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.

In this study, drug nanocarriers were designed using linear copolymers with different contents of cholinium-based ionic liquid units, i.e., [2-(methacryloyloxy)ethyl]trimethylammonium chloride (TMAMA/Cl: 25, 50, and 75 mol%). The amphiphilicity of the copolymers was evaluated on the basis of their critical micelle concentration (CMC = 0.055–0.079 mg/mL), and their hydrophilicities were determined by water contact angles (WCA = 17°–46°). The chloride anions in the polymer chain were involved in ionic exchange reactions to introduce pharmaceutical anions, i.e., p-aminosalicylate (PAS⁻), clavulanate (CLV⁻), piperacillin (PIP⁻), and fusidate (FUS⁻), which are established antibacterial agents for treating lung and respiratory diseases. The exchange reaction efficiency decreased in the following order: CLV⁻ > PAS⁻ > PIP⁻ >> FUS⁻. The hydrophilicity of the ionic drug conjugates was slightly reduced, as indicated by the increased WCA values. The major fraction of particles with sizes ~20 nm was detected in systems with at least 50% TMAMA carrying PAS or PIP. The influence of the drug character and carrier structure was also observed in the kinetic profiles of the release processes driven by the exchange with phosphate anions (0.5–6.4 μg/mL). The obtained polymer-drug ionic conjugates (especially that with PAS) are promising carriers with potential medical applications.

Polymerizable choline-based ionic liquid (IL), i.e., [2-(methacryloyloxy)ethyl]-trimethylammonium (TMAMA/Cl¯), was functionalized by an ion exchange reaction with pharmaceutical anions, i.e., cloxacillin (CLX¯) and fusidate (FUS¯), as the antibacterial agents. The modified biocompatible IL monomers (TMAMA/CLX¯, TMAMA/FUS¯) were copolymerized with methyl methacrylate (MMA) to prepare the graft copolymers (19–50 mol% of TMAMA units) serving as the drug (co)delivery systems. The in vitro drug release, which was driven by the exchange reaction of the pharmaceutical anions to phosphate ones in PBS medium, was observed for 44% of CLX¯ (2.7 μg/mL) and 53% of FUS¯ (3.6 μg/mL) in the single systems. Similar amounts of released drugs were detected for the dual system, i.e., 41% of CLX¯ (2.2 μg/mL) and 33% of FUS¯ (2.0 μg/mL). The investigated drug ionic polymer conjugates were examined for their cytotoxicity by MTT test, showing a low toxic effect against human bronchial epithelial cells (BEAS-2B) and normal human dermal fibroblasts (NHDF) as the normal cell lines. The satisfactory drug contents and the release profiles attained for the well-defined graft polymers with ionically bonded pharmaceuticals in the side chains make them promising drug carriers in both separate and combined drug delivery systems.

Graft copolymers based on a choline ionic liquid (IL), [2-(methacryloyloxy)ethyl]-trimethylammonium chloride (TMAMA), were obtained by atom transfer radical polymerization. The presence of chloride counterions in the trimethylammonium groups promoted anion exchange to introduce fusidate anions (FUS, 32–55 mol.%) as the pharmaceutical anions. Both the choline-based IL copolymers and their ionic drug-carrier conjugates (FUS systems as the first type, 26–208 nm) formed micellar structures (CMC = 0.011–0.025 mg/mL). The amphiphilic systems were advantageous for the encapsulation of rifampicin (RIF, 40–67 mol.%), a well-known antibiotic, resulting in single-drug (RIF systems as the second type, 40–95 nm) and dual-drug systems (FUS/RIF as the third type, 31–65 nm). The obtained systems released significant amounts of drugs (FUS > RIF), which could be adjusted by the content of ionic units and the length of the copolymer side chains. The dual-drug systems released 31–55% FUS (4.3–5.6 μg/mL) and 19–31% RIF (3.3–4.0 μg/mL), and these results were slightly lower than those for the single-drug systems, reaching 45–81% for FUS (3.8–8.2 μg/mL) and 20–37% for RIF (3.4–4.0 μg/mL). The designed polymer systems show potential as co-delivery systems for combined therapy against drug-resistant strains using two drugs in one formula instead of the separate delivery of two drugs.

Previously reported amphiphilic linear and graft copolymers, derived from the ionic liquid [2-(methacryloyloxy)ethyl]trimethylammonium chloride (TMAMA_Cl‾), along with their conjugates obtained through modification either before or after polymerization with p-aminosalicylate anions (TMAMA_PAS‾), were employed as matrices in drug delivery systems (DDSs). Based on the counterion type in TMAMA units, they were categorized into single drug systems, manifesting as ionic polymers with chloride counterions and loaded isoniazid (ISO), and dual drug systems, featuring ISO loaded in self-assembled PAS conjugates. The amphiphilic nature of these copolymers was substantiated through the determination of the critical micelle concentration (CMC), revealing an increase in values post-ion exchange (from 0.011–0.063 mg/mL to 0.027–0.181 mg/mL). The self-assembling properties were favorable for ISO encapsulation, with drug loading content (DLC) ranging between 15 and 85% in both single and dual systems. In vitro studies indicated ISO release percentages between 16 and 61% and PAS release percentages between 20 and 98%. Basic cytotoxicity assessments using the 2,5-diphenyl-2H-tetrazolium bromide (MTT) test affirmed the non-toxicity of the studied systems toward human non-tumorigenic lung epithelial cell line (BEAS-2B) cell lines, particularly in the case of dual systems bearing both ISO and PAS simultaneously. These results confirmed the effectiveness of polymeric carriers in drug delivery, demonstrating their potential for co-delivery in combination therapy.

In vitro cytotoxicity of polymer-carriers, which in the side chains contain the cholinum ionic liquid units with chloride (Cl) or pharmaceutical anions dedicated for antituberculosis therapy, i.e., p-aminosalicylate (PAS) and clavulanate (CLV), was investigated. The carriers and drug conjugates were examined, in the concentration range of 3.125–100 μg/mL, against human bronchial epithelial cells (BEAS-2B) and adenocarcinomic human alveolar basal epithelial cells (A549) as an experimental model cancer cell line possibly coexisting in tuberculosis. The cytotoxicity was evaluated by MTT test and confluency index, as well as by the cytometric analyses, including Annexin-V FITC apoptosis assay. The polymer systems showed supporting activity towards the normal cells and no tumor progress, especially at the highest concentration (100 μg/mL). The analysis of cell death did not show meaningful changes in the case of the BEAS-2B, whereas in the A549 cell line, the cytostatic activity was observed, especially for the drug-free carriers, causing death in up to 80% of cells. This can be regulated by the polymer structure, including the content of cationic units, side-chain length and density, as well as the type and content of pharmaceutical anions. The results of MTT tests, confluency, as well as cytometric analyses, distinguished the polymer systems with Cl/PAS/CLV containing 26% of grafting degree and 43% of ionic units or 46% of grafting degree and 18% of ionic units as the optimal systems.