Dendritic Molecules Research Articles

Effect of the Combination of Levofloxacin with Cationic Carbosilane Dendron and Peptide in the Prevention and Treatment of Staphylococcus aureus Biofilms.

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 MalG2(SNHMe2Cl)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.

Crowding-Induced Unconventional Phase Behaviors in Dendritic Rodlike Molecules via Side-Chain Engineering.

Dendritic molecules with a fanlike or conelike conformation are common molecular building blocks to construct supramolecular columnar or spherical phases. Although it is well-accepted that the preferred molecular conformation of dendritic molecules dictates their packing schemes, manipulation of this crucial parameter usually requires significant changes in molecular structures and tedious synthetic efforts. Herein, we report a simple yet highly efficient strategy to tune the molecular conformation of dendritic rodlike molecules by adjusting the length of alkyl side chains tethered to the rods. Strikingly, tiny chemical structure differences can largely change the "crowding" near the branching point to induce the "fanlike to conelike" conformational transitions and thus result in the formation of diverse supramolecular structures, including the columnar phase, double gyroid phase, and the unconventional Frank-Kasper σ and A15 phases. Our study provides a practical platform for further investigation of unconventional structure formation and phase transitions in soft matter.

Dendrimer applications: a brief review

: Dendrimers are highly branched three-dimensional macromolecules with a highly controlled structure, a single molecular weight, numerous controllable dendritic branches and peripheral functionalities, as well as the tendency to adopt an ellipsoid or spheroid shape once a certain size is reached. These features have made them attractive for application in pharmaceutical and medicinal chemistry in gene transfection, as medical imaging agents, and as drug carriers in potential drug delivery agents. The incorporation of metallic species into dendritic molecules has also been reported; the focus has been on organometallic dendrimers with metallic species only at specific positions of the molecules, such as the core, dendritic branches and the periphery, studied for their magnetic, electronic, and photo-optical or catalytic properties. Dendrimers have been investigated for optoelectronic applications (adsorption, emission, laser emission, nonlinear optics) through the encapsulation of active units by dendritic branches, core and peripheral. This review briefly discusses their use in nanomedicine, cancer treatment, treatment of other diseases, tissue repair, catalysis and applications in OLEDs and solar cells.

Design of flexible dendritic systems bearing donor-acceptor groups (pyrene-porphyrin) for FRET applications

Herein, we report the synthesis and characterization of a novel series of dendritic compounds, bearing peripheral pyrene groups and a porphyrin core, of zero and first generation with different spacer lengths. These compounds were further metallated with Zn(II) and Mg(II). The optical properties of these dendritic molecules were studied by absorption and fluorescence spectroscopy. After metallation, the dendritic porphyrins exhibited a red shift in the Soret absorption band and a blue shift in the emission band. All compounds exhibited high energy transfer efficiency, reaching values of EFRET above 99%.

Nanomedical Applications of Amphiphilic Dendrimeric Micelles.

In recent years, polymeric materials with the ability to self-assemble into micelles have been increasingly investigated for application in various fields, mainly in biomedicine. Micellar morphology is interesting in the field of drug transport and delivery since micelles can encapsulate hydrophobic molecules in their nucleus, have active molecules in their outer layer, and due to their nanometric size, can take advantage of the enhanced permeability and retention (EPR) effect, prolong the time in circulation and avoid renal clearance. In addition, nanobioactive molecules (joined in covalent form or by host-host interaction), such as drugs, bioimaging molecules, targeting ligands, "crosslinkable" molecules or bonds, sensitive to internal or external stimuli, can be incorporated into them and showed better activity as anticancer agents, siRNA delivery agents as well as antiviral and antiparasitic compounds. The present work is a review of the information published, which is the most important about the synthesis and biological importance of the confined multivalent cooperation and the ability to modify the dendritic structure, provide the versatility to create and improve the amphiphiles used in the micellar supramolecular field. The most studied structures are the hybrid copolymers formed by the combination of linear polymers and dendrons. However, small dendritic molecules that do not involve linear polymers have also been developed, such as Janus dendrimers, facial dendrons, and dendritic amphiphiles with only one dendron. Amphiphilic dendrimer micelles have achieved efficient and promising results, both in in vitro and in vivo tests, which encourage their research for future application in nanotherapies.

Vitamin E Attenuates FasL-Induced Apoptotic Death of Dendritic Cells Through PI3K Signalling

Vitamin E Attenuates FasL-Induced Apoptotic Death of Dendritic Cells Through PI3K Signalling

Elaborated study of Cu(II) carbosilane metallodendrimers bearing substituted iminopyridine moieties as antitumor agents.

Iminopyridine-decorated carbosilane metallodendrimers have recently emerged as a promising strategy in the treatment of cancer diseases. Their unique features such as the nanometric size, the multivalent nature and the structural perfection offer an extraordinary platform to explore structure-to-property relationships. Herein, we showcase the outstanding impact on the antitumor activity of a parameter not explored before: the iminopyridine substituents in meta position. New Cu(II) carbosilane metallodendrimers, bearing methyl or methoxy substituents in the pyridine ring, were synthesized and thoroughly characterized. Electron Paramagnetic Resonance (EPR) was exploited to unveil the properties of the metallodendrimers. This study confirmed the presence of different coordination modes of the Cu(II) ion (Cu-N2O2, Cu-N4 and Cu-O4), whose ratios were determined by the structural features of the dendritic molecules. These metallodendrimers exhibited IC50 values in the low micromolar range (<6μM) in tumor cell lines such as HeLa and MCF-7. The subsequent invitro assays on both healthy (PBMC) and tumor (U937) myeloid cells revealed two key facts which improved the cytotoxicity and selectivity of the metallodrug: First, maximizing the Cu-N2O2 coordination mode; second, adequately selecting the pair ring-substituent/metal-counterion. The most promising candidates, G1(-CH3)Cl (8) and G1(-OCH3)NO3(17), exhibited a substantial increase in the antitumor activity in U937 tumor cells, compared to the non-substituted counterparts, probably through two different ROS-production pathways.

Solid-state reversible optical switch based on two dendritic molecules with dual sensitivity of mechanochromism and photochromism

Achieving excellent solid photochromic properties by designing dendritic chromophores.

Synthesis and two-photon properties of phenothiazine-based dendrimers with tetraphenylmethane cores

We have synthesized two new two-photon active dendritic molecules with tetraphenylmethane core with four phenothiazine-based arms. They show good solubility in organic solvents, including dichloromethane, chloroform, toluene and tetrahydrofuran. It is found that the two dendrimers display strong two-photon absorption and two-photon excited up-conversion fluorescence at 800 nm. • Two new phenothiazine-based dendrimers with tetraphenylmethane cores have been synthesized. • The dendritic molecules display two-photon absorption activity. • The two-photon absorption cross section increased with the increasing of the conjugation degree.

Synthesis and fluorescence properties of two dendritic molecules based on naphthalimide and triphenylamine.

Artificial light-harvesting systems have attracted great interest in biological photosynthesis and photo-voltaic devices areas due to their unique structures, easy purification, low-cost, and convenient processing abilities. Here, two dendritic molecules based on triphenylamine and naphthalimide have been designed and synthesized, their structures were confirmed by 1 H NMR, ESI-MS, and high resolution mass spectrometry. In these molecules, triphenylamine units perform as the electron donor moiety, and naphthalimide units perform as the electron acceptor. The obvious quenched fluorescence intensity and considerably shortened lifetime of the dendritic molecules combined with the molecular frontier orbital energy levels proved that the dendritic molecules not only are good candidates as hole-transporting materials but also are two excellent photo-induced electron transfer materials. Therefore, it is believed that these dendritic molecules have potential application value in photo-voltaic devices.

In Vitro Activity of Carbosilane Cationic Dendritic Molecules on Prevention and Treatment of Candida Albicans Biofilms.

Candida spp. are one of the most common fungal pathogens. Biofilms formed by Candida albicans offer resistance mechanisms against most antifungal agents. Therefore, development of new molecules effective against these microorganisms, alone or in combination with antifungal drugs, is extremely necessary. In the present work, we carried out a screening process of different cationic carbosilane dendritic molecules against C. albicans. In vitro activity against biofilm formation and biofilms was tested in both Colección Española de Cultivos Tipo (CECT) 1002 and clinical C. albicans strains. Cytotoxicity was studied in human cell lines, and biofilm alterations were observed by scanning electron microscopy (SEM). Antifungal activity of the carbosilane dendritic molecules was assessed by monitoring cell viability using both established and novel cell viability assays. One out of 14 dendritic molecules tested, named BDSQ024, showed the highest activity with a minimum biofilm inhibitory concentration (MBIC) for biofilm formation and a minimum biofilm damaging concentration (MBDC) for existing biofilm of 16–32 and 16 mg/L, respectively. Synergy with amphotericin (AmB) and caspofungin (CSF) at non-cytotoxic concentrations was found. Therefore, dendritic compounds are exciting new antifungals effective at preventing Candida biofilm formation and represent a potential novel therapeutic agent for treatment of C. albicans infection in combination with existing clinical antifungals.

PH-Sensitive Dendrimersomes of Hybrid Triazine-Carbosilane Dendritic Amphiphiles-Smart Vehicles for Drug Delivery.

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.

Facile biomimetic self-coacervation of tannic acid and polycation: Tough and wide pH range of underwater adhesives

Bioinspired underwater adhesives with tough and stable performance are increasingly in demand for biomedical and engineering applications. However, the current methods of synthesizing them usually require sophisticated chemical conjugation or modification and expensive adhesive building blocks. Here, by taking advantage of the catecholic and polyelectrolyte features of mussel foot proteins, we report a facile yet powerful strategy to the development of a strong and cost-effective self-coacervating adhesive based on a coacervation-induced adhesion mechanism. The adhesive comprises a low-cost, commercially available cationic polyelectrolyte—polyamidoamine-epichlorohydrin (PAE)—that is crosslinked in situ by naturally occurring dendritic molecules of tannic acid (TA). A complex coacervate gel (TAPA) is formed after directly mixing pyrogallol-containing TA with PAE polycation. With the gel matrix serving as a robust adhesive when applied underwater to various substrates owing to its synergistic azetidinium–phenolic electrostatic and hydrogen bonding interactions. Compared to previously reported catechol-based adhesives, the polyelectrolyte coacervate gel has a widely tunable underwater adhesive strength (50.8 ± 6.8 to 604.8 ± 9.5 kPa) in wide ranges of pH (3–11) and ionic strength (0–1 M NaCl) and displays reusable adhesiveness (<10 cycles). This adhesive strength increases substantially in basic conditions (pH > 9), which trigger the self-crosslinking of PAE chains. By synergistically combining electrostatic adsorption and macroscopic-scale interactions, the incorporated nanocellulose fillers further contribute to the strong cohesion of coacervate adhesives. The easy-to-prepare TAPA adhesive also has excellent antibacterial activity. This in-situ formation strategy opens an innovative and facile route to mimic the self-coacervation and adhesion stability of biomimetic source, leading to a multifunctional bonding solution for biological/engineering adhesive applications.

Heterofunctional ruthenium(II) carbosilane dendrons, a new class of dendritic molecules to fight against prostate cancer.

A family of heterofunctional Schiff base carbosilane metallodendrons with [Ru(η5-C5H5)(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-3cells, with the second generation derivative standing out as the most promising with the lowest IC50. 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 exvivo experiment in nude mice with advanced prostate cancer inhibiting the tumour growth in a 40% compared to control mice.

Remalleable, Healable, and Highly Sustainable Supramolecular Polymeric Materials Combining Superhigh Strength and Ultrahigh Toughness.

To build a sustainable society, it is of significant importance but highly challenging to develop remalleable, healable, and biodegradable polymeric materials with integrated high strength and high toughness. Here, we report a superstrong and ultratough sustainable supramolecular polymeric material with a toughness of ca. 282.3 J g-1 (395.2 MJ m-3) in combination with a tensile strength as high as ca. 104.2 MPa and a Young's modulus of ca. 3.53 GPa. The toughness is even higher than that of the toughest spider silk (ca. 354 MJ m-3) ever found in the world, while the material also exhibits a superior tensile strength over most engineering plastics. This material is fabricated by topological confinement of the biodegradable linear polymer of poly(vinyl alcohol) (PVA) via the naturally occurring dendritic molecules of tannic acid (TA) based on high-density hydrogen bonds. Simply blending TA and PVA in aqueous solutions at acidic conditions leads to the formation of TA-PVA complexes as precipitates, which can be processed into dry TA-PVA composite products with desired shapes via the compression molding method. Compared to the conventional solution casting method for the fabrication of PVA-based thin films, the as-developed strategy allows large-scale production of bulk TA-PVA composites. The TA-PVA composites consist of interpenetrating three-dimensional supramolecular TA-PVA clusters. Such a structural feature, revealed by computational simulations, is crucial for the integrated superhigh strength and ultrahigh toughness of the material. The biodegradable TA-PVA composites are remalleable for multiple generations of recycling and healable after break, at room temperature, by the assistance of water to activate the reversibility of the hydrogen bonds. The TA-PVA composites show high promise as sustainable substitutes for conventional plastics because of their remalleability, healability, and biodegradability. The integrated superhigh strength and ultrahigh toughness of the TA-PVA composites ensure their high reliability and broad applicability.

Triazine‐cored dendritic molecules containing multiple o‐carborane clusters

AbstractA series of C3‐symmetricaltriazine‐cored small dendritic molecules containing three to nine peripheral o‐carborane clusters were synthesized through Cu(I)‐catalyzedazide–alkyne cycloaddition reactions. The newly synthesized molecules containing multiple o‐carborane moieties were characterized using nuclear magnetic resonance and matrix‐assisted laser desorption/ionization‐time of flight mass spectral analysis. The biological evaluation of these three to nine cage dendrimers was performed using breast cancer cells (Michigan Cancer Foundation 7). All these dendritic compounds showed cytotoxicity toward breast cancer cells, and the toxicity increased as the number of peripheral o‐carboranes increased. The 9‐cage molecule showed the highest cytotoxicity, and the half maximal inhibitory concentration (IC50) value was found to be 80.67 ng/ml. Its cytotoxicity was significantly higher than the common chemotherapy agent cisplatin. As expected, the boron‐richo‐carborane‐appended molecules showed high thermal stability. The thermal stability increased as the number of peripheral o‐carborane moieties increased.

Discovery of Structural Complexity through Self-Assembly of Molecules Containing Rodlike Components.

Hierarchical structures are important for transferring and amplifying molecular functions to macroscopic properties of materials. In this regard, rodlike molecules have emerged as one of the most promising molecular building blocks to construct functional materials. Although the self-assembly of conventional molecules containing rodlike components generally results in nematic or layered smectic phases, due to the preferred parallel arrangements of rodlike components, extensive efforts have revealed that rational molecular design provides a versatile platform to engineer rich self-assembled structures. Herein, first successes achieved in polyphilic liquid crystals and rod-coil block systems are summarized. Special attention is paid to recent progress in the conjugation of rodlike building blocks with other molecular building blocks through the molecular Lego approach. Rod-based giant surfactants, sphere-rod conjugates, and dendritic rodlike molecules are covered. Future perspectives of the self-assembly of molecules containing rodlike components are also provided.

Auto-fluorescent PAMAM-based dendritic molecules and their potential application in pharmaceutical sciences.

The epithelial permeation of water-soluble fluorescent PAMAM dendrons based on 7H-benz[de] benzimidazo [2,1-a] isoquinoline-7-one as a fluorescent core across epithelial cell models MDCK I and MDCK II has been quantified. Hydrodynamic radii have been derived from self-diffusion coefficients obtained via pulsed-gradient spin-echo Nuclear Magnetic Resonance (PGSE-NMR). Results indicate that these dendritic molecules are molecularly disperse, non-aggregating, and only slightly larger than their parent homologues. MDCK I permeability studies across epithelial barriers show that these dendritic molecules are biocompatible with the chosen epithelial in-vitro model and can permeate across MDCK cell monolayers. Permeability is demonstrated to be a property of dendritic size and cell barrier restrictiveness indicating that paracellular mechanisms play the predominant role in the transport of these molecules.

Theoretical study of thermoresponsive dendritic polymeric micelles: Micellar phase control and the extraction of organic molecules by temperature effects

Smart dendritic micelles are stimuli-sensitive dendritic polymeric micelles that combine the characteristics of double-hydrophilic diblock copolymers and hyperbranched dendritic molecules. The micellar phase control of the smart dendritic micelles consisting of Boltorn-H40 hyperbranched dendrimer and poly(N,N-diethylacrylamide)-b-poly(2-(dimethylamino)ethyl methacrylate) diblock copolymer (H40-PDEA–PDMA) and their capacity to extract organic molecules in an aqueous environment are explored using dissipative particle dynamics simulations. The mesoscopic outcomes show that the H40-PDEA–PDMA micelles exhibit two consecutive low critical solution temperatures and three specific conformations with a cloud point: (1) stable dendritic micelles with a dendritic-H40 core and double micellar corona (PDEA-PDMA) at room temperature, (2) dendritic micelles with a core-shell (dendrimer-H40-PDEA) and PDMA corona at intermediate temperature, and (3) polymeric particles with a dendritic-H40 core and polymeric double-shell (PDEA-PDMA) at high temperature. The thermal behaviour of smart dendritic micelles is exploited for the extraction of rose bengal organic molecules from an aqueous solution. The extraction process of organic molecules consists of three transitory stages: molecular loading on the dendritic-H40 core, molecular encapsulation via core-shell formation, and the generation of compact polymeric particles with a dendritic-H40 core and polymeric double-shell via a cloud point through temperature effects. All micellar phases and transitory states that include the H40-PDEA–PDMA micelles in the thermal process are analysed in detail. Our simulations are in agreement with the experimental outcomes observed for this smart dendritic material.

Synthesis and effect of pegylation on citric acid dendritic nano architectures anchored with cefotaxime sodium

In recent years dendrimers have fascinated the investigators towards targeted drug delivery because of their versatile framework and exhibit immense potentiality in entrapping drug moieties through host-guest interactions and serve as a promising vector in biological applications. The current investigation is focused on developing pegylated citric acid cefotaxime dendrimers through the divergent method and its characterization through spectroscopic, microscopic, thermal and microscopic techniques. Among the spectroscopic techniques, 1H NMR and 13C NMR elucidated the key functional groups at various chemical shifts while ESI-MS pointed out the molecular weight of cefotaxime sodium in various generations. Similarly, FTIR, DSC, and AFM investigations detailed that the generations are devoid of incompatibilities, structural deformities and can be opted for targeted drug delivery. The drug entrapment studies and in-vitro drug release studies highlight CFTX G5 containing 92.4% entrapment efficacy and 83.8% drug release in 48 h and specifies a sustain release characteristics. In connection to the above, the in-vivo studies reveal a potent antibacterial activity against various gram-positive and gram-negative microorganisms with a decreased hemolysis and cytotoxicity effects and reflect a high margin of safety regarding pegylated CFTX dendrimers. Further, the antibacterial activities are supported through confocal microscopy that clarified the cellular uptake of dendritic molecules and their internalization.