Metin Tülü

Synthesis, characterization and antimicrobial activity of water soluble dendritic macromolecules.

Several families of water soluble dendrimers were synthesized based on poly(propyleneoxide) amines (Jeffamines) (P(1)). P(1)-core and branched units were constructed from both methylacrylate and ethylenediamine (P(2)-P(9), and generations 0-3 with -NH(2), -COOH functionalities). They were characterized by elemental analysis (EA), gel permeation chromatography (GPC), FT-IR, (1)H, and (13)C NMR. The antimicrobial activities of only water soluble compounds (P(1), P(3), P(4), P(6), P(7) and P(9)) were evaluated using disk diffusion method in water as well as the minimal inhibitory concentration (MIC) dilution method against 9 bacteria. The obtained results from disk diffusion method are assessed in side-by-side comparison with those of Penicillin-g, Ampicillin, Cefotaxime, Vancomycin, Oflaxacin, and Tetracycline, well-known antibacterial agents. The results from dilution procedure are compared with Gentamycin as antibacterial and Nystatin as antifungal. The antifungal activities are reported on five yeast cultures namely, Candida albicans, Kluyveromyces fragilis, Rhodotorula rubra, Debaryomyces hansenii, and Hanseniaspora guilliermondii, and the results are referenced with Nystatin, Ketaconazole, and Clotrimazole, commercial antifungal agents. In most cases, the compounds show broad-spectrum (gram-positive and gram-negative bacteria) activities that are comparatively higher or equipotent to the antibiotic and antifungal agents in the comparison tests.

Synthesis and properties of hydrophilic polymers. Part 7. Preparation, characterization and metal complexation of carboxy‐functional polyesters based on poly(ethylene glycol)

Novel water-soluble polyesters with pendant carboxylic groups were synthesized by polycondensation of ethylenediaminetetra-acetic acid (EDTA) dianhydride and diethylenetriaminepenta-acetic acid (DTPA) dianhydride with poly(ethylene glycol)s of different chain-lengths. Two experimental approaches (polycondensation using various solvents and in the melt) were studied, and melt condensation was found to give higher yields of polyesters. The polymeric products were soluble in water, acetone, chloroform and toluene, and were characterized by elemental analysis, IR and NMR spectroscopy. In addition, the carboxyl functionalities were determined by titration and the hydrolytic stability studied as a function of pH. The complexing capacity of the functional polyesters was determined in dependence of pH for copper in aqueous solution using the Liquid-Phase Polymer-Based Retention (LPR) technique and found to be 257 mg g−1 for the EDTA-based copolymer at pH 5 and 230 mg g−1 for the DTPA-based copolymer, respectively. © 1999 Society of Chemical Industry

Cytotoxicity and in vitro characterization studies of synthesized Jeffamine-cored PAMAM dendrimers.

Abstract The objective of this study is to make comprehensive cytotoxicity evaluation and in vitro characterization of Jeffamine-cored polyamidoamine (PAMAM) dendrimers on L929 cell lines for oral drug delivery purposes. Ester-, amine- and carboxylic acid-terminated PAMAMs were investigated for their cytotoxicity on L929 cells at different generations and concentrations. Cationic surface charge caused highest cytotoxicity on L929 cells, while ester-terminated PAMAMs showed generation- and concentration-dependent toxicity. Anionic dendrimers were determined as the lowest cytotoxic group, and highest generation number presented lowest cellular toxicity. Encapsulation studies were performed with anionic PAMAMs at 2.5, 3.5 and 4.5 generations and different concentrations. Increasing generation number provides greater loaded naproxen amounts and larger particle size. Moreover, formulations provide controlled release at simulated terminal ileum conditions. Consequently, Jeffamine-cored carboxylic acid-terminated PAMAMs can be a promising option for oral drug delivery of poorly water-soluble drugs.

Water-soluble TRIS-terminated PAMAM dendrimers: microwave-assisted synthesis, characterization and Cu(II) intradendrimer complexes

This study is the first report describing the microwave-assisted synthesis (MAS) of poly(amido amine) (PAMAM) dendrimers with TRIS surface functional groups (PAMAM–TRIS). Six PAMAM–TRIS dendrimers were synthesized using both newly developed conventional and microwave methods. Five of them are novel. Three different cores, one polymeric Jeffamine® T-403 and two monomeric, ethylenediamine and diethylenetriamine, were used in the syntheses. All the reactions were monitored by attenuated total reflectance (ATR). It was observed that microwave reactions proceeded 3.5 to 4.0 times faster than conventional reactions. Therefore, a fast, easy and one-pot MAS of six different water-soluble PAMAM–TRIS dendrimers was accomplished with high (90–96%) yields in short (110–140 min) reaction times and under mild reaction conditions, using methanol as solvent. The other ester terminated half generation precursor PAMAM (PAMAM–OCH3) dendrimers used for the synthesis of the PAMAM–TRIS dendrimers were obtained by utilizing conventional and microwave methods together. For the purification of all the PAMAM dendrimers, a liquid phase polymer-based retention (LPR) technique was used. The PAMAM–TRIS dendrimers were characterized by 1H NMR, 13C NMR, ATR (IR), EA, potentiometric and spectroscopic titrations. Furthermore, Cu(II)–PAMAM–TRIS dendrimer complexes were prepared and characterized by UV-Vis spectroscopy. The synthesized PAMAM–TRIS dendrimers can be considered as new drug carrier systems and should find use in widespread application fields, especially in future pharmaceutical and catalytic studies but also in other fields.

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.

Simultaneous quantification of Myelin Basic Protein and Tau proteins in cerebrospinal fluid and serum of Multiple Sclerosis patients using nanoimmunosensor.

This study was aimed at the development of an immunosensor for the simultaneous quantification of Myelin Basic Protein (MBP) and Tau proteins in cerebrospinal fluid (CSF) and serum, obtained from Multiple Sclerosis (MS) patients. The newly developed GO/pPG/anti-MBP/anti-Tau nanoimmunosensor has been established by immobilization of MBP and Tau antibodies. The newly developed nanoimmunosensor was tested, optimized and characterized using differential pulse voltammetry (DPV) and electrochemical impedance spectroscopy (EIS). The developed nanoimmunosensor was seen to have detection limits of 0.30nM for MBP and 0.15nM for Tau proteins which were sufficient for the levels to be analysed in neuro-clinic. The clinical study performed using CSF and serum of MS patients showed that the designed nanoimmunosensor was capable of detecting the proteins properly, that were essentially proven by ELISA.

The effect of PAMAM dendrimer concentration, generation size and surface functional group on the aqueous solubility of candesartan cilexetil

Abstract This article investigates the aqueous solubility of the poorly soluble drug candesartan cilexetil (CC) in the presence of poly(amidoamine) (PAMAM) dendrimers. The effect of variables such as concentration, generation size (G2–G4), and surface groups (NH2, COOH and TRIS) of PAMAMs on the aqueous solubility of CC was studied. A two-factor factorial (3 × 3) ANOVA design was used to study the effect of generation size and surface functional group of the PAMAMs. The results showed that the aqueous solubility of CC in the presence of carboxyl and TRIS-terminated PAMAMs was higher than those of amine-terminated PAMAMs, and the effect of surface functional group of the PAMAMs on the aqueous solubility of CC was dependent on the generation size (p < 0.05). The sequence of the observed solubility fold enhancement due to PAMAMs was G4.COOH (8378)>G3.COOH (3456)>G4.TRIS (2362)>G2.COOH (1013)>G3.TRIS (749)>G2.TRIS (293)>G4.NH2 (91)>G3.NH2 (50)>G2.NH2 (37). The CC-PAMAM dendrimer inclusion complexes were characterized by UV–Vis, attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR) and differential thermal analysis (DTA) techniques. Regarding the results of these techniques, improvement in the solubility of CC is expected primarily through the intermolecular hydrogen bonding between the drug and internal tertiary and surface functional groups of the studied PAMAMs.

Synthesis and proton conductivity of anhydrous dendritic electrolytes

Water soluble PEG cored dendritic hexa-acid which comprises peripheral carboxylic acidic groups were prepared via nucleophilic substitution reactions. Novel anhydrous proton conducting electrolytes were prepared by incorporation of the heterocyclic protogenic solvent imidazole (Im) into PEG cored dendritic hexa acid, (PEG-HA), at several molar ratios of Im to-COOH units of PEG-HA. The complexation of PEG-HA and Im was illustrated by infrared spectroscopy (FT-IR). The materials are thermally stable up to 150 °C as evidenced by thermogravimetry analysis (TGA). Differential scanning calorimetry (DSC) results verified that the organic electrolytes are homogeneous and amorphous. The proton conductivities were characterized by means of AC impedance spectroscopy and a maximum conductivity of 1 × 10−3 S/cm was measured at 120 °C in the anhydrous state.

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

Abstract 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.

Synthesis of surface-modified TREN-cored PAMAM dendrimers and their effects on the solubility of sulfamethoxazole (SMZ) as an analog antibiotic drug

Abstract Sulfamethoxazole (SMZ) is a sulfonamide and used widely in the treatment of bacteriostatic and urinary tract infections with trimethoprim as an antibiotic. The problem with SMZ is its poor water solubility, therefore, low bioavailability in clinical applications. In this study, we synthesized new-generation Tris(2-aminoethyl)amine (TREN)-cored amine (NH2), Tris(hydroxymethyl)aminomethane (TRIS), and carboxyl (COOH) terminated different generations T2–T4 poly(amidoamine) PAMAM dendrimers. Synthesized PAMAMs were characterized by 1H NMR, 13C NMR, ATR-FTIR, spectroscopic titrations, and evaluated as potential solubility enhancers and drug carriers of sulfonamides by taking SMZ as a model drug. The effect of concentration, generation, and surface groups of PAMAMs on the solubility of SMZ was also investigated. Results showed that the solubility of SMZ improved significantly with an increasing generation size (T2–T4) and PAMAM dendrimer concentration (0–2 mM). The role of PAMAMs in the solubility enhancement of SMZ was in the order of T4.NH2 > T4.COOH > T3.NH2 > T4.TRIS > T2.NH2 > T3.COOH > T3.TRIS > T2.COOH > T2.TRIS, and in the ranges of 5- to 45-fold with maximum SMZ loading 7 to 61 mole/mole per PAMAM dendrimer molecule. In vitro release studies demonstrated that SMZ-PAMAM dendrimer complexes at the end of 2-h drug release (16–26%) was considerable slower than pure SMZ (38.8%).