Core PAMAM Dendrimers Research Articles

Novel fluorescein isothiocyanate (FITC) cored PAMAM dendrimers as drug delivery agent

Fluorescent dyes, or fluorophores, enable researchers to visualize specific biological molecules by fluorescence microscopy. Herein, a novel fluorescent FITC-poly(amidoamine) (FITC-PAMAM) dendrimers have been synthesized via divergent approach. The molecular structure of the FITC-PAMAM dendrimers (G-0 to G5) was characterized by 1H NMR, 13C NMR spectroscopy and by FTIR. In order to emphasize the structural efficacy of FITC-PAMAM dendrimer, the drug delivery behavior has been evaluated by using 5-fluorouracil (5-FU) as a model cancer therapy drug. Anti-proliferative activity of FITC-cored PAMAM dendrimers in all generations (G0-G5) with or without 5-FU were analyzed on human gastric carcinoma cells (AGS) by WST-1 cell proliferation assay. Initially, the nontoxic dose of unloaded FITC-PAMAM dendrimers was assessed for further drug loading experiments. Loading of 5-FU into FITC-PAMAM dendrimers, regardless of generation, increased the toxicity of the drug. Besides, 5-FU loaded FITC-PAMAM dendrimers induced a generation-based gradual inhibition of cell proliferation. FITC and phase contrast merged images indicated that FITC-PAMAM dendrimers facilitate the entry of the drug into the cells, in a generation-dependent manner. The FITC- dendrimers may serve as a promising intracellular drug delivery agent for 5-FU by increasing cell uptake into cells and thereby, enhancing antiproliferative activity on AGS cells in a generation-dependent manner.

Photophysics and photochemistry of porphyrin core PAMAM dendrimers. Excited states interaction with quinones

Quenching of excited states of the meso-substituted tetraphenyl porphyrins with PAMAM branches, and one with PAMAM generation 1 peripherally-modified with thiazole groups by p-benzoquinones, were studied in DMF solution. Fluorescence lifetime measurements evidence a static component in the quenching process. The dynamic quenching rate constants were close to the diffusional limit except for the case of duroquinone. Apparent association constants of the porphyrin compounds with the quinones were determined by comparison of static and dynamic measurements of fluorescence quenching. The ground state interaction is very weak with the exception of tetrachlorobenzoquinone. The triplet state decay kinetics and the transient absorption spectra in the presence of the quinones were determined by laser flash photolysis. Triplet quenching rate constants were lower than those of singlet quenching. An electron transfer mechanism was proposed to explain the results. The long-time transient absorption spectra were assigned to the radical cation of the dyes. Relative radical yields were determined and a dependence on the side chains and the quencher was observed.

Preparation of Cu Nanocomposites from EDA, DETA, and Jeffamine Cored PAMAM Dendrimers with TRIS and Carboxyl Surface Functional Groups.

This study presents the synthesis and UV-Vis characterization of Cu nanocomposites from ethylenediamine (EDA) (E), diethylenetriamine (DETA) (D), and Jeffamine® T-403 (P) cored PAMAM dendrimers (PAMAMs) with TRIS and carboxyl surface functional groups. Cu-PAMAM dendrimer encapsulated nanoparticles (Cu-DENs) were characterized by UV-Vis spectroscopy. Disappearance of the 680 nm d-d transition and 270-300 nm ligand to metal charge transfer (LMCT) peaks and the formation of monotically increasing exponential band were used as the evidence of the successful synthesis of Cu-DENs in addition to immediate color change of dendrimer-metal mixture solutions from blue to golden brown by reduction. Synthesized Cu-DENs could be facilitated as novel alternatives to the existing nanomaterials used in a wide range of applications involving bio and chemical sensors, catalysis, hydrogenations, oxidations, semiconductors, noble metals, magnetic dendrimer nanocomposites, environmental cleanup and many others.

Effective targeting of gemcitabine to pancreatic cancer through PEG-cored Flt-1 antibody-conjugated dendrimers

Tumor-targeted delivery of anticancer drugs using dendrimers has been recognized as a promising strategy to increase efficiency and reduce adverse effects of chemotherapy. Herein, we developed a dendrimer-based drug delivery system targeting Flt-1 (a receptor for vascular endothelial growth factors (VEGF)) receptor to improve therapeutic efficacy of gemcitabine in pancreatic cancer. Synthesized polyethylene glycol (PEG)-cored PAMAM dendrimers, which bear anionic carboxylic acid groups on the surface were modified with PEG chains, which were then conjugated with Flt-1 antibody. Following structural and chemical characterization studies, gemcitabine HCl-dendrimer inclusion complexes were successfully prepared. These complexes were efficiently engulfed by Flt-1 expressing pancreatic cancer cells, which enhanced the cytotoxicity of gemcitabine. Moreover, pancreatic tumors established in mice were highly targeted by PEG-cored Flt-1 antibody-conjugated dendrimers and increased accumulation of these gemcitabine-loaded complexes exhibited satisfactory in vivo anti-cancer efficacy. In conclusion, dendrimer-based targeted delivery of chemotherapeutics may serve as a promising approach for the treatment of malignancies such as pancreatic cancer that do not benefit from conventional chemotherapy.

Cytotoxicity and biodistribution studies on PEGylated EDA and PEG cored PAMAM dendrimers

Starting from Ethylenediamine (EDA) or poly(ethylene glycol) tetra amine (4-arm-PEG) cores, two different peripheral methylester (–COOCH3) or amine (–NH2) PAMAM dendrimers have been synthesized. In the growth phase of dendrimers, two important building blocks, methyl acrylate for the half generation and EDA for the full generations, have been used. In order to improve the yield and decrease the time for the aminolysis step, a microwave-assisted technique was applied. Both of these dendrimers with different cores were grown up to 4.5 generations where surface modification, i.e. PEGylation, with 10% Poly(ethylene glycol) bis(amine) was performed. In order to increase the solubility of dendrimers, esteric surfaces were converted to carboxylic acid groups. Accordingly, the dendrimers were soluble in water or in water–methanol mixture which enabled their purification by liquid-phase polymer-based retention in each step. Finally, the resulting products that were characterized with (NMR and FTIR) spectroscopy were evaluated in vitro and in vivo. The analytical grade dendrimers were not cytotoxic to mouse fibroblasts and their biodistribution was mainly determined in the site of injection (peritoneum), liver and kidneys.

Construction of novel electrochemical immunosensor for detection of prostate specific antigen using ferrocene-PAMAM dendrimers

In this study, an immunosensor was designed to utilize for the detection of prostate specific antigen (PSA) based on three different generations (G1, G2 and G3) of ferrocene (Fc) cored polyamidiamine dendrimers (Fc-PAMAM) gold (Au) electrode. The self-assembled monolayer principle (SAM) was used to fabricate the sensitive, selective and disposable immunosensor electrodes. In electrode fabrication cysteamine (Cys) was the first agent covalently linked on the Au electrode surface. Immobilized redox center (ferrocene) cored PAMAM dendrimers served as a layer for the further binding of biological components. The monoclonal antibody of PSA (anti-PSA) was covalently immobilized on dendrimers which were attached onto the modified Au surface (Au/Cys/Fc-PAMAMs/anti-PSA). PSA levels were quantitatively analyzed by using electrochemical differential pulse voltammetry (DPV) whose lowest detection limit was calculated as 0.001ngmL−1. The Au/Cys/FcPAMAM/anti-PSA immunosensor showed excellent performance for PSA at the pulse amplitude; 50mV and the scan rate; 10mV/s in a wide linear concentration range of 0.01ng–100ngmL−1. Analytical performance and specificity assays were carried out using human serum and different proteins.

Microwave assisted synthesis of Jeffamine cored PAMAM dendrimers

This study reports the use of a new microwave assisted amidation method for the synthesis of Jeffamine cored poly (amidoamine) (PAMAM) dendrimers up to fourth generations. Reaction proceeding is monitored by attenuated total reflectance (ATR) without final purification. It was found that current method decreases the aminolysis time, and minimizes the excessive use of reagents and solvents. Synthesized dendrimers were purified by liquid-phase polymer-based retention (LPR) technique and characterized by 1H-NMR, 13C-NMR, EA, GPC and UV–VIS spectroscopy.

Copper(ii) binding to flexible triethanolamine-core PAMAM dendrimers: a combined experimental/in silico approach

The structure of copper(II) complexes formed with triethanolamine (TEA) core poly(amidoamine) (PAMAM) dendrimers from generation 0 (G0) to 4 (G4) were investigated by the electron paramagnetic resonance (EPR) technique and molecular simulations. Different square planar coordination modes were detected as a function of copper(II) concentration, whose dynamic evolution relates to the high structural flexibility peculiar to this dendrimer family. Modulated by generation and solvation effects, copper(II) complexation begins at the dendrimer core and progresses to the dendrimer periphery. Differently from the ethylenediamine (EDA) core PAMAM dendrimers, the copper complexes involving the TEA core showed high mobility and saturation of the internal sites above the 1 : 1 molar ratio between the dendrimers and the ions. Therefore, by combining EPR and molecular simulations for the first time, ultimately we obtained unique information on structure, dynamics and copper interacting ability of these dendrimers which could be successfully exploited in biomedical applications.

Structurally Flexible Triethanolamine Core PAMAM Dendrimers Are Effective Nanovectors for DNA Transfection in Vitro and in Vivo to the Mouse Thymus

With the aim of developing dendrimer nanovectors with a precisely controlled architecture and flexible structure for DNA transfection, we designed PAMAM dendrimers bearing a triethanolamine (TEA) core, with branching units pointing away from the center to create void spaces, reduce steric congestion, and increase water accessibility for the benefit of DNA delivery. These dendrimers are shown to form stable nanoparticles with DNA, promote cell uptake mainly via macropinocytosis, and act as effective nanovectors for DNA transfection in vitro on epithelial and fibroblast cells and, most importantly, in vivo in the mouse thymus, an exceedingly challenging organ for immune gene therapy. Collectively, these results validate our rational design approach of structurally flexible dendrimers with a chemically defined structure as effective nanovectors for gene delivery, and demonstrate the potential of these dendrimers in intrathymus gene delivery for future applications in immune gene therapy.

Jeffeamine cored PAMAM dendrimers in the efficient transfer of GFP gene into HeLa cells

Jeffeamine cored PAMAM dendrimers in the efficient transfer of GFP gene into HeLa cells

PAMAM Dendrimers Mediate siRNA Delivery to Target Hsp27 and Produce Potent Antiproliferative Effects on Prostate Cancer Cells

RNA interference (RNAi) holds great promise for the treatment of inherited and acquired diseases, provided that safe and efficient delivery systems are available. Herein we report that structurally flexible triethanolamine (TEA) core PAMAM dendrimers are able to deliver an Hsp27 siRNA effectively into prostate cancer (PC-3) cells by forming stable nanoparticles with siRNA, protecting the siRNA nanoparticles from enzymatic degradation, and enhancing cellular uptake of siRNA. The Hsp27 siRNA resulted in potent and specific gene silencing of heat-shock protein 27, an attractive therapeutic target in castrate-resistant prostate cancer. Silencing of the hsp27 gene led to induction of caspase-3/7-dependent apoptosis and inhibition of PC-3 cell growth in vitro. In addition, the siRNA-dendrimer complexes are non-cytotoxic under the conditions used for siRNA delivery. Altogether, TEA core PAMAM dendrimer-mediated siRNA delivery, in combination with RNAi that specifically targets Hsp27, may constitute a promising approach for combating castrate-resistant prostate cancer, for which there is no efficacious treatment.

Dendrimer Enhanced Ultrafiltration. 1. Recovery of Cu(II) from Aqueous Solutions Using PAMAM Dendrimers with Ethylene Diamine Core and Terminal NH2 Groups

This article discusses the feasibility of using dendrimer enhanced ultrafiltration (DEUF)to recover Cu(II) from aqueous solutions. Building upon the results of fundamental investigations of Cu(II) binding to PAMAM dendrimers with ethylenediamine (EDA) core and terminal NH2 groups, we combine (i) dead-end ultrafiltration (UF) experiments with (ii) atomic force microscopy (AFM) characterization of membrane fouling to assess the feasibility of using DEUF to recover Cu(II) from aqueous solutions. On a mass basis, the Cu(II) binding capacities of the EDA core PAMAM dendrimers are much larger and more sensitive to solution pH than those of linear polymers with amine groups. The dendrimer-Cu(II) complexes can be efficiently separated from aqueous solutions by ultrafiltration. The metal ion laden dendrimers can be regenerated by decreasing the solution pH to 4.0; thus enabling the recovery of the bound Cu(II) ions and recycling of the dendrimers. The UF measurements and AFM characterization studies show that EDA core PAMAM dendrimers with terminal NH2 groups have very lowtendency to foul the commercially available regenerated cellulose (RC) membranes evaluated in this study. The overall results of these experiments suggest that DEUF is a promising process for recovering metal ions such as Cu(II) from aqueous solutions.

Dendritic Chelating Agents. 1. Cu(II) Binding to Ethylene Diamine Core Poly(amidoamine) Dendrimers in Aqueous Solutions

This paper describes an investigation of the uptake of Cu(II) by poly(amidoamine) (PAMAM) dendrimers with an ethylenediamine (EDA) core in aqueous solutions. We use bench scale measurements of proton and metal ion binding to assess the effects of (i) metal ion-dendrimer loading, (ii) dendrimer generation/terminal group chemistry, and (iii) solution pH on the extent of binding of Cu(II) in aqueous solutions of EDA core PAMAM dendrimers with primary amine, succinamic acid, glycidol, and acetamide terminal groups. We employ extended X-ray absorption fine structure (EXAFS) spectroscopy to probe the structures of Cu(II) complexes with Gx-NH2 EDA core PAMAM dendrimers in aqueous solutions at pH 7.0. The overall results of the proton and metal ion binding measurements suggest that the uptake of Cu(II) by EDA core PAMAM dendrimers involves both the dendrimer tertiary amine and terminal groups. However, the extents of protonation of these groups control the ability of the dendrimers to bind Cu(II). Analysis of the EXAFS spectra suggests that Cu(II) forms octahedral complexes involving the tertiary amine groups of Gx-NH2 EDA core PAMAM dendrimers at pH 7.0. The central Cu(II) metal ion of each of these complexes appears to be coordinated to 2-4 dendrimer tertiary amine groups located in the equatorial plane and 2 axial water molecules. Finally, we combine the results of our experiments with literature data to formulate and evaluate a phenomenological model of Cu(II) uptake by Gx-NH2 PAMAM dendrimers in aqueous solutions. At low metal ion-dendrimer loadings, the model provides a good fit of the measured extent of binding of Cu(II) in aqueous solutions of G4-NH2 and G5-NH2 PAMAM dendrimers at pH 7.0.