Dendrimer Complexes Research Articles

Analytical model study of complexation of dendrimer as an ion penetrable sphere with DNA

Poly (amidoamine) (PAMAM) dendrimers, being protonated under physiological conditions, have great potential as nonviral vectors for gene transfection. Many experimental and simulation studies have been performed to study the effect of dendrimer size, charge, and salt concentration on the structure and transfection efficiency of condensed DNA aggregates. In this study a theoretical model describing a linear polyelectrolyte (LPE) and ion-penetrable spheres has been developed and applied to investigate the interaction between linearized DNA and positively charged dendrimer of different generations. Throughout the study, we emphasized on the effect of the medium’s environments on the complexation of LPE chain with one dendrimer. It is found that the wrapping degree of the chain around the dendrimer increases by increasing dendrimer’s charge (decreasing pH), Bjerum length, salt concentration, and decreases by increasing the rigidity of the chain. Also, the effect of 1:1 salt concentration on complexation of DNA plasmids with one dendrimer of different generations has been investigated, and found that the optimal wrapping length of the LPE chain around the dendrimer depends on dendrimer generation.

Computational Modeling of Environmentally Responsive Hydrogels (ERH) for Drug Delivery System

The present work aims at computational analysis of environmentally responsive hydrogels with enormous prospective in the formulation aspect of drug delivery systems. The drug delivery potential of hydrogels to the targets is owing to the specific stimuli responsive nature of the hydrogels. The environmental factors looked upon in the study are changes in pH, alteration of temperature and glucose concentration rise originated in the body as a result of various disease conditions. Polymers, synthetic polypeptides and dendrimers have been used in the present work to study the feasibility of drug delivery. The computational methods have been used to formulate polymer properties, pharmacokinetics and toxicity studies. Diverse interactions approximating electrostatic, hydrophobic and hydrogen bond interactions acquire place during incorporation of drugs within the polymer and dendrimers. The covalent and electrostatic interactions between a drug and the surface of polymer and dendrimer have been analyzed. The docking interaction studies have been performed and the best polymer and dendrimer complex have been selected based on the docking score, binding energy and interaction energy with the drugs. G5 generation of poly amidoamine dendrimers and poly N-Ndiethyl acrylamide (PDEAAM) have been identified as most suitable stimuli-responsive effective drug carriers for anti diabetic drugs and diuretics. Favorable results have been obtained while using poly acrylic acid (PAA) for corticosteroids and polylysine for diabetic drugs. ConA protein along with poly aspartic acid also showed good results. Keywords: Absorption, dendrimers, docking, polymer, pharmacokinetics, toxicity, ConA protein, modeling and simulation, Environmentally Responsive Hydrogels, drug delivery systrem

Long-lived photoinduced charge separation for solar cell applications in supramolecular complexes of multi-metalloporphyrins and fullerenes

Monomers, dimers, trimers, dendrimers and oligomers of metalloporphyrins form supramolecular complexes with fullerene derivatives via electrostatic interactions, π-π interactions and coordination bonds. Photoexcitation of the supramolecular complexes resulted in photoinduced electron transfer from the porphyrin moiety to the fullerene moiety to produce the charge-separated states as revealed by laser flash photolysis measurements. The rate constants of photoinduced charge separation and charge recombination in supramolecular complexes of multi-metalloporphyrins and fullerenes were also determined by laser flash photolysis measurements and the results depending on the number of porphyrins in the supramolecular complexes are discussed in terms of efficiency of photoinduced energy transfer and charge separation as well as the lifetimes of charge-separated states. The photoelectrochemical performances of solar cells composed of supramolecular complexes of monomers, dimers, dendrimers and oligomers of metalloporphyrins with fullerenes are compared in relation to the rate constants of photoinduced charge separation and charge recombination.

CEST: From basic principles to applications, challenges and opportunities

Chemical Exchange Saturation Transfer (CEST) offers a new type of contrast for MRI that is molecule specific. In this approach, a slowly exchanging NMR active nucleus, typically a proton, possessing a chemical shift distinct from water is selectively saturated and the saturated spin is transferred to the bulk water via chemical exchange. Many molecules can act as CEST agents, both naturally occurring endogenous molecules and new types of exogenous agents. A large variety of molecules have been demonstrated as potential agents, including small diamagnetic molecules, complexes of paramagnetic ions, endogenous macromolecules, dendrimers and liposomes. In this review we described the basic principles of the CEST experiment, with emphasis on the similarity to earlier saturation transfer experiments described in the literature. Interest in quantitative CEST has also resulted in the development of new exchange-sensitive detection schemes. Some emerging clinical applications of CEST are described and the challenges and opportunities associated with translation of these methods to the clinical environment are discussed.

Stoichiometry and equilibrium constant of the complex of PAMAM-NH2 G4 and 5-fluorouracil

Polyamidoamine dendrimer (PAMAM-NH2 G4) complex with 5-fluorouracil, an oncological drug, was investigated by the technique of equilibrium dialysis at temperatures of 20°C and 45°C. The results obtained were worked out by means of the modified model of two sets of active sites proposed by Bobrovnik. Based on the analysis of the results obtained, it was calculated that at a temperature of 20°C the dendrimer molecule can bind about 12 molecules of the ligand with equilibrium constant K1≅5600 and about 37 molecules with equilibrium constant K2≅150. At a temperature of 45°C the number of the dendrimer binding sites is similar but the equilibrium constants of binding 5-fluorouracil with both sets of active sites are clearly lower (K1≅1820, K2≅70). The saturation of both the sets of active sites is of an exothermic character.

ChemInform Abstract: Dendrimer Therapeutics: Covalent and Ionic Attachments

AbstractReview: 95 refs.

SiRNA carriers based on carbosilane dendrimers affect zeta potential and size of phospholipid vesicles

One of the major limitations in gene therapy is an inability of naked siRNA to passively diffuse through negatively charged cell membranes. Therefore, the siRNA transport into a cell requires efficient carriers. In this work we analyzed the charge-dependent interaction of the complexes of cationic carbosilane dendrimers (CBD) and anti-HIV siRNA (dendriplexes) with the model membranes — large unilamellar vesicles (LUV). We used the second generation of branched with CBD carbon–silicon bonds (CBD-CS) which are water-stable and that of oxygen–silicon bonds (CBD-OS) which are slowly hydrolyzed in aqueous solutions. The LUVs were composed of zwitterionic dimyristoylphosphatidylcholine (DMPC), negatively charged dipalmitoylphosphatidylglycerol (DPPG) and their mixture (DMPC/DPPG, molar ratio 7:3). The interaction of dendriplexes with LUVs affected both zeta potential and size of the vesicles. The changes of these values were larger for the negatively charged LUV. CBD-CS resulted in the decrease of zeta potential values to more negative ones, whereas an opposite effect took place for CBD-OS suggesting a different kind of interaction between LUVs and the dendriplexes. The results indicate that both CBD-CS and CBD-OS can be used for transport of siRNA into the cells. However, CBD-CS are preferred due to a better stability in water and improved bioavailability of siRNA on their surface.

Poly(amidoamine) dendrimer-mediated synthesis and stabilization of silver sulfonamide nanoparticles with increased antibacterial activity

Silver sulfadiazine (AgSD) is a topical antibiotic with limited aqueous solubility. In this study, it was shown that poly(amido amine) (PAMAM) dendrimer complexes with SD (SDZ) and silver (Ag) could be used for a bottom-up approach to synthesize highly-soluble AgSD nanoparticles (NPs). These NPs were stabilized against crystal growth by electrostatic layer-by-layer (LBL) coating with various PAMAM dendrimers. Additionally, AgNPs can be incorporated in the dendrimer shells that augmented AgSD release. NP formulation in a cream base provided a topical drug-delivery platform with enhanced antibacterial properties against burn-wound infections, comprising three nanostructures i.e., nano-AgSD, AgNPs as well as PAMAM dendrimers, in one efficient, elegant nanosystem. From the Clinical EditorIn this paper an elegant silver sulfadiazine-based nanoparticle complex is demonstrated with enhanced antibacterial properties and improved solubility for the treatment of burn-wound infections in a topical crème formulation.

Luminescent Lanthanide Complexes for Advanced Photonics Applications

Luminescent lanthanide complexes have been overviewed for advanced photonics applications. Lanthanide(III) ions (<TEX>$Ln^{3+}$</TEX>) were encapsulated by the luminescent ligands such as metalloporphyrins, naphthalenes, anthracene, push-pull diketone derivatives and boron dipyrromethene(bodipy). The energy levels of the luminescent ligands were tailored to maintain the effective energy transfer process from luminescent ligands to <TEX>$Ln^{3+}$</TEX> ions for getting a higher optical amplification gain. Also, key parameters for emission enhancement and efficient energy transfer pathways for the sensitization of <TEX>$Ln^{3+}$</TEX> ions by luminescent ligands were investigated. Furthermore, to enhance the optophysical properties of novel luminescent <TEX>$Ln^{3+}$</TEX> complexes, aryl ether-functionalized dendrons as photon antennas have been incorporated into luminescent <TEX>$Ln^{3+}$</TEX> complexes, yielding novel <TEX>$Ln^{3+}$</TEX>-cored dendrimer complex such as metalloporphyrins, naphthalenes, and anthracenes bearing the Fr<TEX>$\acute{e}$</TEX>chet aryl-ether dendrons, namely, (<TEX>$Er^{3+}-[Gn-Pt-Por]_3$</TEX> (terpy), <TEX>$Er^{3+}-[Gn-Naph]_3$</TEX>(terpy) and <TEX>$Er^{3+}-[Gn-An]_3$</TEX>(terpy)). These complexs showed much stronger near-IR emission bands at 1530 nm, originated from the 4f-4f electronic transition of the first excited state (<TEX>$^4I_{13/2}$</TEX>) to the ground state (<TEX>$^4I_{15/2}$</TEX>) of the partially filled 4f shell. A significant decrease in the fluorescence of metalloporphyrins, naphthalenes and anthracene ligand were accompanied by a strong increase in the near IR emission of the <TEX>$Ln^{3+}$</TEX> ions. The near IR emission intensities of <TEX>$Ln^{3+}$</TEX> ions in the lanthanide(III)-encapsulated dendrimer complexes were dramatically enhanced with increasing the generation number (n) of dendrons, due to the site-isolation and the light-harvesting(LH) effects. Furthermore, it was first attempted to distinguish between the site-isolation and the light-harvesting effects in the present complexes. In this review, synthesis and photophysical studies of inert and stable luminescent <TEX>$Ln^{3+}$</TEX> complexes will be dealt for the advanced photonics applications. Also, the review will include the exploratory investigation of the key parameters for emission enhancement and the effective energy transfer pathways from luminescent ligands to <TEX>$Ln^{3+}$</TEX> ions with <TEX>$Ln^{3+}$</TEX>-chelated prototype complexes.

Polyamidomine dendrimers: an excellent drug carrier for improving the solubility and bioavailability of puerarin

The potential of polyamidoamine (PAMAM) dendrimers as solubility enhancers and oral drug delivery system was well known. Herein, we investigated the possibility of PAMAM dendrimers for promoting the solubility and oral bioavailability of puerarin. In the present study, the effect of PAMAM dendrimers with different generations (G1.5, G2, G2.5, and G3) on the solubility of puerarin was evaluated at different concentrations and pH conditions. Further more, the puerarin–G2 dendrimer complex was conducted for the in vitro hemolytic toxicity studies and pharmacokinetics studies in rats. The solubility of puerarin was significantly higher in the presence of the full generation dendrimers (e.g. G2 and G3). No significant hemolysis was observed on erythrocytes (G2, 0–2.5 mg/mL) in the hemolytic toxicity studies. The pharmacokinetics parameters Tmax, Cmax, and AUC0–8 h of puerarin suspension solution and puerarin–G2 dendrimer complex solution were 0.76 h, 1.50 µg/mL, 7.33 µg·h/mL and 0.33 h, 6.49 µg/mL, 14.02 µg·h/mL, respectively. These studies demonstrate that PAMAM dendrimers may be a promising strategy for peroral delivery of puerarin.

Dendrimer-Enabled Modulation of Gene Expression in Chlamydia trachomatis

The obligate intracellular bacterium Chlamydia trachomatis is an important human pathogen. The genome of this organism is small but encodes many genes of currently unknown function that are thought to be involved in virulence. Lack of a system for genetic manipulation has been a key challenge to advancing the understanding of molecular genetics underlying virulence for this bacterium. We developed a dendrimer-enabled system for transformation of C. trachomatis, and used it to demonstrate the efficient and highly specific knockdown of transcript levels from targeted genes. Antisense, sense, and other control oligonucleotides targeting two sets of duplicated genes on the chlamydial chromosome were designed, commercially synthesized, and complexed with generation-4 polyamidoamine (PAMAM) dendrimers. The complexes were given to HEp-2 cell cultures infected for 16 h with C. trachomatis serovar K and then removed three hours later. Infected cultures were harvested 6 h after pulsing, and DNA and RNA/cDNA were prepared for assessment of transcript levels compared to those for the same genes in infected cultures, without dendrimer complexation. In all cases, the targeted gene complexed to dendrimer, but not its duplicate, showed up to 90% transcript attenuation. The duration of attenuation can be extended by repeated pulsing, and in some cases transcript levels from multiple genes can be attenuated in the same organism. This system will allow study of chlamydial gene function in pathogenesis, leading to more effective therapies to treat Chlamydia-induced diseases in a targeted manner.

Dendrimer therapeutics: covalent and ionic attachments

This concise review focuses on dendrimers functionalized by different linkers required for covalent and ionic attachments of drugs to the dendrimer's surface and highlights the importance of the chemical nature of linkers for controlled release of free drugs. The stability of linkers under physiological conditions and their lability under acidic conditions such as those of endosomes and lysosomes or under enzymatic conditions will be discussed. Especially, we review functionality of the most recently reported drug–dendrimer conjugates. Then, we give a short comparison of dendrimer conjugates versus either dendrimer complexes or polymer therapeutics and finally we briefly summarize the importance of both targeted and nontargeted covalently conjugated drugs.

Application of Fused-Heterocyclic Compounds in Red Phosphorescent Iridium(III) Complexes

Organic light-emitting diodes (OLEDs) have attracted considerable attention during the last decade because of the potential advantages associated with their usage in full-color displays. Electroluminescent phosphorescent materials have also enjoyed similar levels of attention because of their excellent luminescent properties. The three primary colors, blue, green, and red, are essential for the practical application of phosphorescent complexes in flat-panel displays. Relative to the efficient green phosphorescent materials, red phosphorescent materials suffer many problems, including poor color purity, low efficiency, and low luminance, and the design of appropriate red colored materials therefore represents a significant challenge. Fused-heterocyclic compounds have been widely used in red phosphorescent iridium(III) complexes because of their high quantum efficiency, color adjustability, and balanced charge injection and migration. This review summarizes the development and application of fused-heterocyclic compounds in recent years in small molecule, dendrimer and polymeric red phosphorescent iridium(III) complexes. The influence of the molecular structures of iridium(III) complexes on the optical and electrical properties and device performances has also been described. Finally, a discussion of the prospect of developing fused-heterocyclic compounds in the red phosphorescent materials has also been provided.

Peptide-Conjugated PAMAM Dendrimer as a Universal DNA Vaccine Platform to Target Antigen-Presenting Cells

DNA-based vaccines hold promise to outperform conventional antigen-based vaccines by virtue of many unique features. However, DNA vaccines have thus far fallen short of expectations, due in part to poor targeting of professional antigen-presenting cells (APC) and low immunogenicity. In this study, we describe a new platform for effective and selective delivery of DNA to APCs in vivo that offers intrinsic immune-enhancing characteristics. This platform is based on conjugation of fifth generation polyamidoamine (G5-PAMAM) dendrimers, a DNA-loading surface, with MHC class II-targeting peptides that can selectively deliver these dendrimers to APCs under conditions that enhance their immune stimulatory potency. DNA conjugated with this platform efficiently transfected murine and human APCs in vitro. Subcutaneous administration of DNA-peptide-dendrimer complexes in vivo preferentially transfected dendritic cells (DC) in the draining lymph nodes, promoted generation of high affinity T cells, and elicited rejection of established tumors. Taken together, our findings show how PAMAM dendrimer complexes can be used for high transfection efficiency and effective targeting of APCs in vivo, conferring properties essential to generate effective DNA vaccines.

Enhancement of optical properties of dyes for bioprobes by freezing effect of molecular motion using POSS-core dendrimers

We demonstrate that the POSS-core dendrimer induced various kinds of favourable properties of trisvinyl-pyridinium triphenylamine (TP3PY) as a bioprobe. By using the amphiphilicity of the POSS core, the complexes of TP3PY with G2 POSS-core dendrimer were prepared, and the series of properties were investigated for the application as a bioprobe. Initially, it was shown that the adsorption of TP3PY onto the vessels was highly prohibited by the complex formation with the dendrimers. The solution states of the dendrimer complexes were maintained at least for 7days. Moreover, it was found that the improvement of quantum yields and the elongation of fluorescent lifetimes were observed by the complexation with the dendrimers. Similar photochemical properties were obtained in a glassy state of 2-methyltetrahydrofuranat –196°C. The molecular rotations occurring at the excited state could be restricted by the complex formation with dendrimers. These characteristics induced by the complexation with the POSS-core dendrimer are of significance to improve the signal to noise ratio and the accuracy on the detection as a bioprobe.

Secure and effective gene vector of polyamidoamine dendrimer pharmaceutically modified with anionic polymer

The purpose of this study was to develop a new type of gene vector, polyamidoamine (PAMAM) dendriplex pharmaceutically modified, based on electrostatic interactions, by various anionic polymers. The γ-polyglutamic acid (γ-PGA)/PAMAM dendriplex and the α-PGA/PAMAM dendriplex formed a stable complex, although α-polyaspartic acid and heparin released pDNA from the complex. The addition of anionic polymer decreased the ζ-potential, although it did not greatly affect the size of the complex. As a result of an in vitro gene expression study of mouse melanoma cells, we found that the γ-PGA/PAMAM dendriplex showed high gene expression comparable to the PAMAM dendriplex, although the α-PGA/PAMAM dendriplex showed lower gene expression. Tail vein injection of the γ-PGA/PAMAM dendriplex into mice also led to high gene expression in the spleen and lung. The γ-PGA/PAMAM dendriplex showed no cytotoxicity and no agglutination, although severe cytotoxicity and agglutination were observed in the PAMAM dendriplex. Thus, we discovered that complexes of pDNA, PAMAM dendrimers, and γ-PGA showed higher gene expression in vitro and in vivo, and markedly lower toxicity. This complex is valuable and is expected to be a safe and effective gene vector.

Preferential accumulation within tumors and in vivo imaging by functionalized luminescent dendrimer lanthanide complexes

We have created a dendrimer complex suitable for preferential accumulation within liver tumors and luminescence imaging by substituting thirty-two naphthalimide fluorophores on the surface of the dendrimer and incorporating eight europium cations within the branches. We demonstrate the utility and performance of this luminescent dendrimer complex to detect hepatic tumors generated via direct subcapsular implantation or via splenic injections of colorectal cancer cells (CC531) into WAG/RijHsd rats. Luminescence imaging of the tumors after injection of the dendrimer complex via hepatic arterial infusion revealed that the dendrimer complex can preferentially accumulate within liver tumors. Further investigation indicated that dendrimer luminescence in hepatic tumors persisted in vivo. Due to the incorporation of lanthanide cations, this luminescence agent presents a strong resistance against photobleaching. These studies show the dendrimer complex has great potential to serve as an innovative accumulation and imaging agent for the detection of metastatic tumors in our rat hepatic model.

A novel dendrimer based on poly (L-glutamic acid) derivatives as an efficient andbiocompatible gene delivery vector

Non-viral gene delivery systems based on cationic polymers have faced limitations relatedto their relative low gene transfer efficiency, cytotoxicity and system instability in vivo. Inthis paper, a flexible and pompon-like dendrimer composed of poly (amidoamine)(PAMAM) G4.0 as the inner core and poly (L-glutamic acid) grafted low-molecular-weightpolyethylenimine (PLGE) as the surrounding multiple arms was synthesized (MGIdendrimer). The novel MGI dendrimer was designed to combine the merits ofsize-controlled PAMAM G4.0 and the low toxicity and flexible chains of PLGE. Inphosphate-buffered saline dispersions the well-defined DNA/MGI complex above aN/P ratio of 30 showed good stability with particle sizes of approximately 200 nm and acomparatively low polydispersity index. However, the particle size of the DNA/25 kDapolyethylenimine (DNA/PEI 25K) complex was larger than 700 nm under the same saltconditions. The shielding of the compact amino groups at the periphery of flexible PAMAMand biocompatible PLGE chains in MGI resulted in a dramatic decrease of the cytotoxicitycompared to native PAMAM G4.0 dendrimer. The in vitro transfection efficiency ofDNA/MGI dendrimer complex was higher than that of PAMAM G4.0 dendrimer.Importantly, in serum-containing medium, DNA/MGI complexes at their optimalN/P ratio maintained the same high levels of transfection efficiency as in serum-free medium,while the transfection efficiency of native PAMAM G4.0, PEI 25K and Lipofectamine 2000were sharply decreased. In vivo gene delivery of pVEGF165/MGI complex intoballoon-injured rabbit carotid arteries resulted in significant inhibition of restenosis byincreasing VEGF165 expression in local vessels. Therefore, the pompon-like MGIdendrimer may be a promising vector candidate for efficient gene delivery in vivo.

Determination of puerarin in rabbit aqueous humor by liquid chromatography tandem mass spectrometry using microdialysis sampling after topical administration of puerarin PAMAM dendrimer complex

To study pharmacokinetic properties of puerarin poly(amido amine) (PAMAM) dendrimer complex, a sensitive liquid chromatography tandem mass spectrometry method (LC-MS/MS) was developed and validated to determine puerarin in rabbit aqueous humor using microdialysis sampling. Astilbin was used as the internal standard. The linear range for puerarin was from 2 to 1000 ng/mL ( r = 0.9986) based on 20 μL of aqueous humor. The coefficients of variations for intra-day and inter-day precisions were less than 10.0%, and the relative error of accuracy was within ±6.3%. The mean extraction recovery of puerarin varied from 80.4% to 85.5%. Microdialysis provides a complete concentration versus time profile. A significant difference was observed in main pharmacokinetic parameters of C max, AUC and t 1/2 between puerarin solution and puerarin PAMAM dendrimer complex. Complex formation resulted in an obvious increase in bioavailability of puerarin after topical administration to rabbit according to the above LC-MS/MS assay method.

Synthesis and characterization of polyamide metallodendrimers and their anti-bacterial and anti-tumor activities

Pt(II) and Pd(II) complexes with aromatic amine terminated first generation (G1) and second generation (G2) polyamide dendrimers [PAD-(NH2)n] (n = 6 for G1 and 12 for G2) were synthesized. All the synthesized dendrimers and metallodenrimers were characterized by elemental and spectral analysis. These novel dendrimers and their metallodendrimers (metal complexes of dendrimers) were screened for their anti-bacterial activity against Bacillus subtilis and Staphylococcus aureus (Gram positive) and Escherichia coli and Salmonella typhi (Gram negative) using agar disk diffusion method. The cytotoxicity assay of the dendrimers and metallodendrimers has been performed against MFC-7 cell lines using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Anti-bacterial evaluation indicates that the second generation dendrimer exhibit stronger biological activity against all the pathogenic bacterial strains in comparison to the first generation dendrimers. PdG2 exhibited lowest value of MIC 70 μg/ml against E. coli, while MIC value of PtG2 was 78 μg/ml. PdG2 and PtG2 show lowest anti-bacterial activity against S. typhi with 102 and 110 μg/ml (MIC value), respectively. In general, the metallodendrimers showed lower cytotoxicity than cisplatin (standard drug) and Pt(II) containing metallodendrimers were found to be more efficient in the induction of MFC-7 death than Pd(II) containing metallodendrimers.