Biocompatible Ionic Liquids Research Articles

Choline geranate (CAGE): A multifaceted ionic liquid for drug delivery

Ionic liquids, organic salts in a liquid state below 100 °C, have traditionally been associated with industrial applications. Recent research has introduced a new generation of ionic liquids, designed from biocompatible ions, to enable applications in drug delivery. Here, I provide a historical perspective, development status and applications of a leading example of biocompatible ionic liquids, a salt of Choline And Geranic acid (CAGE). Since its first report in 2014, CAGE has opened multiple drug delivery applications including transdermal, oral, buccal, sustained release, tissue ablation, periodontitis and hand hygiene, among others. CAGE-based products have been tested in more than 200 patients through multiple Phase 1 and Phase 2 clinical studies, including successful use in a Phase 2 clinical study in Atopic Dermatitis patients. CAGE became the first ‘drug delivery ionic liquid’ to enter into clinical trials. This article summarizes the key fundamental and translational aspects of CAGE as pertained to its use in drug delivery.

A miniaturized feedstocks-to-fuels pipeline for screening the efficiency of deconstruction and microbial conversion of lignocellulosic biomass.

Sustainably grown biomass is a promising alternative to produce fuels and chemicals and reduce the dependency on fossil energy sources. However, the efficient conversion of lignocellulosic biomass into biofuels and bioproducts often requires extensive testing of components and reaction conditions used in the pretreatment, saccharification, and bioconversion steps. This restriction can result in a significant and unwieldy number of combinations of biomass types, solvents, microbial strains, and operational parameters that need to be characterized, turning these efforts into a daunting and time-consuming task. Here we developed a high-throughput feedstocks-to-fuels screening platform to address these challenges. The result is a miniaturized semi-automated platform that leverages the capabilities of a solid handling robot, a liquid handling robot, analytical instruments, and a centralized data repository, adapted to operate as an ionic-liquid-based biomass conversion pipeline. The pipeline was tested by using sorghum as feedstock, the biocompatible ionic liquid cholinium phosphate as pretreatment solvent, a "one-pot" process configuration that does not require ionic liquid removal after pretreatment, and an engineered strain of the yeast Rhodosporidium toruloides that produces the jet-fuel precursor bisabolene as a conversion microbe. By the simultaneous processing of 48 samples, we show that this configuration and reaction conditions result in sugar yields (~70%) and bisabolene titers (~1500 mg/L) that are comparable to the efficiencies observed at larger scales but require only a fraction of the time. We expect that this Feedstocks-to-Fuels pipeline will become an effective tool to screen thousands of bioenergy crop and feedstock samples and assist process optimization efforts and the development of predictive deconstruction approaches.

Biocompatible Ionic Liquids Functionalized Activated Carbon of Local Agri-Waste for Wastewater Purification and Cytotoxic Evaluation of Purified Water

Biocompatible Ionic Liquids Functionalized Activated Carbon of Local Agri-Waste for Wastewater Purification and Cytotoxic Evaluation of Purified Water

Mechanistic understanding of enhancing bioactivity via bio-ionic liquid functionalization of biomaterials

The selection of biomaterials is a pivotal criterion for designing tissue engineering scaffolds, crucial for diverse biomedical applications. While natural biomaterials offer inherent bioactivity and biocompatibility, fine-tuning their properties for specific applications poses challenges. Conversely, synthetic biomaterials, while highly customizable, are often bio-inert. Functionalizing materials with bioactive molecules can improve cell-material interactions. Prevailing approaches utilizing RGD peptides or natural/synthetic composites have drawbacks including cost and immunogenicity. Bio-ionic liquids (BILs), a class of biocompatible ionic liquids derived from natural or synthetic biomolecules, offer a potential alternative. Herein, we present the biofunctionalization of a bio-inert polyethylene glycol diacrylate (PEGDA) with an acrylated choline-based BIL (“BioPEG”) as a method for enhancing the bioactivity of biomaterials. Cell studies using mouse myoblast C2C12 and human mesenchymal stem cells (hMSCs) revealed the excellence of BioPEG hydrogels in promoting cell attachment, growth, proliferation, and differentiation. Computational molecular dynamics (MD) simulations elucidated the mechanism by which BIL facilitates cell interaction with PEGDA. 3D printability of BioPEG hydrogel was showcased using a digital light processing (DLP) bioprinter, with printed scaffolds demonstrating excellent cytocompatibility. Collectively, these findings present BIL as a versatile bioactive agent for augmenting cell adhesion to materials, thus enriching the repertoire of biomaterials for advanced tissue engineering.

Cytotoxicity and cell membrane interactions of choline-based ionic liquids: Comparing amino acids, acetate, and geranate anions

Ionic liquids (ILs) have found diverse applications in research and industry. Biocompatible ILs, a subset considered less toxic than traditional ILs, have expanded their applications into biomedical fields. However, there is limited understanding of the toxicity profiles, safe concentrations, and underlying factors driving their toxicity. In this study, we investigated the cytotoxicity of 13 choline-based ILs using four different cell lines: Human dermal fibroblasts (HDF), epidermoid carcinoma cells (A431), cervical cancer cells (HeLa), and gastric cancer cells (AGS). Additionally, we explored the haemolytic activity of these ILs. Our findings showed that the cytotoxic and haemolytic activities of ILs can be attributed to the hydrophobicity of the anions and the pH of the IL solutions. Furthermore, utilising quartz crystal microbalance with dissipation (QCM-D), we delved into the interaction of selected ILs, including choline acetate [Cho][Ac] and choline geranate [Cho][Ge], with model cell membranes composed of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC). The QCM-D data showed that ILs with higher toxicities exhibited more pronounced interactions with membranes. Increased variations in frequency and dissipation reflected substantial changes in membrane fluidity and mass following the addition of the more toxic ILs. Furthermore, total internal reflection fluorescence microscopy study revealed that [Cho][Ac] could cause lipid rearrangements and pore formation in the membrane, while [Cho][Ge] disrupted the bilayer packing. This study advances our understanding of the cellular toxicities associated with choline-based ILs and provides valuable insights into their mechanisms of action concerning IL-membrane interactions. These findings have significant implications for the safe and informed utilisation of biocompatible ILs in the realm of drug delivery and biotechnology.

Biocompatible ionic liquid self-assembled transdermal delivery system (P-M IL/AKE) for significantly improved skin photoaging and reduced wrinkles

Most peptide drugs have good biological activity and safety, but their stability and permeability are poor, limiting their applications in the field of local drug delivery. Snake venom peptide (AKE) is a tripeptide with good anti-wrinkle effects, but its weak esterophilicity, poor penetration, and low bioavailability limit its full anti-wrinkle potential. To address this issue, a bioactive ionic liquid (P-M IL) was prepared and an efficient self-assembled peptide drug delivery system was constructed through AKE loading, which increased the cumulative absorption of AKE in the skin by more than five-fold, resulting in good biocompatibility. Further, P-M IL/AKE can significantly increase collagen protein secretion by human fibroblasts, improved skin photoaging and reduce the areas and volume of wrinkle in the eye tail lines. In addition, for the first time, quantum chemical calculations, homology modeling, molecular docking and binding free energy calculations were used to analyze the structural stability of the system, construct the 3D model, explore the interaction mode and reveal the theoretical basis of anti-wrinkle effect. Therefore, this supramolecular self-assembled transdermal drug delivery system has potential advantages, providing a novel approach for the highly efficient and non-invasive delivery of peptide drugs.

Enhancing cannabidiol bioaccessibility using ionic liquid as emulsifier to produce nanosystems: Characterization of structures, cytotoxicity assessment, and in vitro digestion

The emulsifying potential of a biocompatible ionic liquid (IL) to produce lipid-based nanosystems developed to enhance the bioaccessibility of cannabidiol (CBD) was investigated. The IL (cholinium oleate) was evaluated at concentrations of 1 % and 2 % to produce nanoemulsions (NE-IL) and nanostructured lipid carriers (NLC-IL) loaded with CBD. The IL concentration of 1 % demonstrated to be sufficient to produce both NE-IL and NLC-IL with excellent stability properties, entrapment efficiency superior to 99 %, and CBD retention rate of 100 % during the storage period evaluated (i.e. 28 days at 25 °C). The in vitro digestion evaluation demonstrated that the NLC-IL provided a higher stability to the CBD, while the NE-IL improved the CBD bioaccessibility, which was mainly related to the composition of the lipid matrices used to obtain each nanosystem. Finally, it was observed that the CBD cytotoxicity was reduced when the compound was entrapped into both nanosystems.

Ionic Liquid Pretreatment Enhances Skin Penetration of 5-Aminolevulinic Acid: A Promising Scheme for Photodynamic Therapy for Acne Vulgaris.

Acne vulgaris is one of the most prevalent skin disorders; it affects up to 85% of adolescents and often persists into adulthood. Topical 5-aminolevulinic acid (ALA)-based photodynamic therapy (PDT) provides an alternative treatment for acne; however, its efficacy is greatly undermined by the limited skin permeability of ALA. Herein, biocompatible ionic liquids (ILs) based on aliphatic acid/choline were employed to enhance the dermal delivery of ALA, thereby improving the efficacy of PDT. In addition to the one-step delivery of ALA by utilizing ILs as carriers, a two-step strategy of pretreating the skin with blank ILs, followed by the administration of free ALA, was employed to test the IL-facilitated dermal delivery of ALA in vitro. The cumulative permeation of ALA through the excised rat skin after IL pretreatment was significantly greater than that in the untreated group, the 20% dimethyl sulfoxide (DMSO) penetration enhancer group, and the one-step group. The penetration efficiency was influenced by formulation and treatment factors, including the type of IL, pretreatment duration, water content in the ILs, and concentration of ALA. In rats, IL pretreatment facilitated faster, greater, and deeper ALA-induced protoporphyrin IX (PpIX) accumulation. Moreover, the IL pretreatment regimen significantly improved the efficacy of ALA-based PDT against acne vulgaris in a rat ear model. The model IL choline citrate ([Ch]3[Cit]1) had a moderate effect on the skin barrier. Trans-epidermal water loss could be recovered 1 h after IL treatment, but no irritation to the rat skin was detected after 7 days of consecutive treatment. It was concluded that biocompatible IL pretreatment enhances the penetration of ALA and thus facilitates the transformation of PpIX and improves the efficacy of PDT against acne vulgaris.

Solvation of Model Biomolecules in Choline-Aminoate Ionic Liquids: A Computational Simulation Using Polarizable Force Fields.

One can foresee a very near future where ionic liquids will be used in applications such as biomolecular chemistry or medicine. The molecular details of their interaction with biological matter, however, are difficult to investigate due to the vast number of combinations of both the biological systems and the variety of possible liquids. Here, we provide a computational study aimed at understanding the interaction of a special class of biocompatible ionic liquids (choline-aminoate) with two model biological systems: an oligopeptide and an oligonucleotide. We employed molecular dynamics with a polarizable force field. Our results are in line with previous experimental and computational evidence on analogous systems and show how these biocompatible ionic liquids, in their pure form, act as gentle solvents for protein structures while simultaneously destabilizing DNA structure.

Progress in the applications of biocompatible ionic liquids: renewable commodity production, catalytic and pharmaceutical approaches – a review

This review addressed the recent advances of biocompatible ionic liquids that include the production of renewable commodities and approaches in catalysis and the pharmaceutical field. Likewise, patents and future perspectives are discussed.

A green pathway for lignin valorization: Enzymatic lignin depolymerization in biocompatible ionic liquids and deep eutectic solvents

Lignin depolymerization, which enables the breakdown of a complex and heterogeneous aromatic polymer into relatively uniform derivatives, serves as a critical process in valorization of lignin. Enzymatic lignin depolymerization has become a promising biological strategy to overcome the heterogeneity of lignin, due to its mild reaction conditions and high specificity. However, the low solubility of lignin compounds in aqueous environments prevents efficient lignin depolymerization by lignin-degrading enzymes. The employment of biocompatible ionic liquids (ILs) and deep eutectic solvents (DESs) in lignin fractionation has created a promising pathway to enzymatically depolymerize lignin within these green solvents to increase lignin solubility. In this review, recent research progress on enzymatic lignin depolymerization, particularly in a consolidated process involving ILs/DESs is summarized. In addition, the interactions between lignin-degrading enzymes and solvent systems are explored, and potential protein engineering methodology to improve the performance of lignin-degrading enzymes is discussed. Consolidation of enzymatic lignin depolymerization and biocompatible ILs/DESs paves a sustainable, efficient, and synergistic way to convert lignin into value-added products.

Regulating the structural polymorphism and protein corona composition of phytantriol-based lipid nanoparticles using choline ionic liquids

Lipid-based lyotropic liquid crystalline nanoparticles (LCNPs) face stability challenges in biological fluids during clinical translation. Ionic Liquids (ILs) have emerged as effective solvent additives for tuning the structure of LCNP’s and enhancing their stability. We investigated the effect of a library of 21 choline-based biocompatible ILs with 9 amino acid anions as well as 10 other organic/inorganic anions during the preparation of phytantriol (PHY)-based LCNPs, followed by incubation in human serum and serum proteins. Small angle X-ray scattering (SAXS) results show that the phase behaviour of the LCNPs depends on the IL concentration and anion structure. Incubation with human serum led to a phase transition from the inverse bicontinuous cubic (Q2) to the inverse hexagonal (H2) mesophase, influenced by the specific IL present. Liquid chromatography-mass spectrometry (LC-MS) and proteomics analysis of selected samples, including PHY control and those with choline glutamate, choline hexanoate, and choline geranate, identified abundant proteins in the protein corona, including albumin, apolipoproteins, and serotransferrin. The composition of the protein corona varied among samples, shedding light on the intricate interplay between ILs, internal structure and surface chemistry of LCNPs, and biological fluids.

3D bioactive ionic liquid-based architectures: An anti-inflammatory approach for early-stage osteoarthritis

3D bioprinting enables the fabrication of biomimetic cell-laden constructs for cartilage regeneration, offering exclusive strategies for precise pharmacological screenings in osteoarthritis (OA). Synovial inflammation plays a crucial role in OA's early stage and progression, characterized by the increased of the synovial pro-inflammatory mediators and cytokines and chondrocyte apoptosis. Therefore, there is an urgent need to develop solutions for effectively managing the primary events associated with OA. To address these issues, a phenolic-based biocompatible ionic liquid approach, combining alginate (ALG), acemannan (ACE), and cholinium caffeate (Ch[Caffeate]), was used to produce easily printable bioinks. Through the use of this strategy 3D constructs with good printing resolution and high structural integrity were obtained. The encapsulation of chondrocytes like ATDC5 cells provided structures with good cell distribution, viability, and growth, for up to 14 days. The co-culture of the constructs with THP-1 macrophages proved their ability to block pro-inflammatory cytokines (TNF-α and IL-6) and mediators (GM-CSF), released by the cultured cells. Moreover, incorporating the biocompatible ionic liquid into the system significantly improved its bioactive performance without compromising its physicochemical features. These findings demonstrate that ALG/ACE/Ch[Caffeate] bioinks have great potential for bioengineering cartilage tissue analogs. Besides, the developed ALG/ACE/Ch[Caffeate] bioinks protected encapsulated chondrocyte-like cells from the effect of the inflammation, assessed by a co-culture system with THP-1 macrophages. These results support the increasing use of Bio-ILs in the biomedical field, particularly for developing 3D bioprinting-based constructs to manage inflammatory-based changes in OA. Statement of significanceCombining natural resources with active biocompatible ionic liquids (Bio-IL) for 3D printing is herein presented as an approach for the development of tools to manage inflammatory osteoarthritis (OA). We propose combining alginate (ALG), acemannan (ACE), and cholinium caffeate (Ch[Caffeate]), a phenolic-based Bio-IL with anti-inflammatory and antioxidant features, to produce bioinks that allow to obtain 3D constructs with good printing resolution, structural integrity, and that provide encapsulated chondrocyte-like cells good viability. The establishment of a co-culture system using the printed constructs and THP-1-activated macrophages allowed us to study the encapsulated chondrocyte-like cells behaviour within an inflammatory scenario, a typical event in early-stage OA. The obtained outcomes support the beneficial use of Bio-ILs in the biomedical field, particularly for the development of 3D bioprinting-based models that allow the monitoring of inflammatory-based events in OA.

Porous Ionic Liquids Go Green.

This Perspective points toward pathways to prepare porous ionic liquids using easily accessible materials, aiming for reduced environmental impact. We demonstrate that suspensions of porous solids are stable in eutectic mixtures, underscoring their potential for the preparation of porous ionic liquids. Porous ionic liquids retain the wide electrochemical window observed in their precursor pure ionic liquids, rendering them well-suited for green electrochemical reactions, particularly those involving gases whose solubility is enhanced in the porous suspensions. Moreover, their capacity as gas-rich media points to sustainable biomedical and pharmaceutical applications, provided nontoxic, biocompatible ionic liquids and porous solids are utilized.

Creating a new biocatalytic complex with extremolipases and biocompatible ionic liquids for improved transesterification reactions

The ongoing energy crisis has spurred increased research into sustainable and more competitive methods for producing biofuels, including biodiesel. In this context, the focus of the current study is to underscore the viability of investing in a novel biocatalytic complex. This complex incorporates extremophilic lipases and biocompatible ionic liquids with the aim of achieving exceptionally high conversions in transesterification reactions without generating glycerol. Through a meticulous screening process encompassing various amino acid and dipeptide-based ionic liquids from the ammonium family, cholinium glycinate turned out to be the optimal choice. This selection was driven not only by its enhanced compatibility with a commercially available Candida antarctica lipase B (CaLB) but also with extremophilic enzymes synthesized in-house, derived from halophilic (Halomonas spLM1C) and thermophilic (Thermus thermophilus HB27) strains. Following rigorous testing of both free and immobilized enzymes, the ideal concentration of the ionic liquid in transesterification reactions was determined to be 1% relative to the sunflower oil content. Comparative analysis of conversion rates between immobilized thermophilic lipase and immobilized CaLB revealed the efficacy of the proposed approach. Maximum conversions were found to increase by 20%, with specific conversion rates soaring by approximately 180% when utilizing the immobilized thermophilic lipase. In conclusion, this research ushers in new prospects for advancing the competitiveness of biocatalytic solutions in glycerol-free transesterification reactions, underscoring its potential to revolutionize the landscape of sustainable energy production.

Elucidating the role of 2-methyl imidazolium dihydrogen phosphate in preventing aggregation of Bevacizumab: A biophysical investigation

Evaluating the stability and biological activity of monoclonal antibodies is an essential step during the development process in order to ensure their optimum performance. Monoclonal antibodies (mAbs) are stable against aggregation over a narrow pH range and rapidly aggregate in solutions with pH outside these ranges. The pH of solutions can be controlled by using pH buffers, which determine the surface charge on mAbs and thereby affect their electrostatic interactions. Lower pH may lead to protein cleavage and isomerization, while higher pH may cause deamidation and oxidation reactions, increasing the aggregation potential. Surfactants generally prevent aggregation by reducing the tension at the air–water interface, which reduces the possibility of interactions of mAbs with this interface. Apart from surfactants, salts and sugars are also conventionally added to mAb formulation buffers to prevent aggregation. In this work, we have investigated the role of a biocompatible ionic liquid, 2-methyl imidazolium dihydrogen phosphate (2-MIDHP), to prevent aggregation of Bevacizumab. We employed a pH stress model to study the aggregation behaviour of Bevacizumab. The aggregation behaviour of Bevacizumab was analysed using size exclusion-High performance liquid chromatography (SE-HPLC) dynamic light scattering (DLS), differential scanning calorimetry (DSC), and field flow fractionation (FFF). The aggregation and monomer content were monitored over the pH range of 2 to 6.2 using SE-HPLC. Results indicated that 2-MIDHP was able to control aggregation of Bevacizumab at pH 2, for upto 4 days, as compared to the control sample, which showed an increase in aggregate content for upto 4 days, followed by degradation. These results were further orthogonally confirmed using techniques like DLS, DSC, and FFF. 2-MIDHP was thus found to be a potent, acid-resistant, mAb aggregation controlling agent.

Unveiling the Rational Development of Stimuli-Responsive Silk Fibroin-Based Ionogel Formulations.

We present an approach for the rational development of stimuli-responsive ionogels which can be formulated for precise control of multiple unique ionogel features and fill niche pharmaceutical applications. Ionogels are captivating materials, exhibiting self-healing characteristics, tunable mechanical and structural properties, high thermal stability, and electroconductivity. However, the majority of ionogels developed require complex chemistry, exhibit high viscosity, poor biocompatibility, and low biodegradability. In our work, we overcome these limitations. We employ a facile production process and strategically integrate silk fibroin, the biocompatible ionic liquids (ILs) choline acetate ([Cho][OAc]), choline dihydrogen phosphate ([Cho][DHP]), and choline chloride ([Cho][Cl]), traditional pharmaceutical excipients, and the model antiepileptic drug phenobarbital. In the absence of ILs, we failed to observe gel formation; yet in the presence of ILs, thermoresponsive ionogels formed. Systems were assessed via visual tests, transmission electron microscopy, confocal reflection microscopy, dynamic light scattering, zeta potential and rheology measurements. We formed diverse ionogels of strengths ranging between 18 and 642 Pa. Under 25 °C storage, formulations containing polyvinylpyrrolidone (PVP) showed an ionogel formation period ranging over 14 days, increasing in the order of [Cho][DHP], [Cho][OAc], and [Cho][Cl]. Formulations lacking PVP showed an ionogel formation period ranging over 32 days, increasing in the order of [Cho][OAc], [Cho][DHP] and [Cho][Cl]. By heating from 25 to 60 °C, immediately following preparation, thermoresponsive ionogels formed below 41 °C in the absence of PVP. Based on our experimental results and density functional theory calculations, we attribute ionogel formation to macromolecular crowding and confinement effects, further enhanced upon PVP inclusion. Holistically, applying our rational development strategy enables the production of ionogels of tunable physicochemical and rheological properties, enhanced drug solubility, and structural and energetic stability. We believe our rational development approach will advance the design of biomaterials and smart platforms for diverse drug delivery applications.

Non-Invasive Transdermal Delivery of Antisense Oligonucleotides with Biocompatible Ionic Liquids.

Nucleic acid drugs, including antisense oligonucleotides (ASOs), have received considerable attention as novel therapeutics for the treatment of intractable diseases. Despite their potential benefits, ASOs are currently administered via injection, which can negatively impact patient quality of life because of the prevalence of severe injection site reactions. Non-invasive transdermal administration of ASOs is desirable but highly challenging owing to the strong barrier imposed by the stratum corneum, which only permits the penetration of small molecules under 500 Da. For ASOs to exert their antisense effect, they must traverse the negatively charged cell membrane and reach the cytoplasm. In this study, we used the solid-in-oil (S/O) dispersion technology to facilitate the skin permeation of ASOs by coating the drug with a hydrophobic surfactant molecule, specifically lipid-based ionic liquid (IL) surfactants with high biocompatibility and transdermal penetration-enhancing properties. To induce the antisense effect, it was important to achieve simultaneous transdermal delivery and intracellular entrapment of ASOs. In vitro investigations indicated that the newly prepared IL-S/O enhanced the transdermal penetration and intracellular delivery of ASOs, thus inhibiting mRNA translation of the target TGF-β. In addition, in vivo investigations of tumor-bearing mice suggested that the anti-tumor effect of the IL-S/O was similar to that of injection. This study demonstrates the potential of non-invasive transdermal delivery carriers based on biocompatible ILs, which can be applied to a variety of nucleic acid drugs.

Effect of Choline Amino Acid-Based Ionic Liquids on Stability and Structure of Hemoglobin.

Ionic liquids (ILs) can stabilize or destabilize proteins, which motivates us to examine their effect on hemoglobin. The native state of hemoglobin (Hb) is disrupted at different physical conditions such as pressure, temperature, and solvents. Herein, we have monitored the stability of Hb in a nontoxic and biocompatible IL, i. e., choline amino acid-based Ils (ChAAILs), using various spectroscopic techniques like UV-Vis and fluorescence spectroscopy, circular dichroism (CD), and isothermal titration calorimetry (ITC) measurements. It was observed that Hb stays neither in its native state nor in its fully denatured state; rather, it achieves an intermediate state in the presence of ChAAILs. The research on the intermediate state of Hb is still unexplored. Research has been pursued to find a suitable ligand or IL that can stabilize the intermediate state of Hb. In that context, ChAAILs are among the best choices. Molecular docking studies unravel the binding of ChAAILs with Hb. The obtained binding energies of the docked complex are -7.2 kcal/mol and -8.7 kcal/mol for binding of Hb with [Chl][Gly] and [Chl][Met], respectively, which was in line with the ITC results. The quantum chemical calculations show that H-bond plays a significant role for the interaction between Hb and ChAAILs.

Alginate/acemannan-based beads loaded with a biocompatible ionic liquid as a bioactive delivery system

Combining biomacromolecules with green chemistry principles and clean technologies has proven to be an effective approach for drug delivery, providing a prolonged and sustained release of the encapsulated material. The current study investigates the potential of cholinium caffeate (Ch[Caffeate]), a phenolic-based biocompatible ionic liquid (Bio-IL) entrapped in alginate/acemannan beads, as a drug delivery system able to reduce local joint inflammation on osteoarthritis (OA) treatment. The synthesized Bio-IL has antioxidant and anti-inflammatory actions that, combined with biopolymers as 3D architectures, promote the entrapment and sustainable release of the bioactive molecules over time. The physicochemical and morphological characterization of the beads (ALC, ALAC0,5, ALAC1, and ALAC3, containing 0, 0.5, 1, and 3 %(w/v) of Ch[Caffeate], respectively) revealed a porous and interconnected structure, with medium pore sizes ranging from 209.16 to 221.30 μm, with a high swelling ability (up 2400 %). Ch[Caffeate] significantly improved the antioxidant activities of the constructs by 95 % and 97 % for ALAC1 and ALAC3, respectively, when compared to ALA (56 %). Besides, the structures provided the environment for ATDC5 cell proliferation, and cartilage-like ECM formation, supported by the increased GAGs in ALAC1 and ALAC3 formulations after 21 days. Further, the ability to block the secretion of pro-inflammatory cytokines (TNF-α and IL-6), from differentiated THP-1 was evidenced by ChAL-Ch[Caffeate] beads. These outcomes suggest that the established strategy based on using natural and bioactive macromolecules to develop 3D constructs has great potential to be used as therapeutic tools for patients with OA.