Synthesis and Characterization of Linear Copolymers Based on Pharmaceutically Functionalized Monomeric Choline Ionic Liquid for Delivery of p-Aminosalicylate

Abstract

Bioactive linear poly(ionic liquid)s (PIL) were designed as carriers in drug delivery systems (DDS). Their synthesis was based on a monomeric ionic liquid (MIL) with a relevant pharmaceutical anion to create therapeutically functionalized monomers, which further can be used in the controlled atom transfer radical polymerization (ATRP). The presence of chloride counterions in the quaternary ammonium groups of choline MIL, e.g., [2-(methacryloyloxy)ethyl]trimethyl-ammonium chloride (ChMACl), was stimulated to undergo the anion exchange with p-aminosalicylate sodium salt (NaPAS) as the source of the pharmaceutical anion with antibacterial activity. The resultant [2-(methacryloyloxy)ethyl]trimethylammonium p-aminosalicylate (ChMAPAS) was copolymerized to attain the well-defined linear choline-based copolymers with various contents of PAS anions (24–42%), which were regulated by the initial ratio of ChMAPAS to MMA and conversion degree. The length of polymeric chains was evaluated by the total monomer conversion (31–66%) yielding degree of polymerization (DPn = 133–272). Depending on the polymer carrier composition, PAS anions were exchanged by 60–100% within 1 h, 80–100% within 4 h, and completely after 24 h by phosphate anions in PBS imitating a physiological fluid.

Characterization of Graft Copolymers Synthesized from p-Aminosalicylate Functionalized Monomeric Choline Ionic Liquid

“…The quantity of PAS, introduced during the polymerization of the biomodified TMAMA, increased simultaneously with the ionic unit content in the corresponding linear PILs [34]. This trend was also observed among the graft copolymers with the same grafting density, where a near-linear correlation between ionic content and DC was The drug content (DC) represented by the percentage of PAS incorporated into the copolymer and assessed by UV-Vis spectroscopy ranged between 16% and 49%.…”

“…An exception was 8B, containing the longest side chains, where Mn,NMR was noticeably higher than Mn,SEC, probably because of its more rigid, rod-like conformation. In the analogous linear PILs containing PAS, which were characterized with narrower range of index Ð (1.12-1.36), the smallest discrepancy in Mn was observed at the highest ionic content [34]. The drug content (DC) represented by the percentage of PAS incorporated into the copolymer and assessed by UV-Vis spectroscopy ranged between 16% and 49%.…”

“…Biofunctionalization of TMAMA/Cl to TMAMA/PAS was performed as described previously [34] using the equimolar amounts of PAS sodium salt. The ion exchange process was completed in 4 h, achieving an efficiency of 92%.…”

“…Their biocompatibility has been utilized in medical applications [10,[29][30][31], but, in the case of such polymerizable ILs, the polymeric conjugates have been attained [14]. So far, using this strategy, PILs with various topologies bearing salicylate [32], fusidate and/or cloxacillin [33], and p-aminosalicylate (PAS) ions [34] have been successfully synthesized.…”

“…In this paper, we present an innovative approach to producing ionic graft conjugates bearing PAS anions. While conjugates containing PAS have been previously obtained, such as in designing linear PIL [34] or through post-polymerization modification of graft polymers [18], our method stands out as it involves the direct synthesis of a polymerizable choline methacrylate with a PAS counterion using the grafting from technique. Considering the previous results of the amphiphilic nature of the PAS-conjugates, the nanoparticle sizes suitable for drug delivery, and in vitro cytotoxicity tests indicating no significant changes in human bronchial epithelial cells, and adverse effects on the tumor cell line [35], we decided to complete these studies by identifying the characteristics of directly synthesized PAS conjugates with grafted topology.…”