Choline, identified as 2-hydroxyethyl trimethylammonium chloride, is naturally synthesized by the human liver and is present in phospholipids like phosphatidylcholine or lecithin. This organic salt represents ionic liquids (ILs) [1], which possess chemical stability, ability to enhance solubility, and modifiability by ion exchange for adjustment of physical and chemical properties [2, 3, 4]. Their biological attributes include enhancing skin penetration [5], acting as antibacterial properties [6], functioning as stabilizers [7, 8], cytotoxic and local anesthetic properties, anti-fungal and anti-acne activities, and antibiotic actions [9, 10, 3]. Furthermore, the versatility of ILs extends to their ability to accommodate a wide range of pharmaceutical substances, including antiviral and antimicrobial agents, antioxidants, anticoagulants, nonsteroidal anti-inflammatory drugs, anticancer drugs, and others [11, 12, 13, 14, 15, 16, 3]. The widely employed cholinium cation offers biodegradability, water-solubility, and low cost for various applications [17, 18, 19]. Its properties have been investigated in combination with various bioactive compounds, including phenytoin [20], ampicillin (AMP) [21], nalidixic acid, niflumic acid, p-aminosalicylic acid, pyrazinoic acid, and picolinic acid [18]. These systems have demonstrated enhanced solubility for the active pharmaceutics, elevating their capability to permeate the cell membrane [17].
In recent decades, the synthesis of precisely designed polymers with the desired architecture, composition, chain homogeneity, site-specific functionality [22, 23, 24, 25], physicochemical and biochemical attributes (e.g. mechanical strength, softness, self-healing, processability, tissue adhesiveness, bioactivity, and biodegradation) [26, 27] appeared to be a powerful material enabling the development of versatile nanostructures applicable in biology and medicine [28]. The tailored-made polymers synthesized by the controlled polymerization methods had influenced on significant progress in drug delivery systems (DDS) offering linear and branched polymer carriers with bio-therapeutics functions [29, 30, 31]. Both, drug conjugated or encapsulated by polymers have been intensively studied to address challenges related to the drug's hydrophilicity [32, 33]. Furthermore, the delivery of more than one bioactive compound has been tested to enhance the main drug's activity [34, 35, 36].
The commercial choline ester derivative, [2-(methacryloyloxy)ethyl]trimethyl-ammonium chloride, referred to methacroylcholine (TMAMA/Cl), functions as a choline-based ionic liquid, which serves as the monomer for obtaining the polymerized ionic liquid (PIL) [37]. This PIL has been reported as delivering pharmaceutical anions through the anion exchange in the polymer matrix[38, 39, 40] or encapsulating various bioactive compounds [40, 41, 42, 43, 44, 45, 46] to create a pharmaceutically active polymeric systems. The pharmaceutically active choline-based PILs have been also designed by direct polymerization of pharmaceutically functionalized choline monomers with salicylate [37, 47, 48], p-aminosalicylate [49, 50], fusidate [51], and cloxacillin (CLX)[51] counterions.
In this research, we investigated the well-defined linear copolymers based on the biofunctionalized choline ionic liquids with ionically conjugated AMP and CLX as the pharmaceutical anions. Depending on the strategy employed, the linear copolymers were designed either as single DDS carrying CLX¯ or dual DDS with CLX¯ and AMP¯ (Fig. 1), where the drug anion is linked via an ionic bond to a polymer matrix. Both drugs are antibiotics deriving from semi-synthetic penicillin, which demonstrates antimicrobial efficacy from the existence of a beta-lactam ring [52, 53]. Because of effectiveness against both gram-positive and some gram-negative microorganisms [54] they are employed for the treatment of bacterial infections affecting the ear, nose, throat, bones, lungs, as well as post-operative wound infections [55]. The commercially available combination of AMP and CLX is marketed under various brand names, such as Ampiclox, Apen, Cloxam, and Megamox, in the form of capsules or oral suspensions. Therefore, both pharmaceuticals are well-suited for utilization in either individual treatment or combined therapies. The obtained polymer systems were characterized to show their effectiveness in drug delivery through the evaluation of drug content and (co)release during an in vitro study. The advantage of this novel DDSs is featured by the selected antibiotics carried by the ionic polymers, where pharmaceutical anions are released by physiological solution by exchange with phosphate anions.