Synthesis and Characterization of Ionic Graft Copolymers: Introduction and In Vitro Release of Antibacterial Drug by Anion Exchange

Abstract

Amphiphilic graft copolymers based on [2-(methacryloyloxy)ethyl]trimethyl- ammonium chloride (TMAMA) were obtained for the delivery of pharmaceutical ionic drugs, such as p-aminosalicylate (PAS) and clavunate (CLV) anions. The side chains were attached by grafting from a multifunctional macroinitiator via atom transfer radical polymerization (ATRP) to get polymers with different grafting degrees and ionic content. The self-assembling ability, confirmed by determining the critical micelle concentration (CMC) through interfacial tension (IFT) with the use of goniometry, was reduced after ion exchange (CMC twice higher than for chloride anions contained copolymers 0.005–0.026 mg/mL). Similarly, the hydrophilicity level (adjusted by the content of ionic fraction) evaluated by the water contact angle (WCA) of the polymer film surfaces was decreased with the increase of trimethylammonium units (68°–44°) and after introduction of pharmaceutical anions. The exchange of Cl− onto PAS− and CLV− in the polymer matrix was yielded at 31%–64% and 79%–100%, respectively. The exchange onto phosphate anions to release the drug was carried out (PAS: 20%–42%, 3.1–8.8 μg/mL; CLV: 25%–73%, 11–31 μg/mL from 1 mg of drug conjugates). Because of the bacteriostatic activity of PAS and the support of the action of the antibiotics by CLV, the designed water-soluble systems could be alternatives for the treatment of bacterial infections, including pneumonia and tuberculosis.

Linear Copolymers Based on Choline Ionic Liquid Carrying Anti-Tuberculosis Drugs: Influence of Anion Type on Physicochemical Properties and Drug Release

“…The WCA values for polymer matrices containing Cl anions changed from 46 • to 17 • , indicating that they were hydrophilic systems. The same correlation between WCA and TMAMA content has been described previously for graft copolymers with TMAMA units in the side chains [42], but their wettability was lower than that of the linear copolymers studied herein because of the hydrophobic backbone. After anion exchange, the wettability of the polymer films was reduced, yielding higher WCA values relative to their polymer matrices, meaning that the selected drugs did not improve the hydrophilicity of ionic conjugates.…”

“…In comparison with linear copolymers, the easier access to the pharmaceutical ions in grafted ones should facilitate drug release, but this aspect is much more composite due to higher stability of the graft polymer with the micelle-like structure. The exchange of Cl − onto PAS − and CLV − in the graft polymer matrix was yielded at 31–64% and 79–100%, respectively, and then the exchange onto phosphate anions was carried out during drug release in 20–42% (3–9 µg/mL from 1 mg of drug conjugates) for PAS and 25–73% (11–31 µg/mL) for CLV within 3 h [ 42 ]. These results indicated similar levels of PAS release independently on polymer topology, whereas the percentage amounts of released CLV was ~10 times lower for the linear polymers.…”

“…Methanol and tetrahydrofuran (THF) were purchased from Chempur (Piekary Śląskie, Poland) and dried over the same molecular sieves as MMA. Copper(I) bromide (CuBr; Fluka, 98%, Steinheim, Germany) was purified using a procedure described previously in the literature [ 42 ]. N,N,N′,N ″ ,N ″-pentamethyldiethylenetriamine (PMDETA, 98%), ethyl 2-bromoisobutyrate (EBiB, 98%), potassium clavulanate (KCLV), and bis(trifluoromethane)sulfonimide lithium salt (LiTf 2 N) were obtained from Sigma Aldrich (Poznań, Polska).…”

“…On the other hand, the combination of quaternary ammonium cations with chloride counter ions has been convenient for anion exchange reactions to introduce the ionic drug [ 40 ], thus forming the ionic type of polymer-drug conjugates. These systems comprised the graft topology of PTMAMA carrying the pharmaceutical anions, such as salicylate [ 41 ], p -aminosalicylate, or clavulanate [ 42 ]. In these cases, the drug release occurred in the solution containing the stronger ions (i.e., phosphate ions), which is in contrast to conventional conjugates, where the drug is released by hydrolytic degradation of a linker (usually ester- or amide-type).…”

“…The influence of the carrier composition and the anion type on the physicochemical properties, exchange effect, and progress of pharmaceutics release are investigated in this work, in order to inform the design single-drug delivery systems with potential for the treatment of lung and respiratory diseases. Previously, PAS − and CLV − based systems have been studied in combination with PTMAMA graft copolymers [ 42 ]. However, in those cases the TMAMA units were located in the side chains, which were formed by grafting from polymethacrylate macroinitiator.…”