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

<p>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. <i>In vitro</i> 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%).</p

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

<p>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 (<i>p</i> < 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.</p

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

<p>Starting from <i>Ethylenediamine</i> (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% <i>Poly(ethylene glycol</i>) <i>bis(amine</i>) 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 <i>in vitro</i> and <i>in vivo</i>. 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.</p