Search Results (60)

Since the discovery of cisplatin in the 1960s, the search for metallo-drugs that are more efficient than platinum complexes with negligible side effects has attracted much interest. Among the other metals that have been examined for potential applications as anticancer agents is copper. The interest in copper was recently boosted by the discovery of cuproptosis, a recently evidenced form of cell death mediated by copper. However, copper is also known to induce the proliferation of cancer cells. In view of these contradictory results, there is a need to find the most suitable copper chelators, among which Schiff-based derivatives offer a wide range of possibilities. Gathering several metal complexes in a single, larger entity may provide enhanced properties. Among the nanometric objects suitable for such purpose are dendrimers, precisely engineered hyperbranched macromolecules, which are outstanding candidates for improving therapy and diagnosis. In this review article, we present an overview of the use of a particular Schiff base, namely pyridine–imine, linked to the surface of dendrimers, suitable for complexing copper, and the use of such dendrimer complexes in biology, in particular against cancers. Full article

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. Full article

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. Full article

Resistance and toxicity associated with current treatments for human cytomegalovirus (HCMV) infection highlight the need for alternatives and immunotherapy has emerged as a promising strategy. This study examined the in vitro immunological effects of co-administration of Thymosin-alpha-1 (Tα1) and polyanionic carbosilane dendrimers (PCDs) on peripheral blood mononuclear cells (PBMCs) during HCMV infection. The biocompatibility of PCDs was assessed via MTT and LDH assays. PBMCs were pre-treated with the co-administered compounds and then exposed to HCMV for 48 h. Morphological alterations in PBMCs were observed using optical microscopy and total dendritic cells (tDCs), myeloid dendritic cells (mDCs), and plasmacytoid dendritic cells (pDCs), along with CD4+/CD8+ T cells and regulatory T cells (Treg), and were characterized using multiparametric flow cytometry. The findings revealed that Tα1 + PCDs treatments increased DC activation and maturation. Furthermore, increased co-receptor expression, intracellular IFNγ production in T cells and elevated Treg functionality and reduced senescence were evident with Tα1 + G2-S24P treatment. Conversely, reduced co-receptor expression, intracellular cytokine production in T cells, lower functionality and higher senescence in Treg were observed with Tα1 + G2S16 treatment. In summary, Tα1 + PCDs treatments demonstrate synergistic effects during early HCMV infection, suggesting their use as an alternative therapeutic for preventing virus infection. Full article

Due to the absence of specific interactions, carbosilane dendrimers are ideal models to study the effect of a hyperbranched regular structure on the molecular response to external influences. In this work, we have studied the conformational behavior of single polybutylcarbosilane dendrimers under confinement between impermeable flat surfaces using atomistic molecular dynamics simulations. Dendrimers of different generations belonging to two homologous series with a tetra-functional core and three- and four-functional branches were simulated. The analysis of the dependence of the internal energy of the dendrimers on the wall distance allowed us to determine the critical degree of compression at which the dendrimers are able to change their shape without energy loss. The effects of generation number and branching functionality on the number of wall contacts, density distribution and shape changes were elucidated. It was found that for high generation dendrimers, the inner layers are not accessible for external interaction. It was shown that the excess stresses occurring at high compressions are concentrated in the structural center of the dendrimer. The nature of the elastic response, which is strongly nonlinear, was analyzed at different compressions depending on the dendrimer architecture and generation. We believe that our results are useful for further studies of dendrimer films under compression and can also serve as a basis for developing model concepts to describe the dynamics of dendrimer melts. Full article

Glioblastoma is a rapidly progressing tumor quite resistant to conventional treatment. These features are currently assigned to a self-sustaining population of glioblastoma stem cells. Anti-tumor stem cell therapy calls for a new means of treatment. In particular, microRNA-based treatment is a solution, which in turn requires specific carriers for intracellular delivery of functional oligonucleotides. Herein, we report a preclinical in vitro validation of antitumor activity of nanoformulations containing antitumor microRNA miR-34a and microRNA-21 synthetic inhibitor and polycationic phosphorus and carbosilane dendrimers. The testing was carried out in a panel of glioblastoma and glioma cell lines, glioblastoma stem-like cells and induced pluripotent stem cells. We have shown dendrimer-microRNA nanoformulations to induce cell death in a controllable manner, with cytotoxic effects being more pronounced in tumor cells than in non-tumor stem cells. Furthermore, nanoformulations affected the expression of proteins responsible for interactions between the tumor and its immune microenvironment: surface markers (PD-L1, TIM3, CD47) and IL-10. Our findings evidence the potential of dendrimer-based therapeutic constructions for the anti-tumor stem cell therapy worth further investigation. Full article

Copper carbosilane metallodendrimers containing chloride ligands and nitrate ligands were mixed with commercially available conventional anticancer drugs, doxorubicin, methotrexate and 5-fluorouracil, for a possible therapeutic system. To verify the hypothesis that copper metallodendrimers can form conjugates with anticancer drugs, their complexes were biophysically characterized using zeta potential and zeta size methods. Next, to confirm the existence of a synergetic effect of dendrimers and drugs, in vitro studies were performed. The combination therapy has been applied in two cancer cell lines: MCF-7 (human breast cancer cell line) and HepG2 (human liver carcinoma cell line). The doxorubicin (DOX), methotrexate (MTX) and 5-fluorouracil (5-FU) were more effective against cancer cells when conjugated with copper metallodendrimers. Such combination significantly decreased cancer cell viability when compared to noncomplexed drugs or dendrimers. The incubation of cells with drug/dendrimer complexes resulted in the increase of the reactive oxygen species (ROS) levels and the depolarization of mitochondrial membranes. Copper ions present in the dendrimer structures enhanced the anticancer properties of the whole nanosystem and improved drug effects, inducing both the apoptosis and necrosis of MCF-7 (human breast cancer cell line) and HepG2 (human liver carcinoma cell line) cancer cells. Full article

Previously, we reported the synthesis of carbosilane and carbosilane-siloxane dendrons of various generations based limonene, a natural terpene. Limonene that contains two double bonds, namely cyclohexene and isoprenyl ones, was shown to undergo regioselective hydrosilylation exclusively at its isoprenyl double bond. This finding was used to prepare carbosilane dendrons (CDs) with a limonene moiety at the focal point. In this study, we present variants for the functionalization of the cyclohexene double bond by an epoxidation reaction in order to use the resulting dendrons for the preparation of various macromolecular objects, including Janus dendrimers (JDs), dendronized polymers, and macroinitiators. Moreover, it was shown that dendrons with peripheral azide functions could be obtained. These methods offer both the possibilities of the further growth of branches and the addition of polymers with a different nature by the azide–alkyne cycloaddition reaction. Full article

The threat of antimicrobial-resistant bacteria is ever increasing and over the past-decades development of novel therapeutic counter measurements have virtually come to a halt. This circumstance calls for interdisciplinary approaches to design, evaluate and validate the mode of action of novel antibacterial compounds. Hereby, carbosilane dendritic systems that exhibit antimicrobial properties have the potential to serve as synthetic and rationally designed molecules for therapeutic use. The bow-tie type topology of BDTL049 was recently investigated against the Gram-positive model organism Bacillus subtilis, revealing strong bactericidal properties. In this study, we follow up on open questions concerning the usability of BDTL049. For this, we synthesized a fluorescent-labeled version of BDTL049 that maintained all antimicrobial features to unravel the interaction of the compound and bacterial membrane. Subsequently, we highlight the bacterial sensitivity against BDTL049 by performing a mutational study of known resistance determinants. Finally, we address the cytotoxicity of the compound in human cells, unexpectedly revealing a high sensitivity of the eukaryotic cells upon BDTL049 exposure. The insights presented here further elaborate on the unique features of BDTL049 as a promising candidate as an antimicrobial agent while not precluding that further rounds of rational designing are needed to decrease cytotoxicity to ultimately pave the way for synthetic antibiotics toward clinical applicability. Full article

The fact that cancer is one of the leading causes of death requires researchers to create new systems of effective treatment for malignant tumors. One promising area is genetic therapy that uses small interfering RNA (siRNA). These molecules are capable of blocking mutant proteins in cells, but require specific systems that will deliver RNA to target cells and successfully release them into the cytoplasm. Dendronized and PEGylated silver nanoparticles as potential vectors for proapoptotic siRNA (siMCL-1) were used here. Using the methods of one-dimensional gel electrophoresis, the zeta potential, dynamic light scattering, and circular dichroism, stable siRNA and AgNP complexes were obtained. Data gathered using multicolor flow cytometry showed that AgNPs are able to deliver (up to 90%) siRNAs efficiently to some types of tumor cells, depending on the degree of PEGylation. Analysis of cell death showed that complexes of some AgNP variations with siMCL-1 lead to ~70% cell death in the populations that uptake these complexes due to apoptosis. Full article

Enzyme immobilization is a powerful strategy for enzyme stabilization and recyclability. Materials covered with multipoint molecules are very attractive for this goal, since the number of active moieties to attach the enzyme increases with respect to monofunctional linkers. This work evaluates different dendrimers supported on silica to immobilize a protease enzyme, Alcalase. Five different dendrimers were employed: two carbosilane (CBS) dendrimers of different generations (SiO₂-G₀Si-NH₂ and SiO₂-G₁Si-NH₂), a CBS dendrimer with a polyphenoxo core (SiO₂-G₁O₃-NH₂), and two commercial polyamidoamine (PAMAM) dendrimers of different generations (SiO₂-G₀PAMAM-NH₂ and SiO₂-G₁PAMAM-NH₂). The results were compared with a silica support modified with a monofunctional molecule (2-aminoethanethiol). The effect of the dendrimer generation, the immobilization conditions (immobilization time, Alcalase/SiO₂ ratio, and presence of Ca²⁺ ions), and the digestion conditions (temperature, time, amount of support, and stirring speed) on Alcalase activity has been evaluated. Enzyme immobilization and its activity were highly affected by the kind of dendrimer and its generation, observing the most favorable behavior with SiO₂-G₀PAMAM-NH₂. The enzyme immobilized on this support was used in two consecutive digestions and, unlike CBS supports, it did not retain peptides released in the digestion. Full article

The controllable synthesis of novel hybrid dendrimers composed of flexible and rigid components was accomplished via effective Cu-catalyzed azide–alkyne cycloaddition (“click”) reaction between azide-functionalized carbosilane cores of two generations and monoethynyl-substituted hexaphenylbenzene dendron. A comprehensive analysis of the thermal and phase behavior of dendrimers allows us to detect a similar performance of dendrimers of both generations which, in our opinion, can be due to the similar ratio of rigid and flexible blocks in the dendrimers regardless the generation of carbosilane cores. The propensity to crystallization and ordering after the annealing procedure was confirmed by DSC and SWAXS. We found that hybrid dendrimers have a tendency to order depending on their constituents of different structures. This is in contrast to homogeneous dendrimers whose propensity to order is determined by the dendrimer molecule as a whole. Full article

In this work, carbosilane dendrons of the first, second, and third generations were obtained on the basis of a natural terpenoid, limonene. Previously, we have shown the possibility of selective hydrosilylation and hydrothiolation of limonene. It is proved that during hydrosilylation, only the isoprenyl double bond reacts, while the cyclohexene double bond does not undergo into the hydrosilylation reaction. However, the cyclohexene double bond reacts by hydrothiolation. This selectivity makes it possible to use limonene as a dendron growth center, while maintaining a useful function—a double bond at the focal point. Thus, the sequence of hydrosilylation and Grignard reactions based on limonene formed carbosilane dendrons. After that, the end groups were blocked by heptamethyltrisiloxane or butyllithium. The obtained substances were characterized using NMR spectroscopy, elemental analysis and GPC. Thus, the proposed methodology for the synthesis of carbosilane dendrons based on the natural terpenoid limonene opens up wide possibilities for obtaining various macromolecules: dendrimers, Janus dendrimers, dendronized polymers, and macroinitiators. Full article

Cationic dendrimers are effective carriers for the delivery of siRNA into cells; they can penetrate cell membranes and protect nucleic acids against RNase degradation. Two types of dendrimers (CBD-1 and CBD-2) and their complexes with pro-apoptotic siRNA (Mcl-1 and Bcl-2) were tested on MCF-7 cells cultured as spheroids. Cytotoxicity of dendrimers and dendriplexes was measured using the live–dead test and Annexin V-FITC Apoptosis Detection Kit (flow cytometry). Uptake of dendriplexes was examined using flow cytometry and confocal microscopy. The live–dead test showed that for cells in 3D, CBD-2 is more toxic than CBD-1, contrasting with the data for 2D cultures. Attaching siRNA to a dendrimer molecule did not lead to increased cytotoxic effect in cells, either after 24 or 48 h. Measurements of apoptosis did not show a high increase in the level of the apoptosis marker after 24 h exposure of spheroids to CBD-2 and its dendriplexes. Measurements of the internalization of dendriplexes and microscopy images confirmed that the dendriplexes were transported into cells of the spheroids. Flow cytometry analysis of internalization indicated that CBD-2 transported siRNAs more effectively than CBD-1. Cytotoxic effects were visible after incubation with 3 doses of complexes for CBD-1 and both siRNAs. Full article

Infections caused by viruses from the Herpesviridae family produce some of the most prevalent transmitted diseases in the world, constituting a serious global public health issue. Some of the virus properties such as latency and the appearance of resistance to antiviral treatments complicate the development of effective therapies capable of facing the infection. In this context, dendrimers present themselves as promising alternatives to current treatments. In this study, we propose the use of PEGylated cationic carbosilane dendrimers as inhibitors of herpes simplex virus 2 (HSV-2) and human cytomegalovirus (HCMV)infections. Studies of mitochondrial toxicity, membrane integrity, internalization and viral infection inhibition indicated that G2-SN15-PEG, G3-SN31-PEG, G2-SN15-PEG fluorescein isothiocyanate (FITC) labeled and G3-SN31-PEG-FITC dendrimers are valid candidates to target HSV-2 and HCMV infections since they are biocompatible, can be effectively internalized and are able to significantly inhibit both infections. Later studies (including viral inactivation, binding inhibition, heparan sulphate proteoglycans (HSPG)binding and surface plasmon resonance assays) confirmed that inhibition takes place at first infection stages. More precisely, these studies established that their attachment to cell membrane heparan sulphate proteoglycans impede the interaction between viral glycoproteins and these cell receptors, thus preventing infection. Altogether, our research confirmed the high capacity of these PEGylated carbosilane dendrimers to prevent HSV-2 and HCMV infections, making them valid candidates as antiviral agents against Herpesviridae infections. Full article