Anionic Carbosilane Dendrimers Research Articles

Ruthenium(II) complexes containing PEGylated N-heterocyclic carbene ligands for tunning biocompatibility in the fight against cancer

A synthetic procedure was designed for the preparation and characterization of Ag and Ru complexes containing NHC ligands functionalized with PEG fragments. Stability studies were conducted to gain insight of the species in water and other solvents like DMSO, or with reagents like imidazole as representative group for histidine amino acid. The presence of Cl atoms instead of H in the 4,5 positions of the N-heterocyclic carbene afforded higher water stability. The complexes containing PEG units must be considered inactive as anticancer agents. To enhance the anticancer activity of PEG-containing complexes, the balance between hydrophilicity and hydrophobicity was adjusted using a silane moiety, and an anionic carbosilane dendrimer as a lipophilic carrier.

Dendritic Nanotheranostic for the Delivery of Infliximab: A Potential Carrier in Rheumatoid Arthritis Therapy.

Antibodies are macromolecules that specifically recognize their target, making them good candidates to be employed in various therapies. The possibility of attaching a drug to an immunoglobulin makes it possible to release it specifically into the affected tissue as long as it overexpresses the target. However, chemical coupling could affect the functionality (specificity and affinity) of the antibody. It has been observed that the use of intermediaries, such as dendrimers, could resolve this issue. Because carbosilane dendrimers have aroused great interest in the field of biomedicine, this report describes the synthesis of an anionic carbosilane dendrimer with a fluorochrome on its surface that then forms a conjugate with an antibody. It has been used as immunoglobulin and infliximab, whose target is TNF-α, which is a cytokine that is overexpressed in the inflamed area or even in the blood of patients with autoimmune diseases, such as rheumatoid arthritis. In addition, the integrity and functionality of the antibody has been studied to see if they have been affected after the chemical coupling process.

High Preventive Effect of G2-S16 Anionic Carbosilane Dendrimer against Sexually Transmitted HSV-2 Infection.

Anionic carbosilane dendrimers such as G2-S16 are very effective in preventing HSV-2 infection both in vitro and in vivo. We present the main achievements obtained for the G2-S16 dendrimer in vivo, especially related to its efficacy against HSV-2 infection. Moreover, we discuss the mechanisms by which the G2-S16 dendrimer applied vaginally as a topical microbicide has been demonstrated to be safe and harmless for the vaginal microbiome balance, as both conditions present an essential step that has to be overcome during microbicide development. This review points to the marked protective effect of the G2-S16 dendrimer against sexually transmitted HSV-2 infection, supporting its role as a possible microbicide against HSV-2 infection.

Feasibility of cationic carbosilane dendrimers for sustainable protein sample preparation

Protein sample preparation is the bottleneck in the analysis of proteins. The aim of this work is to evaluate the feasibility of carbosilane dendrimers functionalized with cationic groups to make easier this step. Anionic carbosilane dendrimers (sulphonate- and carboxylate-terminated) have already demonstrated their interaction with proteins and their potential in protein sample preparation. In this work, interactions between positively charged carbosilane dendrimers and different model proteins were studied when working under different pH conditions, dendrimer concentrations, and dendrimer generations. Amino- and trimethylammonium-terminated carbosilane dendrimers presented, in some cases, weak interactions with proteins. Unlike them, carbosilane dendrimers with terminal dimethylamino groups could interact, in many cases, with proteins and these interactions were affected by the pH, the dendrimer concentration, and the dendrimer generation. Moreover, dendrimer precipitation was observed at all pHs, although just second and fourth generation (2 G and 4 G) dendrimers resulted in the formation of complexes with proteins. Under experimental conditions promoting dendrimer-protein interactions, 2 G dimethylamino-terminated dendrimers were proposed as an alternative to other methods used in analytical chemistry or analysis in which an organic solvent or a resin are required to enrich/purify proteins in a complex sample.

Anionic Carbosilane Dendrimers Destabilize the GP120-CD4 Complex Blocking HIV-1 Entry and Cell to Cell Fusion.

Cell-to-cell transmission is the most effective pathway for the spread of human immunodeficiency virus (HIV-1). Infected cells expose virus-encoded fusion proteins on their surface as a consequence of HIV-1 replicative cycle that interacts with noninfected cells through CD4 receptor and CXCR4 coreceptor leading to the formation of giant multinucleated cells known as syncytia. Our group previously described the potent activity of dendrimers against CCR5-tropic viruses. Nevertheless, the study of G1-S4, G2-S16, and G3-S16 dendrimers in the context of X4-HIV-1 tropic cell-cell fusion referred to syncytium formation remains still unknown. These dendrimers showed a suitable biocompatibility in all cell lines studied and our results demonstrated that anionic carbosilane dendrimers G1-S4, G2-S16, and G3-S16 significantly inhibit the X4-HIV-1 infection, as well as syncytia formation, in a dose dependent manner. We also demonstrated that G2-S16 and G1-S4 significantly reduced syncytia formation in HIV-1 Env-mediated cell-to-cell fusion model. Molecular modeling and in silico models showed that G2-S16 dendrimer interfered with gp120-CD4 complex and demonstrated its potential use for a treatment.

Novel Water-Soluble Mucoadhesive Carbosilane Dendrimers for Ocular Administration.

The purpose of this research was to determine the potential use of water-soluble anionic and cationic carbosilane dendrimers (generations 1-3) as mucoadhesive polymers in eyedrop formulations. Cationic carbosilane dendrimers decorated with ammonium -NH3(+) groups were prepared by hydrosylilation of Boc-protected allylamine and followed by deprotection with HCl. Anionic carbosilane dendrimers with terminal carboxylate groups were also employed in this study. In vitro and in vivo tolerance studies were performed in human ocular epithelial cell lines and rabbit eyes respectively. The interaction of dendrimers with transmembrane ocular mucins was evaluated with a surface biosensor. As proof of concept, the hypotensive effect of a carbosilane dendrimer eyedrop formulation containing acetazolamide (ACZ), a poorly water-soluble drug with limited ocular penetration, was tested after instillation in normotensive rabbits. The methodology used to synthesize cationic dendrimers avoids the difficulty of obtaining neutral -NH2 dendrimers that require harsher reaction conditions and also present high aggregation tendency. Tolerance studies demonstrated that both prototypes of water-soluble anionic and cationic carbosilane dendrimers were well tolerated in a range of concentrations between 5 and 10 μM. Permanent interactions between cationic carbosilane dendrimers and ocular mucins were observed using biosensor assays, predominantly for the generation-three (G3) dendrimer. An eyedrop formulation containing G3 cationic carbosilane dendrimers (5 μM) and ACZ (0.07%) (289.4 mOsm; 5.6 pH; 41.7 mN/m) induced a rapid (onset time 1 h) and extended (up to 7 h) hypotensive effect, and led to a significant increment in the efficacy determined by AUC0(8h) and maximal intraocular pressure reduction. This work takes advantage of the high-affinity interaction between cationic carbosilane dendrimers and ocular transmembrane mucins, as well as the tensioactive behavior observed for these polymers. Our results indicate that low amounts of cationic carbosilane dendrimers are well tolerated and able to improve the hypotensive effect of an acetazolamide solution. Our results suggest that carbosilane dendrimers can be used in a safe range of concentrations to enhance the bioavailability of drugs topically administered in the eye.

Nanotechnology as a New Therapeutic Approach to Prevent the HIV-Infection of Treg Cells.

BackgroundHIV-1 has proved to infect regulatory T cells (Treg) modifying their phenotype and impairing their suppressive capacity. As Treg cells are a crucial component in the preservation of the immune homeostasis, we researched that the antiviral capacity of carboxilan dendrimers prevents the HIV-1 infection of Treg and their effects. The phenotype and suppressive capacity of Treg treated or non-treated with carbosilane dendrimers were studied by flow cytometry. Treated and non-treated Treg from healthy donors were infected with HIV-1NL4.3. The infection of Treg cells by HIV-1, and protective effect of two dendrimers were determined by measuring antigen p24gag in the supernatant of the culture and intracellular.ResultsThe Treg cells were treated with cationic and anionic carbosilane dendrimers. The results showed that both dendrimers did not modify the phenotype and functionality of Treg cells compared with non- treated Treg cells. Anionic dendrimers showed high biocompatibility with normal activity of the Treg cells and in antiviral assays. These dendrimers were highly active against HIV-1 preventing the infection of Treg, and were able to protect the Treg from the Foxp3 downregulation induced by the HIV-1 infection.ConclusionsThis is the first work showing that the in vitro use of anionic dendrimers prevent the HIV-1 replication and the infection of expanded Treg cells in culture, which raises the possibility to use Treg cells therapeutically in HIV-1-infected subjects.

Anti-Human Immunodeficiency Virus Activity of Thiol-Ene Carbosilane Dendrimers and Their Potential Development as a Topical Microbicide.

The concept of a "microbicide" was born out of the lack of a vaccine against HIV and the difficulty of women in ensuring the use of preventive prophylaxis by their partners, especially in developing countries. Approaches using polyanionic carbosilane dendrimers have shown promise in the development of new microbicides. We have developed and evaluated two anionic carbosilane dendrimers with sulfonate and carboxylate terminal groups, G2-STE16 and G2-CTE16. Both dendrimers showed high biosafety in human epithelial cell lines derived from the vagina and in primary blood human cells (PBMCs). The dendrimers not only have a greater capacity to block the entry of different X4- and R5-HIV-1 isolates into epithelial cells but also prevent the HIV-1 infection of activated PBMCs. The treatment of epithelial cells with different carbosilane dendrimers did not produce changes in the activation or proliferation of PBMCs or in the expression of CD4, CCR5 or CXCR4. Computational modeling showed significantly higher affinities for the complexes G2-STE16/gp120 and G2-CTE16/gp120. Moreover, no irritation or vaginal lesions were detected in female BALB/c mice after vaginal administration of the dendrimers. Summing up, G2-STE16 and G2-CTE16 are easy to synthesize and compatible with functional groups, and the purification steps are easy and short. Our results have clearly demonstrated that these dendrimers have high potency as a topical microbicide against HIV-1 infection.

Broad-spectrum Anti-HIV-1 Activity of Anionic Carbosilane Dendrimers and Synergy in Combination with Maraviroc and Tenofovir as Topical Microbicide

Broad-spectrum Anti-HIV-1 Activity of Anionic Carbosilane Dendrimers and Synergy in Combination with Maraviroc and Tenofovir as Topical Microbicide

Antiviral Action of Sulfonate Anionic Carbosilane Dendrimer as a Topical Microbicide against HIV Infection

AIDS Research and Human RetrovirusesVol. 30, No. S1 Evaluation of Novel Compounds in Cell-Based SystemsAntiviral Action of Sulfonate Anionic Carbosilane Dendrimer as a Topical Microbicide against HIV InfectionDaniel Sepúlveda-Crepo, Javier Sánchez-Rodriguez, María Jesús Serramia, Ana López, Esther Alonso, Rafael Gomez, Francisco Javier De La Mata, Jos Luis Jiménez, and Ma Ángeles Muñoz-FernándezDaniel Sepúlveda-CrepoHospital General Universitario Gregorio Marañón, IISGM, Networking Research Center of Bioengineering, Madrid, SpainSearch for more papers by this author, Javier Sánchez-RodriguezHospital General Universitario Gregorio Marañón, IISGM, Networking Research Center of Bioengineering, Madrid, SpainSearch for more papers by this author, María Jesús SerramiaHospital General Universitario Gregorio Marañón, IISGM, Networking Research Center of Bioengineering, Madrid, SpainSearch for more papers by this author, Ana LópezHospital General Universitario Gregorio Marañón, IISGM, Networking Research Center of Bioengineering, Madrid, SpainSearch for more papers by this author, Esther AlonsoHospital General Universitario Gregorio Marañón, IISGM, Networking Research Center of Bioengineering, Madrid, SpainSearch for more papers by this author, Rafael GomezUniversidad de Alcalá, Campus Universitario, Alcalá de Henares, Networking Research Center of Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, SpainSearch for more papers by this author, Francisco Javier De La MataUniversidad de Alcalá, Campus Universitario, Alcalá de Henares, Networking Research Center of Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, SpainSearch for more papers by this author, Jos Luis JiménezHospital General Universitario Gregorio Marañón, IISGM, Networking Research Center of Bioengineering, Madrid, SpainSearch for more papers by this author, and Ma Ángeles Muñoz-FernándezHospital General Universitario Gregorio Marañón, IISGM, Networking Research Center of Bioengineering, Madrid, SpainSearch for more papers by this authorPublished Online:30 Oct 2014https://doi.org/10.1089/aid.2014.5443.abstractAboutSectionsView articleView Full TextPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View article"Antiviral Action of Sulfonate Anionic Carbosilane Dendrimer as a Topical Microbicide against HIV Infection." AIDS Research and Human Retroviruses, 30(S1), p. A205FiguresReferencesRelatedDetailsCited bySynthesis and anticancer activity of carbosilane metallodendrimers based on arene ruthenium( ii ) complexes1 January 2016 | Dalton Transactions, Vol. 45, No. 16Dendronized PLGA nanoparticles with anionic carbosilane dendrons as antiviral agents against HIV infection1 January 2016 | RSC Advances, Vol. 6, No. 77 Volume 30Issue S1Oct 2014 InformationCopyright 2014, Mary Ann Liebert, Inc.To cite this article:Daniel Sepúlveda-Crepo, Javier Sánchez-Rodriguez, María Jesús Serramia, Ana López, Esther Alonso, Rafael Gomez, Francisco Javier De La Mata, Jos Luis Jiménez, and M Ángeles Muñoz-Fernández.Antiviral Action of Sulfonate Anionic Carbosilane Dendrimer as a Topical Microbicide against HIV Infection.AIDS Research and Human Retroviruses.Oct 2014.A205-A205.http://doi.org/10.1089/aid.2014.5443.abstractPublished in Volume: 30 Issue S1: October 30, 2014PDF download

Enhanced activity of carbosilane dendrimers against HIV when combined with reverse transcriptase inhibitor drugs: searching for more potent microbicides.

Self-administered topical microbicides or oral preexposure prophylaxis could be very helpful tools for all risk groups to decrease the human immunodeficiency virus (HIV)-1 infection rates. Up until now, antiretrovirals (ARVs) have been the most advanced microbicide candidates. Nevertheless, the majority of clinical trials has failed in HIV-1 patients. Nanotechnology offers suitable approaches to develop novel antiviral agents. Thereby, new nanosystems, such as carbosilane dendrimers, have been shown to be safe and effective compounds against HIV with great potential as topical microbicides. In addition, because most of the attempts to develop effective topical microbicides were unsuccessful, combinatorial strategies could be a valid approach when designing new microbicides. We evaluated various combinations of anionic carbosilane dendrimers with sulfated (G3-S16) and naphthyl sulfonated (G2-NF16) ended groups with different ARVs against HIV-1 infection. The G3-S16 and G2-NF16 dendrimers showed a synergistic or additive activity profile with zidovudine, efavirenz, and tenofovir in the majority of the combinations tested against the X4 and R5 tropic HIV-1 in cell lines, as well as in human primary cells. Therefore, the combination of ARVs and polyanionic carbosilane dendrimers enhances the antiviral potency of the individual compounds, and our findings support further clinical research on combinational approaches as potential microbicides to block the sexual transmission of HIV-1.

Synthesis of anionic carbosilane dendrimers via “click chemistry” and their antiviral properties against HIV

ABSTRACTThe synthesis and characterization of four families of anionic carbosilane dendrimers bearing carboxylate, phosphonate, naphthylsulfonate, and sulfate terminal groups prepared by cycloaddition of azide–alkyne catalyzed by copper (CuAAC) are presented here. For the preparation of these anionic carbosilane dendrimers, two strategies starting from azide‐terminated carbosilane dendrimers were followed: (i) click coupling of neutral alkynes followed by derivatization into anionic moieties or (ii) click coupling of anionic alkynes. Both strategies require different reaction conditions in order to accommodate the different substrate polarities. These anionic dendrimers, in general, do not present cell toxicity in vitro until concentration up to 20 µM. Therefore, they can be used in inhibition experiments in concentrations below this limit. We have observed that dendrimers bearing phosphonate groups possess poor anti‐HIV capabilities in vitro in PBMCs, while carboxylate dendrimers can reduce HIV infection levels moderately. On the other hand, sulfate and naphthylsulfonate dendrimers are powerful anti‐HIV agents and their antiviral activity is generation and concentration dependent. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014, 52, 1099–1112

Synthesis of new anionic carbosilane dendrimers via thiol-ene chemistry and their antiviral behaviour.

A synthetic strategy has been developed for the preparation of anionic carbosilane dendrimers bearing sulfonate or carboxylate groups at their periphery by means of thiol-ene chemistry. It offers significant advantages, such as milder reaction conditions, shorter reaction times and more facile purification methods, when compared with other synthetic protocols used previously, e.g. hydrosilylation followed by a Michael-type addition or azide-alkyne coupling reactions. Molecular dynamics simulations of the second generation anionic dendrimers addressing shape and size effects of the terminal groups and conformational variability indicated that the core eccentricity and flexibility might need to be taken into account for toxicity and interaction with viral and/or cellular receptors, respectively. The biocompatibility of anionic carbosilane dendrimers has been explored showing differences between silicon-cored and polyphenoxo-cored dendrimers. In addition, silicon-cored dendrimers achieved 85-90% of HIV inhibition without inducing inflammation or vaginal irritation in mice, which makes them likely candidates for readily available, good and safe topical vaginal microbicides against HIV.

Synergistic activity profile of carbosilane dendrimer G2-STE16 in combination with other dendrimers and antiretrovirals as topical anti-HIV-1 microbicide

Polyanionic carbosilane dendrimers represent opportunities to develop new anti-HIV microbicides. Dendrimers and antiretrovirals (ARVs) acting at different stages of HIV replication have been proposed as compounds to decrease new HIV infections. Thus, we determined the potential use of our G2-STE16 carbosilane dendrimer in combination with other carbosilane dendrimers and ARVs for the use as topical microbicide against HIV-1. We showed that these combinations obtained 100% inhibition and displayed a synergistic profile against different HIV-1 isolates in our model of TZM.bl cells. Our results also showed their potent activity in the presence of an acidic vaginal or seminal fluid environment and did not activate an inflammatory response. This study is the first step toward exploring the use of different anionic carbosilane dendrimers in combination and toward making a safe microbicide. Therefore, our results support further studies on dendrimer/dendrimer or dendrimer/ARV combinations as topical anti-HIV-1 microbicide. From the Clinical EditorThis paper describes the first steps toward the use of anionic carbosilane dendrimers in combination with antivirals to address HIV-1, paving the way to further studies on dendrimer/dendrimer or dendrimer/ARV combinations as topical anti-HIV-1 microbicides.

Antiviral Properties Against HIV of Water Soluble Copper Carbosilane Dendrimers and their EPR Characterization

We describe here the use of anionic carbosilane dendrimers to obtain new copper complexes. UV-Vis and a computer aided analysis of the EPR spectra provided information about the coordination modes of copper depending on the nature of the dendrimer and about the geometry and structure of the complexes in solution. Some of these metallo-dendrimers have been tested "in vitro" as antiviral compounds in the inhibition of HIV infection in pre and post-infection treatment.

Carbosilane dendrimer nanotechnology outlines of the broad HIV blocker profile

Researchers have been working hard for more than 20years to develop safe and effective microbicides to empower women to better control their own sexual life and to protect themselves against HIV and other sexually transmitted infections (STIs). Microbicide classes include moderately specific macromolecular anionic polymers that block HIV and other STIs, and HIV specific drugs that inhibit viral entry and reverse transcription. Based on innovative nanotechnology design, we showed a novel water-soluble anionic carbosilane dendrimer (2G-S16) as a propitious molecule against HIV-infection. A state-of-the-art research was accomplished that focused on biomedical cutting-edge techniques such as in vitro and in vivo cytotoxicity assays performed on female rabbit genital tracts, simulate in vitro model of vaginal epithelium in order to evaluate HIV transmission blockade through the monolayer, complete gene expression profiling experiment to study deregulated genes after 2G-S16 exposition, molecular dynamics simulation of 2G-S16 molecule against principal proteins of HIV particles and pro- and anti-inflammatory cytokine profile study. Therefore, a high-throughput study and detailed analysis of the results were achieved in this article. We provided promising outcomes to encourage 2G-S16 as a hopeful microbicide.

Synthesis, structure and molecular modelling of anionic carbosilane dendrimers

Anionic carbosilane dendrimers of generations 1-3 have been synthesized containing carboxylate G(n)X(C(2)H(4)CO(2)Na)(m) and sulfonate G(n)X(C(2)H(4)SO(3)Na)(m) peripheral groups and derived from two different cores, 1,3,5-(HO)(3)C(6)H(3) (X = O(3)) and Si(C(3)H(5))(4) (X = Si). The peripheral anionic groups make these dendrimers water soluble, despite their highly hydrophobic framework. These dendrimers present a net negative charge in water, which was influenced by the pH of the medium. This characteristic was studied by pH titration. Also molecular modeling calculations have been performed to study differences in an aqueous medium between carboxylate and sulfonate dendrimers of different cores. The results obtained were also compared with those obtained from DOSY NMR experiments and zeta-potential measurements.