Cationic Dendrimers Research Articles

Erlotinib-Loaded Dendrimer Nanocomposites as a Targeted Lung Cancer Chemotherapy.

Lung cancer is the main cause of cancer-related mortality globally. Erlotinib is a tyrosine kinase inhibitor, affecting both cancerous cell proliferation and survival. The emergence of oncological nanotechnology has provided a novel drug delivery system for erlotinib. The aims of this current investigation were to formulate two different polyamidoamine (PAMAM) dendrimer generations-generation 4 (G4) and generation 5 (G5) PAMAM dendrimer-to study the impact of two different PAMAM dendrimer formulations on entrapment by drug loading and encapsulation efficiency tests; to assess various characterizations, including particle size distribution, polydispersity index, and zeta potential; and to evaluate in vitro drug release along with assessing in situ human lung adenocarcinoma cell culture. The results showed that the average particle size of G4 and G5 nanocomposites were 200 nm and 224.8 nm, with polydispersity index values of 0.05 and 0.300, zeta potential values of 11.54 and 4.26 mV of G4 and G5 PAMAM dendrimer, respectively. Comparative in situ study showed that cationic G4 erlotinib-loaded dendrimer was more selective and had higher antiproliferation activity against A549 lung cells compared to neutral G5 erlotinib-loaded dendrimers and erlotinib alone. These conclusions highlight the potential effect of cationic G4 dendrimer as a targeting-sustained-release carrier for erlotinib.

The effect of cationic polyamide-amine dendrimer on HLD equation and interface behavior of nonionic polyether water clarifier

Cationic polyamide-amine dendrimer can promote the clarification performance of nonionic block polyether water clarifier for treating produced water from heavy oil field, but the reason is lack of study. In this paper, a cationic polyamide-amine dendrimer TA which can effectively improve the oil removal speed of nonionic polyether DMEA-PE and reduce the onset temperature of DMEA-PE clarification performance was prepared, and the reason was explored from both thermodynamic and dynamic aspects by studying the effect of TA on the hydrophilic-lipophilic deviation (HLD) equation and oil-water interface behavior of DMEA-PE. The research results showed that TA moved up the HLD vs T curve of DMEA-PE and decreased its temperature corresponding HLD = 0, which was a favor of decrease in onset temperature of DMEA-PE clarification performance. TA had no effect on the DMEA-PE's capacity of oil-water interface adsorption and decreasing oil-water interface film strength. However, TA can reduce the electronegativity of oil droplet in water and enhance the oil droplets coalescence, hence the oil removal speed and efficiency of DMEA-PE were enhanced. This is the first time that HLD concept was used to investigate the action mechanism of composite water clarifier and the results are useful for the water clarifier design.

98P Cationic dendrimers as prospective vehicles of therapeutic nucleic acids into tumor cells: Approaches, advantages and challenges

98P Cationic dendrimers as prospective vehicles of therapeutic nucleic acids into tumor cells: Approaches, advantages and challenges

Complexes of Cationic Pyridylphenylene Dendrimers with Anionic Liposomes: The Role of Dendrimer Composition in Membrane Structural Changes.

In the last decades, dendrimers have received attention in biomedicine that requires detailed study on the mechanism of their interaction with cell membranes. In this article, we report on the role of dendrimer structure in their interaction with liposomes. Here, the interactions between cationic pyridylphenylene dendrimers of the first, second, and third generations with mixed or completely charged pyridyl periphery (D16+, D215+, D229+, and D350+) with cholesterol-containing (CL/Chol/DOPC) anionic liposomes were investigated by microelectrophoresis, dynamic light scattering, fluorescence spectroscopy, and conductometry. It was found that the architecture of the dendrimer, namely the generation, the amount of charged pyridynium groups, the hydrophobic phenylene units, and the rigidity of the spatial structure, determined the special features of the dendrimer-liposome interactions. The binding of D350+ and D229+ with almost fully charged peripheries to liposomes was due to electrostatic forces: the dendrimer molecules could be removed from the liposomal surfaces by NaCl addition. D350+ and D229+ did not display a disruptive effect toward membranes, did not penetrate into the hydrophobic lipid bilayer, and were able to migrate between liposomes. For D215+, a dendrimer with a mixed periphery, hydrophobic interactions of phenylene units with the hydrocarbon tails of lipids were observed, along with electrostatic complexation with liposomes. As a result, defects were formed in the bilayer, which led to irreversible interactions with lipid membranes wherein there was no migration of D215+ between liposomes. A first-generation dendrimer, D16+, which was characterized by small size, a high degree of hydrophobicity, and a rigid structure, when interacting with liposomes caused significant destruction of liposomal membranes. Evidently, this interaction was irreversible: the addition of salt did not lead to the dissociation of the complex.

The Introduction of Dendrimers as a New Approach to Improve the Performance and Quality of Various Blood Products (Platelets, Plasma and Erythrocytes): A 2010-2022 Review Study

Objectives:Platelet-, erythrocyte- and plasma-related products are vital for some patients. The main problems with these products are storage lesions, shelf life limitations, and function and quality maintenance. Dendrimers, a well-known group of polymeric nanoparticles, may help overcome these challenges due to their special properties.Methods:This review article, for the first time, comprehensively discusses studies from 2010 to 2022 on the compatibility of positive, negative, neutral, and modified charge dendrimers with each blood product. Moreover, it provides information regarding dendrimers' applications for improving the quality and function of blood products.Results:A total of one hundred and twenty-six studies showed that dendrimers affect blood components depending on their load, size, molecular weight, functional group, concentration, and exposure time. Generally, cationic dendrimers with higher concentrations and molecular weight and larger size showed little hemocompatibility, while anionic or neutral dendrimers with lower concentrations and molecular weight, and small size were more hemocompatible. Further, some modifications of cationic dendrimers were found to improve their compatibility. For erythrocytes, they included PEGylation and thiolation of dendrimers or functionalizing them with cyclic RGD, nmaleyl chitosan, zwitterionic chitosan, prednisolone, or carbohydrates. Additionally, dendrimers functionalized with arginine-birch, lysine-Cbz, polyethylene glycol, polyethylene glycol-cyclic RGD, thiol, TiO2, maltotriose, or streptokinase decreased the platelet toxicity of dendrimers. The dendrimers modified with polyethylene glycol, glucose, and gold nanoparticles showed increased compatibility in the case of albumin products. Moreover, the PAMAM-dendrimer-antibody conjugates had no adverse effect on antibodies. Dendrimers have a wide range of applications, including virus detection kits, synthetic O2 carriers, bacterial nanofilters, drug carriers, anticoagulants, and enhanced blood product storage.Conclusion:It can be concluded that due to the outstanding properties of different types of dendrimers, particularly their manipulability, nanomaterials can be promising to enhance the quality of blood products. Thus, further research in this area is required.

Effects of Cationic Dendrimers and Their Complexes with microRNAs on Immunocompetent Cells.

Short regulatory oligonucleotides are considered prospective tools for immunotherapy. However, they require an adequate carrier to deliver potential therapeutics into immune cells. Herein, we explore the potential of polycationic dendrimers as carriers for microRNAs in peripheral blood mononuclear cells of healthy donors. As an oligonucleotide cargo, we use a synthetic mimic and an inhibitor of miR-155, an important factor in the development and functioning of immunocompetent cells. Dendrimers bind microRNAs into low-cytotoxic polyelectrolyte complexes that are efficiently uptaken by immunocompetent cells. We have shown these complexes to affect the number of T-regulatory cells, CD14+ and CD19+ cell subpopulations in non-activated mononuclear cells. The treatment affected the expression of HLA-DR on T-cells and PD-1 expression on T- and B-lymphocytes. It also affected the production of IL-4 and IL-10, but not the perforin and granzyme B production. Our findings suggest the potential of dendrimer-mediated microRNA-155 treatment for immunotherapy, though the activity of microRNA-dendrimer constructions on distinct immune cell subsets can be further improved.

Facially Amphiphilic Skeleton-Derived Antibacterial Cationic Dendrimers.

It is urgent to develop biocompatible and high-efficiency antimicrobial agents since microbial infections have always posed serious challenges to human health. Herein, through the marriage of facially amphiphilic skeletons and cationic dendrimers, high-density positively charged dendrimers D-CA6-N+ (G2) and D-CA2-N+ (G1) were designed and synthesized using the "branch" of facially amphiphilic bile acids, followed by their modification with quaternary ammonium charges. Both dendrimers could self-assemble into nanostructured micelles in aqueous solution. D-CA6-N+ displays potent antibacterial activity against Staphylococcus aureus and Escherichia coli, with minimum inhibitory concentrations (MICs) as low as 7.50 and 7.79 μM, respectively, and has an evidently stronger antibacterial activity than D-CA2-N+. Moreover, D-CA6-N+ can kill S. aureus faster than E. coli. The facial amphiphilicity of the bile acid skeleton facilitates the selective destruction of bacterial membranes and endows dendrimers with negligible hemolysis and cytotoxicity even under a high concentration of 16× MIC. In vivo studies show that D-CA6-N+ is much more effective and safer than penicillin G in treating S. aureus infection and promoting wound healing, which suggests facially amphiphilic skeleton-derived cationic dendrimers can be a promising approach to effectively enhance antibacterial activity and biocompatibility of antibacterial agent, simultaneously.

Toxicity of polyamidoamine dendrimers in vivo

The development of effective drug delivery systems is a crusial task for modern medicine. The main problem is the occurrence of non-specific toxicity leading to undesirable side effects in vivo.This article aims at reviewing resent research on the toxicity of polyamidoamine (PAMAM) dendrimers in vivo. The research results show that the toxicity of PAMAM dendrimers and modified nanoparticles depends both on the characteristics of the particles themselves (size, generation and surface charge) and on the administration parameters. It has been shown that cationic PAMAM dendrimers of small and medium generations are non-toxic in vivo when administered intravenously and intraperitoneally to mice at doses up to 10 mg/kg. In turn, anionic, neutral, and modified PAMAM dendrimers do not exhibit toxicity, regardless of the route of administration. Thus, by varying methods of administration, the dose, and modifying the surface of dendrimers, the decrease in toxicity can be achieved, promising a path towards their successfully aplication as drug carriers.

Nanoparticulate cell-free DNA scavenger for treating inflammatory bone loss in periodontitis

Periodontitis is a common type of inflammatory bone loss and a risk factor for systemic diseases. The pathogenesis of periodontitis involves inflammatory dysregulation, which represents a target for new therapeutic strategies to treat periodontitis. After establishing the correlation of cell-free DNA (cfDNA) level with periodontitis in patient samples, we test the hypothesis that the cfDNA-scavenging approach will benefit periodontitis treatment. We create a nanoparticulate cfDNA scavenger specific for periodontitis by coating selenium-doped hydroxyapatite nanoparticles (SeHANs) with cationic polyamidoamine dendrimers (PAMAM-G3), namely G3@SeHANs, and compare the activities of G3@SeHANs with those of soluble PAMAM-G3 polymer. Both G3@SeHANs and PAMAM-G3 inhibit periodontitis-related proinflammation in vitro by scavenging cfDNA and alleviate inflammatory bone loss in a mouse model of ligature-induced periodontitis. G3@SeHANs also regulate the mononuclear phagocyte system in a periodontitis environment, promoting the M2 over the M1 macrophage phenotype. G3@SeHANs show greater therapeutic effects than PAMAM-G3 in reducing proinflammation and alveolar bone loss in vivo. Our findings demonstrate the importance of cfDNA in periodontitis and the potential for using hydroxyapatite-based nanoparticulate cfDNA scavengers to ameliorate periodontitis.

Multifunctional Therapeutic Cyclodextrin-Appended Dendrimer Complex for Treatment of Systemic and Localized Amyloidosis.

Amyloidosis pathologically proceeds via production of amyloidogenic proteins by organs, formation of protein aggregates through structural changes, and their deposition on tissues. A growing body of evidence demonstrates that amyloidosis generally develops through three critical pathological steps: (1) production of amyloid precursor proteins, (2) amyloid formation, and (3) amyloid deposition. However, no clinically effective therapy that is capable of targeting each pathological step of amyloidosis independently is currently available. Here, we combined therapeutic effects and developed a short hairpin RNA expression vector (shRNA) complex with a cyclodextrin-appended cationic dendrimer (CDE) as a novel multitarget therapeutic drug that is capable of simultaneously suppressing these three steps. We evaluated its therapeutic effects on systemic transthyretin (ATTR) amyloidosis and Alzheimer's disease (AD) as localized amyloidosis, by targeting TTR and amyloid β, respectively. CDE/shRNA exhibited RNAi effects to suppress amyloid protein production and also achieved both inhibition of amyloid formation and disruption of existing amyloid fibrils. The multitarget therapeutic effects of CDE/shRNA were confirmed by evaluating TTR deposition reduction in early- and late-onset human ATTR amyloidosis model rats and amyloid β deposition reduction in AppNL-G-F/NL-G-F AD model mice. Thus, the CDE/shRNA complex exhibits multifunctional therapeutic efficacy and may reveal novel strategies for establishing curative treatments for both systemic and localized amyloidosis.

Catechol-Based Polymers with High Efficacy in Cytosolic Protein Delivery

Catechol-Based Polymers with High Efficacy in Cytosolic Protein Delivery

Electrostatic interactions between cationic dendrimers and anionic model biomembrane

The electrostatic interactions between cationic poly(amidoamine) (PAMAM) dendrimers of different generations, G3, G4, and G6, with net anionic model biomembranes have been predicted by adopting an analytical model based on two dissimilar soft spheres. The influence of bilayer surface charge density, ionic strength, pH, temperature, membrane softness (modeled as changes in bilayer thickness), and dendrimer generation on the attractive interaction was investigated. The attraction was found to decrease with increasing salt concentration, dendrimer charge, and thickness (or softness) of the membrane. On the other hand, the attraction increased with the surface charge density of the membrane, and the size of dendrimer generation. In fact, the attraction was found to be much larger for large generations, like G6 dendrimer that have a higher charge, than it is with small ones like G3 and G4 dendrimers. These results have implications for the use of PAMAM dendrimers as potential gene transfection vectors.

Interaction of Cationic Carbosilane Dendrimers and Their siRNA Complexes with MCF-7 Cells Cultured in 3D Spheroids.

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.

Research progress in the treatment of rheumatoid arthritis

Rheumatoid arthritis RA is a systemic immune inflammation of unknown etiology, which mainly damages the synovium of the joints, leading to joint deformities and loss of function. Its drug treatment currently includes traditional anti-rheumatic drugs, biological agents and various biosimilars. Biological agents have shown obvious advantages in recent years and have been widely used. In recent years, there have been many research related to new treatment methods, such as: microbial therapy, tuned cationic dendrimer therapy, etc. This article focuses on the review of new developments in rheumatoid arthritis treatment drugs and methods.

Comparative Evaluation of Lipofectamine and Dendrimer for Transfection of Short RNA Into Human T47D and MCF-10A Cell Lines.

Purpose: Non-viral transfection approaches are extensively used in cancer therapy. The future of cancer therapy lies on targeted and efficient drug/gene delivery. The aim of this study was to determine the transfection yields of two commercially available transfection reagents (i.e. Lipofectamine 2000, as a cationic lipid and PAMAM G5, as a cationic dendrimer) in two breast cell lines: cancerous cells (T47D) and non-cancerous ones (MCF-10A). Methods: We investigated the efficiencies of Lipofectamine 2000 and PAMAM G5 for transfection/delivery of a labeled short RNA into T47D and MCF-10A. In addition to microscopic assessments, the cellular uptakes of the complexes (fluorescein tagged-scrambled RNA with Lipofectamine or PAMAM dendrimer) were quantified by flow cytometry. Furthermore, the safety of the mentioned reagents was assessed by measuring cell necrosis through the cellular PI uptake. Results: Our results showed significantly better efficiencies of Lipofectamine compared to PAMAM dendrimer for short RNA transfection in both cell types. On the other hand, MCF-10A resisted more than T47D to the toxicity of higher concentrations of the transfection reagents. Conclusion: Altogether, our research demonstrated a route for comprehensive epigenetic modification of cancer cells and depicted an approach to efficient drug delivery, which eventually improves both short RNA-based biopharmaceutical industry and non-viral strategies in epigenetic therapy.

Prevention of Herpesviridae Infections by Cationic PEGylated Carbosilane Dendrimers.

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.

Bacteria capture with magnetic nanoparticles modified with cationic carbosilane dendritic systems

Bacteria elimination from water sources is key to obtain drinkable water. Hence, the design of systems with ability to interact with bacteria and remove them from water is an attractive proposal. A diversity of polycationic macromolecules has shown bactericide properties, due to interactions with bacteria membranes. In this work, we have grafted cationic carbosilane (CBS) dendrons and dendrimers on the surface of iron oxide magnetic nanoparticles (MNP), leading to NP (ca. 10 nm) that interact with bacteria by covering bacteria membrane. Application of an external magnetic field removes MNP from solution sweeping bacteria attached to them. The interaction of the MNP with Gram-positive S. aureus bacteria is more sensible to the size of dendritic system covering the MNP, whereas interaction with Gram-negative E. coli bacteria is more sensible to the density of cationic groups. Over 500 ppm of NPM, MNP covered with dendrons captured over 90% of both type of bacteria, whereas MNP covered with dendrimers were only able to capture S. aureus bacteria (over 90%) but not E. coli bacteria. Modified MNP were characterized by transmission electron microscopy (TEM), thermogravimetric analysis (TGA), Fourier-transform infrared spectroscopy (FTIR), Z potential and dynamic light scattering (DLS). Interaction with bacteria was analyzed by UV, TEM and scanning electron microscopy (SEM). Moreover, the possibility to recycle cationic dendronized MNP was explored.

Structure‐Activity Relationship of Anionic and Cationic Polyamidoamine (PAMAM) Dendrimers against Staphylococcus aureus

Dendrimers are potent synergists, carriers, and delivery molecules for natural biological products and pharmaceuticals. Staphylococcus aureus (S. aureus) infection is causing serious diseases in humans and animals. Given the recorded antibacterial and antiviral activity of terminal‐charged PAMAM dendrimers, the relation between dendrimer charge type and generation is to be established against S. aureus. Three types of polyanionic dendrimers comprising terminal groups sodium carboxylate (generations 1.5, 2.5, 3.5, and 4.5), hydroxyl (generations 2, 3, 4, and 5), and succinamic acid (generations 2, 3, 4, and 5) and polycationic dendrimers containing primary amine (generations 2, 3, 4, and 5) were in antibacterial assays to determine their zone of inhibition and antibacterial activity. Cationic dendrimers were more potent than anionic dendrimers. The largest inhibition was shown by G(5)‐128NH2 followed by G(4)‐64NH2 primary amine dendrimers. Carboxylate, hydroxyl, and succinamic acid dendrimers showed weaker effects. Owing to their antibacterial actions, the addition of dendrimers to antibiotic preparations may increase their efficacy by their intrinsic and bacterial action by damaging the bacterial membranes as well as their usage in drug delivery.

Dendrimer-Based Polyion Complex Vesicles: Loops Make Loose.

Associations of amphiphiles assume their various morphologies according to the so-called packing parameter under thermodynamic control. However, one may raise the question of whether polymers can always relax fast enough to obey thermodynamic control, and how this may be checked. Here, a case of polyion complex (PIC) assemblies where the morphology appears to be subject to kinetic control is discussed. Poly (ethylene oxide)-b-(styrene sulfonate) block copolymers are combined with cationic PAMAM dendrimers of various generations (2-7). The PEO-PSS diblocks, and the corresponding PSS-PEO-PSS triblocks should have nearly identical packing parameters, but surprisingly creat different assemblies, namely core-shell micelles and vesicles, respectively. Moreover, the micelles are very stable against added salt, whereas the vesicles are not only much more sensitive to added salt, but also appear to exchange matter on relevant time scales. The small and largely quenched early-stage precursor complexes are responsible for the morphological and dynamic differences, implying that kinetic control may also be a way to obtain particles with well-defined and useful properties. The exciting new finding that triblocks produce more "active" vesicles will hopefully trigger the exploration of more pathways, and so learn how to tune PICsomes toward specific applications.

Preparation and Physicochemical Characterization of Water-Soluble Pyrazole-Based Nanoparticles by Dendrimer Encapsulation of an Insoluble Bioactive Pyrazole Derivative.

2-(4-Bromo-3,5-diphenyl-pyrazol-1-yl)-ethanol (BBB4) was synthetized and successfully evaluated concerning numerous biological activities, except for antimicrobial and cytotoxic effects. Due to the antimicrobial effects possessed by pyrazole nucleus, which have been widely reported, and the worldwide need for new antimicrobial agents, we thought it would be interesting to test BBB4 and to evaluate its possible antibacterial effects. Nevertheless, since it is water-insoluble, the future clinical application of BBB4 will remain utopic unless water-soluble BBB4 formulations are developed. To this end, before implementing biological evaluations, BBB4 was herein re-synthetized and characterized, and a new water-soluble BBB4-based nano-formulation was developed by its physical entrapment in a biodegradable non-cytotoxic cationic dendrimer (G4K), without recovering harmful solvents as DMSO or surfactants. The obtained BBB4 nanoparticles (BBB4-G4K NPs) showed good drug loading (DL%), satisfying encapsulation efficiency (EE%), and a biphasic quantitative release profile governed by first-order kinetics after 24 h. Additionally, BBB4-G4K was characterized by ATR-FTIR spectroscopy, NMR, SEM, dynamic light scattering analysis (DLS), and potentiometric titration experiments. While, before the nanotechnological manipulation, BBB4 was completely water-insoluble, in the form of BBB4-G4K NPs, its water-solubility resulted in being 105-fold higher than that of the pristine form, thus establishing the feasibility of its clinical application.