerous close appositions as they passed through the arcuate nucleus and into the median eminence. Confocal GCaMP6 imaging in acute horizontal brain slices demonstrated that GnRH neuron distal projections lateral to the median eminence were activated by kisspeptin. These studies indicate the presence of a dendron-like arrangement in the rat with GnRH neuron distal projections receiving synaptic input and responding to kisspeptin., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

A family of heterofunctional Schiff base carbosilane metallodendrons with [Ru(η 5 -C 5 H 5 )(PTA)Cl] (PTA = 1,3,5-triaza-7-phosphatricyclo-[3.3.1.1]decane) at the focal point and dimethylamino groups on the periphery are described. The new systems have proved their ability to interact with biological molecules such as Human Serum Albumin (HSA) without affecting its secondary structure and erythrocytes membranes, causing haemolysis in a dose and generation dependent way. The combination of two active functional groups in one single dendritic platform has shown a cooperative effect in the viability of HeLa and PC-3 cells, with the second generation derivative standing out as the most promising with the lowest IC 50 . Experiments focused on advanced prostate cancer have shown an antimetastasic activity for those metallodendrons, hindering the adhesion of cells in one of the main targets of metastasis, bones, and inhibiting cell migration. Finally, the second generation metallodendron with one single metal centre and four dimethylamino groups on the dendritic wedge, was selected for an ex vivo experiment in nude mice with advanced prostate cancer inhibiting the tumour growth in a 40% compared to control mice., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Supramolecular constructions of amphiphilic dendritic molecules are promising vehicles for anti-cancer drug delivery due to the flexibility of their architecture, high drug loading capacity and avoiding off-target effects of a drug. Herein, we report a new class of amphiphilic dendritic species-triazine-carbosilane dendrons readily self-assembling into pH-sensitive dendrimersomes. The dendrimersomes efficiently encapsulate anticancer drugs doxorubicin and methotrexate. Chemodrug-loaded dendrimersomes have dose-related cytotoxic activity against leukaemia cell lines 1301 and K562. Our findings suggest that triazine-carbosilane dendrimersomes are prospective drug carriers for anti-cancer therapy.

The gonadal steroids estradiol and progesterone exert critical suppressive and stimulatory actions upon the brain to control gonadotropin-releasing hormone (GnRH) release that drives the estrous/menstrual cycle. A simple model for understanding these interactions is proposed in which the activity of the "GnRH pulse generator" is restrained by post-ovulation progesterone secretion to bring about the estrus/luteal phase slowing of pulsatile gonadotropin release, while the activity of the "GnRH surge generator" is primed by the rising follicular phase levels of estradiol to generate the pre-ovulatory surge. The physiological fluctuations in estradiol levels across the cycle are considered to clamp the GnRH pulse generator output at a constant level. Independent pulse and surge generator circuitries regulate the excitability of different compartments of the GnRH neuron. As such, GnRH secretion through the cycle is determined simply by the summed influence of the estradiol-clamped, progesterone-regulated pulse and estradiol-regulated surge generators on the GnRH neuron., (Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.)

Background: Gene delivery to target cells is crucially important to establish gene therapy and regenerative medicine. Although various virus-based and synthetic molecule-based gene vectors have been developed to date, selective transfection in a site or a cell level is still challenging. For this study, both light-responsive and temperature-responsive synthetic gene vectors were designed for spatiotemporal control of a transfection system., Methods: 11-Mercaptoundecanoic acid-coated gold nanorods were mixed with polyamidoamine dendron-bearing lipids of two types having amino-terminus or ethoxydiethylene glycol-terminus to obtain hybrid vectors. Hybrid vectors were mixed further with pDNA. Then we investigated their physicochemical properties and transfection efficacy with or without near infrared laser irradiation., Results: Hybrid vectors formed complexes with pDNA and exhibited enhanced photothermal property under near infrared laser irradiation compared with parent gold nanorods. Transfection efficacy of complexes was promoted considerably by brief laser irradiation soon after complex application to the cells. Analysis of intracellular distribution revealed that laser irradiation promoted the adsorption of complexes to the cells and cytosolic release of pDNA, which is derived from the change in surface hydrophobicity of complexes through dehydration of temperature-responsive groups., Conclusions: Hybrid vector is promising as a light-activatable transfection system.

A glucose-modified dendritic hydrogel is used as a bioink for bacterial encapsulation. This biocompatible hydrogel is a potentially suitable alternative to conventional alginate hydrogel for bacterial encapsulation, as it readily forms gel in the presence of Na + or K + ions without any additional stimuli such as pH, temperature, sonication, or the presence of divalent metal ions. We created a bacterial microhabitat by adding the gelator to phosphate-buffered saline containing live bacteria at physiological pH and using an additive three-dimensional (3D) printing technique. The bacteria remained viable and metabolically active within the 3D printed bacterial microhabitat, as shown with confocal laser scanning microscopy (CLSM) and scanning electrochemical microscopy (SECM)., Competing Interests: The authors declare no competing financial interest.

Fluorophores are used for sensing biologically relevant ions, toxic metals or pathogenic markers. However, the mode of entry of such fluorophores into the cell greatly depends on their size, shape, surface charge, functional groups, and hydrophobicity. In particular, the influence of hydrophobicity on the intracellular uptake of fluorophores is poorly investigated. Self-assembly is a recent strategy to tune the intracellular uptake of fluorophores, facilitating increased intracellular sensing and fluorescence. Herein, self-assembly of three novel poly(aryl ether) dendron derivatives that contain rhodamine units was used to investigate the effect of hydrophobicity on the intracellular uptake of self-assembled fluorophores. The results suggest that monomer hydrophobicity plays an important role in the uptake. The dendron-based fluorophores, which upon self-assembly, formed stable spherical aggregates ranging from 300 to 500 nm. The rhodamine-based dendrons could selectively sense Hg 2+ ions in the presence of other competing metal cations. Intracellular imaging of the dendron-based fluorophores displayed bright red fluorescence in human embryonic kidney cells. The rate of intracellular uptake of the three dendron-based fluorophores was analyzed by flow cytometry. The results establish the importance of the hydrophilic-lipophilic balance of the self-assembled amphiphiles for tuning the intracellular uptake., (Copyright © 2019 Elsevier B.V. All rights reserved.)

For the construction of well-defined hierarchical superstructures of pristine [60]fullerene (C 60 ) arrays, pyrene-based molecular tweezers (PT) were used as host molecules for catching and arranging C 60 guest molecules. The formation of host-guest complexes was systematically studied in solution as well as in the solid state. Two-dimensional proton nuclear magnetic resonance spectroscopic studies revealed that PT-host and C 60 -guest complexes were closely related to the molecular self-assembly of PT. Ultraviolet and fluorescence spectroscopic titrations indicated the formation of stable 1:1 and 2:1 (PT/C 60 ) complexes. From the nonlinear curve-fitting analysis, equilibrium constants for the 1:1 (log K 1 ) and 2:1 (log K 2 ) complexes were estimated to be 4.96 and 5.01, respectively. X-ray diffraction results combined with transmission electron microscopy observations clearly exhibited the construction of well-defined layered superstructures of the PT-host and C 60 -guest complexes. From electron mobility measurements, it was demonstrated that the well-defined hierarchical hybrid nanostructure incorporating a C 60 array exhibited a high electron mobility of 1.7 × 10 -2 cm 2 V -1 s -1 . This study can provide a guideline for the hierarchical hybrid nanostructures of host-guest complex and its applications.

This investigation reports a novel nanoGold-core multifunctional dendrimer for pulsatile chemo-, photothermal- and photodynamic- therapy of rheumatoid arthritis (RA). Architecturally, the nanocomposites comprised of a nanoGold (Au) at the focal whose surface is functionalized by hydroxy-terminated thiolated-dendrons following Au-thiol bond formation to produce nanoGold-core multifunctional dendrimer (Au-DEN). The surface hydroxyl groups of Au-DEN were then conjugated with methotrexate (MTX; a disease-modifying first line anti-rheumatic drug; DMARD; 74.29 ± 0.48% loading) to form Au-DEN-MTX-NPs (Particle size: 100.15 ± 28.36 nm; poly dispersibility index, PDI: 0.39 ± 0.02; surface zeta potential, ζ: -22.45 ± 1.06 mV). MTX was strategically selected to serve as an anti-rheumatic DMARD as well as a targeting ligand to attain selective localization of the formulation in arthritic tissue via folate receptors upregulated on arthritic tissues. The docking study was performed to confirm the viable binding efficiency of MTX towards β-folate receptors that are overexpressed on arthritic tissues taking folic acid as a reference standard. The IR780, a NIR active bioactive was also loaded in Au-DEN-MTX NPs to offer photothermal benefit upon irradiation with NIR laser (wavelength: 808 nm). The hypothesis was tested by elucidation of in vitro drug release profile, photothermal activity, cellular uptake (Fluorescence and confocal laser scanning microscopy; CLSM), cell viability assay (MTT protocol) and Intracellular reactive oxygen species (ROS) generation in mouse macrophage RAW264.7 cells and Lipopolysaccharide (LPS) activated RAW264.7 cells. Furthermore, the hemolytic toxicity and stability studies were also investigated to determine the blood compatibility as well as ideal storage condition of NPs. The outcome of this investigations presents developed multifunctional targeted NPs to be potential therapeutics for the improved treatment of RA. The approach can also be applied to other clinical interventions involving countering inflammatory conditions., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The engineering of iron oxide nanoparticles (IONPs) for biomedical use has received great interest over the past decade. In the present study we investigated the biocompatibility of IONPs grafted with linear (2P) or generation 1 (2PG1) or 2 (2PG2) dendronized oligoethyleneglycol units in THP-1-derived macrophages. To evaluate IONP effects on cell functionality and homeostasis, mitochondrial function (MTT assay), membrane permeability (LDH release), inflammation (IL-8), oxidative stress (reduced glutathione, GSH), NLRP3 inflammasome activation (IL-1β) and nanoparticle cellular uptake (intracellular iron content) were quantified after a 4-h or 24-h cell exposure to increasing IONP concentrations (0-300 µg Fe/mL). IONPs coated with a linear molecule, NP10COP@2P, were highly taken up by cells and induced significant dose-dependent IL-8 release, oxidative stress and NLRP3 inflammasome activation. In comparison, IONPs coated with dendrons of generation 1 (NP10COP@2PG1) and 2 (NP10COP@2PG2) exhibited better biocompatibility. Effect of the dendritic architecture of the surface coating was investigated in a kinetic experiment involving cell short-term exposure (30 min or 1 h 30) to the two dendronized IONPs. NP10COP@2PG2 disrupted cellular homeostasis (LDH release, IL-1β and IL-8 secretion) to a greater extend than NP10COP@2PG1, which makes this last IONP the best candidate as MRI contrast or theranostic agent., (Copyright © 2018 Elsevier B.V. All rights reserved.)

A series of small-sized (about 2.0 nm) gold nanoparticles (AuNPs) with apparent lattice fringes are synthesized by NaBH 4 reduction of HAuCl 4 in the presence of stabilizing linear or dendronized 1,2,3-triazolyl-containing ferrocenyl polymers. These AuNPs show high catalytic activity for biphasic 4-nitrophenol (4-NP) reduction to 4-aminophenol (4-AP) by NaBH 4 . The lower generation G1 dendronized polymers (DPs) is a more efficient stabilizer for AuNP catalytic activity in the reduction of 4-NP than linear G0 polymers or bulky G2 DPs. The G1 DP-stabilized AuNPs are robust and easily recyclable, and the catalyst is recovered and reused at least twenty times with progressive smooth AuNP size increase along with some decrease of catalytic activity., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The construction of fullerene (C 60 ) hierarchical nanostructures with the help of amphiphilic molecules remains a challenging task in nanoscience and nanotechnology. Utilizing the host-guest complex concept, sub-10 nm layered superstructures are constructed from a monofunctionalized C 60 dendron (C 60 D, guest) and tweezer-like pyrene dendron (PD, host). Since C 60 D and PD are asymmetric shape amphiphiles having liquid crystal (LC) dendrons, both C 60 D and PD construct head-to-head bilayer superstructures by themselves. From fluorescence titration experiments, it is realized that the host-guest complex shows 1:1 stoichiometric binding with a binding constant (K sv = 2.45 × 10 5 m -1 ). Based on the morphological observations and scattering analyses, it is found that buckle-like asymmetric building blocks (C 60 D·PD) are self-assembled by the host-guest complex and construct multilayer hybrid nanostructures. The hierarchical hybrid nanostructures consist of the self-assembled C 60 D·PD bilayer with a 2D C 60 ·P nanoarray sandwiched between LC dendrons. This advanced strategy is expected to be a practicable and rational guideline for the fabrication of programmed hierarchical hybrid nanostructures., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The lack of an appropriate intracellular delivery system for therapeutic nucleic acids (TNAs) is a major problem in molecular biology, biotechnology, and medicine. A relatively new class of highly symmetrical hyperbranched polymers, called dendrimers, shows promise for transporting small TNAs into both cells and target tissues. Dendrimers have intrinsic advantages for this purpose: their physico-chemical and biological properties can be controlled during synthesis, and they are able to transport large numbers of TNA molecules that can specifically suppress the expression of single or multiple targeted genes. Numerous chemical modifications of dendrimers extend the biocompatibility of synthetic materials and allow targeted vectors to be designed for particular therapeutic purposes. This review summarizes the latest experimental data and trends in the medical application of various types of dendrimers and dendrimer-based nanoconstructions as delivery systems for short small interfering RNAs (siRNAs) and microRNAs at the cell and organism levels. It provides an overview of the structural features of dendrimers, indicating their advantages over other types of TNA transporters., Competing Interests: The authors declare no conflict of interest.

This review highlights the utilization of dendron-polymer conjugates as building blocks for the fabrication of nanosized drug delivery vehicles. The examples given provide an overview of the evolution of these delivery platforms, from simple micellar containers to smart stimuli- responsive drug delivery systems through their design at the macromolecular level. Variations in chemical composition and connectivity of the dendritic and polymeric segments provide a variety of self-assembled micellar nanostructures that embody desirable attributes of viable drug delivery systems.

Background/aims: Direct sequencing is the gold standard for the detection of drug-resistance mutations in hepatitis B virus (HBV); however, this procedure is time-consuming, labor-intensive, and difficult to adapt to high-throughput screening. In this study, we aimed to develop a dendron-modified DNA microarray for the detection of genotypic resistance mutations and evaluate its efficiency., Methods: The specificity, sensitivity, and selectivity of dendron-modified slides for the detection of representative drug-resistance mutations were evaluated and compared to those of conventional slides. The diagnostic accuracy was validated using sera obtained from 13 patients who developed viral breakthrough during lamivudine, adefovir, or entecavir therapy and compared with the accuracy of restriction fragment mass polymorphism and direct sequencing data., Results: The dendron-modified slides significantly outperformed the conventional microarray slides and were able to detect HBV DNA at a very low level (1 copy/µL). Notably, HBV mutants could be detected in the chronic hepatitis B patient sera without virus purification. The validation of our data revealed that this technique is fully compatible with sequencing data of drug-resistant HBV., Conclusions: We developed a novel diagnostic technique for the simultaneous detection of several drug-resistance mutations using a dendron-modified DNA microarray. This technique can be directly applied to sera from chronic hepatitis B patients who show resistance to several nucleos(t)ide analogues.

Dentromer s (from dentro, δεντρο: tree in Greek), and meros (μεροσ, in greek: part) are introduced as a family of dendrimers constructed according to successive divergent 1 → 3 branching. The smaller dentromers have 27 terminal branches. With alcohol termini they were originally named arborols by Newkome, who pioneered 1 → 3 constructions of dendrimers and dendrons. Giant dentromers have been constructed and decorated in particular with ferrocene and other redox active groups. The synthesis, specific properties, and applications are examined in this mini review article dedicated to Don Tomalia, with an emphasis on dense peripheral packing favoring the functions of encapsulation, redox sensing, and micellar template for catalysis in water and aqueous solvents.

Damage of non-vascularised tissues such as cartilage and cornea can result in healing processes accompanied by a non-physiological angiogenesis. Peptidic aptamers have recently been reported to block the vascular endothelial growth factor (VEGF). However, the therapeutic applications of these aptamers are limited due to their short half-life in vivo. In this work, an enhanced stability and bioavailability of a known VEGF blocker aptamer sequence (WHLPFKC) was pursued through its tethering of molecular scaffolds based on hyperbranched peptides, the poly(ɛ-lysine) dendrons, bearing three branching generations. The proposed design allowed simultaneous and orderly-spaced exposure of 16 aptamers per dendrimer to the surrounding biological microenvironent, as well as a relatively hydrophobic core based on di-phenylalanine aiming to promote an hydrophobic interaction with the hydrophobic moieties of ionically crosslinked methacrylated gellan gum (iGG-MA) hydrogels. The VEGF blocker dendrons were entrapped in iGG-MA hydrogels, and their capacity to prevent endothelial cell sprouting was assessed qualitatively and quantitatively using 3D in vitro models and the in vivo chick chorioallantoic membrane assay. The data demonstrate that at nanoscale concentrations, the dendronised structures were able to enhance control of the biological actvity of WHLPFKC at the material/tissue interface and hence the anti-angiogenic capacity of iGG-MA hydrogels not only preventing blood vessel invasion, but also inducing their regression at the tissue/iGG-MA interface. The in ovo study confirmed that iGG-MA functionalised with the dendron VEGF blockers do inhibit angiogenesis by controlling both size and ramifications of blood vessels in the proximity of the implanted gel surface. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

Autologous chondrocyte transplantation for cartilage repair still has unsatisfactory clinical outcomes because of inter-donor variability and poor cartilage quality formation. Re-differentiation of monolayer-expanded human chondrocytes is not easy in the absence of potent morphogens. The Vascular Endothelial Growth Factor (VEGF) plays a master role in angiogenesis and in negatively regulating cartilage growth by stimulating vascular invasion and ossification. Therefore, we hypothesized that its sole microenvironmental blockade by either VEGF sequestration by soluble VEGF receptor-2 (Flk-1) or by antiangiogenic hyperbranched peptides could improve chondrogenesis of expanded human nasal chondrocytes (NC) freshly seeded on collagen scaffolds. Chondrogenesis of several NC donors was assessed either in vitro or ectopically in nude mice. VEGF blockade appeared not to affect NC in vitro differentiation, whereas it efficiently inhibited blood vessel ingrowth in vivo. After 8 weeks, in vivo glycosaminoglycan deposition was approximately two-fold higher when antiangiogenic approaches were used, as compared to the control group. Our data indicates that the inhibition of VEGF signaling, independently of the specific implementation mode, has profound effects on in vivo NC chondrogenesis, even in the absence of chondroinductive signals during prior culture or at the implantation site., Competing Interests: The authors declare no conflict of interest. The founding sponsors had no role in the design of the study, the collection, analyses, or interpretation of data, the writing of the manuscript, and in the decision to publish the results.

Organic-inorganic hybrid layered materials are proposed as additives in a quasi-solid gel electrolyte for dye-sensitized solar cells. Talcs could provide a low-cost and environmentally friendly, as well as abundant, option as gelators. Here, talcs were prepared by functionalizing an organotalc with three polyamidopyridine dendron generations, PAMPy-talc-Gn (n = 1, 2 and 3). PAMPy dendrons grow parallel to the lamellae plane and form an organized structure by intermolecular interactions. In addition, polyiodide-dendron charge-transfer complexes were prepared onto the organotalc by adsorption of iodine. In this work, the effect of the dendron generation of PAMPy-talc and the influence of polyiodide intercalation on solar cell performance and stability were investigated. The best results were reached with the use of lowest-generation PAMPy-talc (η = 4.5 ± 0.3%, V OC = 710 ± 19 mV, J sc = 10.4 ± 0.9 mA cm -2 , and FF = 61 ± 2%): 15% higher efficiency compared to similar liquid devices. While some previously studied talcs illustrate very strong absorption of the iodide from the electrolyte, in the case of PAMPy-talc such interfering effects were absent: In a 1000 h light soaking test, the PAMPy-talc cells both with and without polyiodide intercalation demonstrated stable performances. Furthermore, the color analysis of the electrolyte indicated that the color of the electrolyte remained stable after an initial period of stabilization, which is a good indication of the compound being stable and not absorbing charge carriers from the electrolyte. The performance and stability results indicate that PAMPy-talc has potential as a gelling method for electrolytes for dye solar cells.

Bifunctional dendrons based on 2,2-bis(methylol)propionic acid (bis-MPA) are highly desirable scaffolds for biomedical applications. This is due to their flawless nature and large and exact number of functional groups as well as being biodegradable and biocompatible. Herein, we describe a facile divergent growth approach to their synthesis from monobenzylated tetraethylene glycol and post functionalization utilizing fluoride-promoted esterification (FPE) chemistry protocols. The scaffolds, presenting selectively deprotectable hydroxyls in the periphery and at the focal point, were isolated on a multigram scale with excellent purity up to the fourth generation dendron with a molecular weight of 2346 Da in seven reactions with a total yield of 50%. The third generation dendron was used as a model compound to demonstrate its functionalizability. Selective deprotection of the dendron's focal point was achieved with an outstanding yield of 94%, and biotin as well as azido functionalities were introduced to its focal point and periphery, respectively, through FPE chemistry. Bulky disperse red dyes were clicked through CuAAC to the dendron's azido groups, giving a biotinylated dendron with multivalent dyes with a molecular weight of 6252 Da in a total yield of 37% in five reactions with an average yield of 82% starting from the third generation focally and peripherally protected dendron. FPE chemistry proved to be a superb improvement over previous protocols towards bis-MPA dendrons as high purity and yields were obtained with less toxic solvents and greatly improved monomer utilization.

A new concept for the magnetic immobilization of catalytically active material has been developed for continuous-flow Suzuki cross-coupling reactions. The reversible immobilization of the magnetic catalyst material inside a novel capillary microreactor has been achieved by utilizing a newly designed reactor housing with 208 small permanent magnets. As a catalyst material, magnetic Fe3O4 nanoparticles decorated with polyphenylenepyridyl dendrons and loaded with Pd nanoparticles have been employed. Both batch and continuous-flow experiments prove the activity of the catalyst and the applicability of this new microreactor concept.

Dendrimers are monodisperse polymers grown in a fractal manner from a central point. They are poised to become the cornerstone of nanoscale devices in several fields, ranging from biomedicine to light-harvesting. Technical difficulties in obtaining these molecules has slowed their transfer from academia to industry. In 2001, the arrival of the "click chemistry" concept gave the field a major boost. The flagship reaction, a modified Hüisgen cycloaddition, allowed researchers greater freedom in designing and building dendrimers. In the last five years, advances in click chemistry saw a wider use of other click reactions and a notable increase in the complexity of the reported structures. This review covers key developments in the click chemistry field applied to dendrimer synthesis from 2010 to 2015. Even though this is an expert review, basic notions and references have been included to help newcomers to the field.

Liposomes are recognized as potentially useful drug carriers but many problems preclude practical medical application. Liposomes bind with serum proteins (opsonization) and are captured by the reticuloendothelial system cells in the liver and spleen, which limits their ability to deliver drugs to other target sites. Modification of lipids with flexible, hydrophilic polymers such as poly(ethylene glycol) (PEG) to yield sterically stabilized liposomes is one approach to improve liposome blood circulation and tissue distribution properties. In this study, we examined liposomes prepared using lipids modified with a new branched oligoglycerol (BGL) moiety for steric stabilization. This novel BGL comprised 14 glycerol units (termed BGL014) connected with flexible ether linkages, resulting in a branched cascade-like structure that is highly expanded in aqueous solution. BGL014 was coupled to 1,2-distearoylphosphatidylethanolamine to yield BGL014-modified lipids. Incorporation of BGL014 into liposomes (BGL014L) resulted in long blood circulation times, despite a much thinner fixed aqueous layer thickness compared to PEG formulations. BGL014 produced a liposome surface coating that appears to function through steric inhibition of non-specific protein binding without strong interference of specific protein-binding reactions. Liposome structure and functionality was maintained following BGL014-modification, as the incorporation ratio of drug remained high. These results suggest that the BGL014 modification of liposomes is a promising approach to produce stable and long circulating drug carriers capable of selective binding to specific proteins.

Functionalized phenols based on tyramine were synthesized in order to be selectively grafted on to hexachlorocyclotriphosphazene, affording a variety of functionalized dendrons of type AB(5). The B functions comprised fluorescent groups (dansyl) or dyes (dabsyl), whereas the A function was provided by either an aldehyde or an amine. The characterization of these dendrons is reported. An unexpected behaviour of a fluorescent and water-soluble dendron based on dansyl groups in mixtures of dioxane/water was observed.