Empowering Naringin's Anti-Inflammatory Effects through Nanoencapsulation.

Abundant in citrus fruits, naringin (NAR) is a flavonoid that has a wide spectrum of beneficial health effects, including its anti-inflammatory activity. However, its use in the clinic is limited due to extensive phase I and II first-pass metabolism, which limits its bioavailability. Thus, lipid nanoparticles (LNPs) were used to protect and concentrate NAR in inflamed issues, to enhance its anti-inflammatory effects. To target LNPs to the CD44 receptor, overexpressed in activated macrophages, functionalization with hyaluronic acid (HA) was performed. The formulation with NAR and HA on the surface (NAR@NPsHA) has a size below 200 nm, a polydispersity around 0.245, a loading capacity of nearly 10%, and a zeta potential of about 10 mV. In vitro studies show the controlled release of NAR along the gastrointestinal tract, high cytocompatibility (L929 and THP-1 cell lines), and low hemolytic activity. It was also shown that the developed LNPs can regulate inflammatory mediators. In fact, NAR@NPsHA were able to decrease TNF-α and CCL-3 markers expression by 80 and 90% and manage to inhibit the effects of LPS by around 66% for IL-1ß and around 45% for IL-6. Overall, the developed LNPs may represent an efficient drug delivery system with an enhanced anti-inflammatory effect.

Targeting the Mannose Receptor with Functionalized Fucoidan/Chitosan Nanoparticles Triggers the Classical Activation of Macrophages.

Understanding how nanoparticles' properties influence their cellular interactions is a bottleneck for improving the design of carriers. Macrophage polarization governs their active role in solving infections or tissue repair. To unravel the effect of carbohydrate-targeting mannose receptors on the macrophage surface, drug-free fucoidan/chitosan nanoparticles were functionalized using mannose (M) and mannan (Mn). Polyelectrolyte complex nanoparticles were obtained upon chitosan self-assembly using fucoidan. The functionalized nanoparticles were characterized in terms of their physicochemical characteristics, chemical profile, and carbohydrate orientation. The nanoparticles varied in size from 200 to 400 nm, were monodisperse, and had a stable negative zeta potential with a low aggregation tendency. The nonfunctionalized and functionalized nanoparticles retained their properties for up to 12 weeks. Cell viability and internalization studies were performed for all the designed nanoparticles in the THP-1 monocytes and THP-1-differentiated macrophages. The expression of the mannose receptor was verified in both immune cells. The carbohydrate-functionalized nanoparticles led to their activation and the production of pro-inflammatory cytokines interleukin (IL)-1ß, IL-6, and tumour necrosis factor (TNF)-α. Both M- and Mn-coated nanoparticles modulate macrophages toward an M1-polarized state. These findings demonstrate the tailoring of these nanoplatforms to interact and alter the macrophage phenotype in vitro and represent their therapeutic potential either alone or in combination with a loaded drug for future studies.

Fluoroquinolone-Based Organic Salts (GUMBOS) with Antibacterial Potential.

Antimicrobial resistance is a silent pandemic considered a public health concern worldwide. Strategic therapies are needed to replace antibacterials that are now ineffective. One approach entails the use of well-known antibacterials along with adjuvants that possess non-antibiotic properties but can extend the lifespan and enhance the effectiveness of the treatment, while also improving the suppression of resistance. In this regard, a group of uniform materials based on organic salts (GUMBOS) presents an alternative to this problem allowing the combination of antibacterials with adjuvants. Fluoroquinolones are a family of antibacterials used to treat respiratory and urinary tract infections with broad-spectrum activity. Ciprofloxacin and moxifloxacin-based GUMBOS were synthesized via anion exchange reactions with lithium and sodium salts. Structural characterization, thermal stability and octanol/water partition ratios were evaluated. The antibacterial profiles of most GUMBOS were comparable to their cationic counterparts when tested against Gram-positive S. aureus and Gram-negative E. coli, except for deoxycholate anion, which demonstrated the least effective antibacterial activity. Additionally, some GUMBOS were less cytotoxic to L929 fibroblast cells and non-hemolytic to red blood cells. Therefore, these agents exhibit promise as an alternative approach to combining drugs for treating infections caused by resistant bacteria.

Validation of a Simple HPLC-Based Method for Lysine Quantification for Ruminant Nutrition.

Robust and selective quantification methods are required to better analyze feed supplementation effectiveness with specific amino acids. In this work, a reversed-phase high-performance liquid chromatography method with fluorescence detection is proposed and validated for lysine quantification, one of the most limiting amino acids in ruminant nutrition and essential towards milk production. To assess and widen method applicability, different matrices were considered: namely Li2CO3 buffer (the chosen standard reaction buffer), phosphate buffer solution (to mimic media in cellular studies), and rumen inoculum. The method was validated for all three matrices and found to be selective, accurate (92% ± 2%), and precise at both the inter- and intra-day levels in concentrations up to 225 µM, with detection and quantification limits lower than 1.24 and 4.14 µM, respectively. Sample stability was evaluated when stored at room temperature, 4 °C, and -20 °C, showing consistency for up to 48 h regardless of the matrix. Finally, the developed method was applied in the quantification of lysine on real samples. The results presented indicate that the proposed method can be applied towards free lysine quantification in ruminant feeding studies and potentially be of great benefit to dairy cow nutrition supplementation and optimization.

Neutral Diclofenac Causes Remarkable Changes in Phosphatidylcholine Bilayers: Relevance for Gastric Toxicity Mechanisms.

The main objective of this study was to clarify the topical mechanisms underlying diclofenac-induced gastric toxicity by considering for the first time both ionization states of this nonsteroidal anti-inflammatory drug. 1,2-Dimyristoyl-sn-glycero-3-phosphocholine (DMPC) liposomes were the model system chosen to mimic the protective phospholipid layers of the gastric mucosa and to describe the interactions with diclofenac, considering the pH gradient found in the gastric mucosa (3 < pH < 7.4). Complementary experimental techniques were combined to evaluate the drug's affinity for DMPC bilayers, as well as to assess the drug's effects on the structural properties of the phospholipid bilayer. The diclofenac-DMPC interactions were clearly dependent on the drug's ionization state. Neutral diclofenac displayed greater affinity for DMPC bilayers than anionic diclofenac. Moreover, the protonated/neutral form of the drug induced more pronounced and/or distinct alterations in the structure of the DMPC bilayer than the deprotonated/ionized form, considering similar membrane concentrations. Therefore, neutral diclofenac-induced changes in the structural properties of the external phospholipid layers of the gastric mucosa may constitute an additional toxicity mechanism of this worldwide-used drug, which shall be considered for the development of safer therapeutic strategies. SIGNIFICANCE STATEMENT: Neutral or anionic diclofenac exerted distinct alterations in phosphatidylcholine bilayers, which are used in this work as models for the protective phospholipid layers of the gastric mucosa. Remarkable changes were induced by neutral diclofenac in the structural properties of the phospholipid bilayer, suggesting that both ionized and neutral states of nonsteroidal anti-inflammatory drugs must be considered to clarify their mechanisms of toxicity and to ultimately develop safer anti-inflammatory drugs.

Insights on Ultrafiltration-Based Separation for the Purification and Quantification of Methotrexate in Nanocarriers.

The evaluation of encapsulation efficiency is a regulatory requirement for the characterization of drug delivery systems. However, the difficulties in efficiently separating nanomedicines from the free drug may compromise the achievement of accurate determinations. Herein, ultrafiltration was exploited as a separative strategy towards the evaluation of methotrexate (MTX) encapsulation efficiency in nanostructured lipid carriers and polymeric nanoparticles. The effect of experimental conditions such as pH and the amount of surfactant present in the ultrafiltration media was addressed aiming at the selection of suitable conditions for the effective purification of nanocarriers. MTX-loaded nanoparticles were then submitted to ultrafiltration and the portions remaining in the upper compartment of the filtering device and in the ultrafiltrate were collected and analyzed by HPLC-UV using a reversed-phase (C18) monolithic column. A short centrifugation time (5 min) was suitable for establishing the amount of encapsulated MTX in nanostructured lipid carriers, based on the assumption that the free MTX concentration was the same in the upper compartment and in the ultrafiltrate. The defined conditions allowed the efficient separation of nanocarriers from the free drug, with recoveries of >85% even when nanoparticles were present in cell culture media and in pig skin surrogate from permeation assays.

Marine Polysaccharides in Pharmaceutical Applications: Fucoidan and Chitosan as Key Players in the Drug Delivery Match Field.

The use of marine-origin polysaccharides has increased in recent research because they are abundant, cheap, biocompatible, and biodegradable. These features motivate their application in nanotechnology as drug delivery systems; in tissue engineering, cancer therapy, or wound dressing; in biosensors; and even water treatment. Given the physicochemical and bioactive properties of fucoidan and chitosan, a wide range of nanostructures has been developed with these polysaccharides per se and in combination. This review provides an outline of these marine polysaccharides, including their sources, chemical structure, biological properties, and nanomedicine applications; their combination as nanoparticles with descriptions of the most commonly used production methods; and their physicochemical and biological properties applied to the design of nanoparticles to deliver several classes of compounds. A final section gives a brief overview of some biomedical applications of fucoidan and chitosan for tissue engineering and wound healing.

Application of pH-Responsive Fucoidan/Chitosan Nanoparticles to Improve Oral Quercetin Delivery.

Polymeric nanoparticles based on fucoidan and chitosan were developed to deliver quercetin as a novel functional food. Through the polyelectrolyte self-assembly method, fucoidan/chitosan (F/C) nanoparticles were obtained with three different weight ratios (1/1, 3/1, and 5/1). The content of quercetin in the fucoidan/chitosan nanoparticles was in the range 110 ± 3 to 335 ± 4 mg·mL-1, with the increase of weight ratio of fucoidan to chitosan in the nanoparticle. Physicochemically stable nanoparticles were obtained with a particle size within the 300⁻400 nm range and surface potential higher than +30 mV for the 1F/1C ratio nanoparticle and around -30 mV for the 3F/1C and 5F/1C ratios nanoparticles. The 1F/1C ratio nanoparticle became larger and more unstable as the pH increased from 2.5 to 7.4, while the 3F/1C and 5F/1C nanoparticles retained their initial characteristics. This result indicates that the latter nanoparticles were stable along the gastrointestinal tract. The quercetin-loaded fucoidan/chitosan nanoparticles showed strong antioxidant activity and controlled release under simulated gastrointestinal environments (in particular for the 3F/1C and 5F/1C ratios), preventing quercetin degradation and increasing its oral bioavailability.

Licofelone-DPPC Interactions: Putting Membrane Lipids on the Radar of Drug Development.

(1) Background: Membrane lipids have been disregarded in drug development throughout the years. Recently, they gained attention in drug design as targets, but they are still disregarded in the latter stages. Thus, this study aims to highlight the relevance of considering membrane lipids in the preclinical phase of drug development. (2) Methods: The interactions of a drug candidate for clinical use (licofelone) with a membrane model system made of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) were evaluated by combining Langmuir isotherms, Brewster angle microscopy (BAM), polarization-modulation infrared reflection-absorption spectroscopy (PM-IRRAS), and grazing-incidence X-ray diffraction (GIXD) measurements. (3) Results: Licofelone caused the expansion of the DPPC isotherm without changing the lipid phase transition profile. Moreover, licofelone induced the reduction of DPPC packing density, while increasing the local order of the DPPC acyl chains. (4) Conclusions: The licofelone-induced alterations in the structural organization of phosphatidylcholine monolayers may be related to its pharmacological actions. Thus, the combination of studying drug-membrane interactions with the pharmacological characterization that occurs in the preclinical stage may gather additional information about the mechanisms of action and toxicity of drug candidates. Ultimately, the addition of this innovative step shall improve the success rate of drug development.

Micro-bead injection spectroscopy for label-free automated determination of immunoglobulin G in human serum.

Immunoglobulin G (IgG) represents the major fraction of antibodies in healthy adult human serum, and deviations from physiological levels are a generic marker of disease corresponding to different pathologies. Therefore, screening methods for IgG evaluation are a valuable aid to diagnostics. The present work proposes a rapid, automatic, and miniaturized method based on UV-vis micro-bead injection spectroscopy (µ-BIS) for the real-time determination of human serum IgG with label-free detection. Relying on attachment of IgG in rec-protein G immobilized in Sepharose 4B, a bioaffinity column is automatically assembled, where IgG is selectively retained and determined by on-column optical density measurement. A "dilution-and-shoot" approach (50 to 200 times) was implemented without further sample treatment because interferences were flushed out of the column upon sample loading, with minimization of carryover and cross-contamination by automatically discarding the sorbent (0.2 mg) after each determination. No interference from human serum albumin at 60 mg mL-1 in undiluted sample was found. The method allowed IgG determination in the range 100-300 µg mL-1 (corresponding to 5.0-60 mg mL-1 in undiluted samples), with a detection limit of 33 µg mL-1 (1.7 mg mL-1 for samples, dilution factor of 50). RSD values were < 9.4 and < 11.7%, for intra and inter-assay precision, respectively, while recovery values for human serum spiked with IgG at high pathological levels were 97.8-101.4%. Comparison to commercial ELISA kit showed no significant difference for tested samples (n = 8). Moreover, time-to-result decreased from several hours to < 5 min and analysis cost decreased 10 times, showing the potential of the proposed approach as a point-of-care method. Graphical abstract Micro-Bead Injection Spectroscopy method for real time, automated and label-free determination of total serum human Immunoglobulin G (IgG). The method was designed for Lab-on-Valve (LOV) platforms using a miniaturised protein G bioaffinity separative approach. IgG are separated from serum matrix components upon quantification with low non-specific binding in less than 5 min.

Acemetacin-phosphatidylcholine interactions are determined by the drug ionization state.

Gastrointestinal (GI) toxicity is a major drawback of the chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs). The NSAIDs topical actions on the protective phospholipid layers of the GI mucosa seem to be a central toxicity mechanism of these pharmaceuticals. This work describes the interactions of acemetacin, a commercialized NSAID, with 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) bilayers at pH 3.0, 5.0, and 7.4. This pH range was chosen to mimic the pH gradient found in the gastric mucosa, and to ultimately gain insights into the mechanisms underlying the acemetacin-induced gastric toxicity. Various experimental techniques were combined to characterize the partitioning of acemetacin in DMPC bilayers, and its effects on the phase transition behavior, as well as the structure and dynamics of DMPC bilayers. The acemetacin-DMPC interactions were clearly pH-dependent. The neutral (protonated) form of acemetacin had more affinity for the DMPC bilayer than the negatively charged form. Due to the higher affinity of neutral acemetacin, the drug effects on the phase transition and the structure and dynamics of the DMPC bilayer were more pronounced at lower pH values. In general, acemetacin decreased the temperature and the cooperativity of the lipid phase transition and induced changes in the packing and dynamics of the DMPC bilayer. These results support the hypothesis that acemetacin-induced gastric toxicity may be related to its effects on the protective phospholipid layers of the mucosal barrier.

Chromatographic method for the simultaneous quantification of dapsone and clofazimine in nanoformulations.

The low bioavailability and nonspecific distribution of dapsone and clofazimine, commonly applied in combination for the treatment of leprosy, can produce toxic effects. Nanotechnological approaches enhance the delivery of these drugs. Therefore, a high-performance liquid chromatography method was developed for the simultaneous determination of dapsone and clofazimine loaded in nanoformulations for quality control purposes. Chromatographic separation was achieved on a reversed-phase Kinetex core-shell C18 column, followed by spectrophotometric detection at 280 nm. Considering the different physicochemical properties of dapsone and clofazimine, elution was performed in gradient mode using an aqueous acetate buffer (50 mmol/L, pH 4.8) and an increasing acetonitrile content from 27 to 63% v/v at a flow rate of 1.0 mL/min with retention times of 6.2 and 14.0 min, respectively. The method was validated according to the European Medicines Agency guideline and it was found to be specific, accurate (99.6-114.0%), and precise for intra- (RSD ≤ 1.8%) and interday assays (RSD ≤ 12.5%). Both drugs showed stability after 24 h at room temperature and over three freeze-thaw cycles with recoveries ≥86.2%. Low temperature (4°C) in the autosampler caused the precipitation of clofazimine and must be avoided. The validated method was successfully applied in the quantification of both drugs in nanoformulations.

Nonsteroidal Anti-Inflammatory Therapy: A Journey Toward Safety.

The efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) against inflammation, pain, and fever has been supporting their worldwide use in the treatment of painful conditions and chronic inflammatory diseases until today. However, the long-term therapy with NSAIDs was soon associated with high incidences of adverse events in the gastrointestinal tract. Therefore, the search for novel drugs with improved safety has begun with COX-2 selective inhibitors (coxibs) being straightaway developed and commercialized. Nevertheless, the excitement has fast turned to disappointment when diverse coxibs were withdrawn from the market due to cardiovascular toxicity. Such events have once again triggered the emergence of different strategies to overcome NSAIDs toxicity. Here, an integrative review is provided to address the breakthroughs of two main approaches: (i) the association of NSAIDs with protective mediators and (ii) the design of novel compounds to target downstream and/or multiple enzymes of the arachidonic acid cascade. To date, just one phosphatidylcholine-associated NSAID has already been approved for commercialization. Nevertheless, the preclinical and clinical data obtained so far indicate that both strategies may improve the safety of nonsteroidal anti-inflammatory therapy.

Resveratrol induces ordered domains formation in biomembranes: Implication for its pleiotropic action.

Resveratrol is a polyphenol compound with great value in cancer therapy, cardiovascular protection, and neurodegenerative disorders. The mechanism by which resveratrol exerts such pleiotropic effects is not yet clear and there is a huge need to understand the influence of this compound on the regulation of lipid domains formation on membrane structure. The aim of the present study was to reveal potential molecular interactions between resveratrol and lipid rafts found in cell membranes by means of Förster resonance energy transfer, DPH fluorescence quenching, and triton X-100 detergent resistance assay. Liposomes composed of egg phosphatidylcholine, cholesterol, and sphingomyelin were used as model membranes. The results revealed that resveratrol induces phase separation and formation of liquid-ordered domains in bilayer structures. The formation of such tightly packed lipid rafts is important for different signal transduction pathways, through the regulation of membrane-associating proteins, that can justify several pharmacological activities of this compound.

Biophysics in cancer: The relevance of drug-membrane interaction studies.

Lipidomics has been proving that membrane lipids play a crucial role in several cell functions and are involved in several pathologies, including cancer. In fact, beyond a scaffold where proteins and other components are embedded, the cell membrane can also act as a barrier or a target for anticancer drugs. From this point of view, the development of new chemotherapeutic agents should also take into account the role of the membrane in their activity. This Review aims to highlight the importance of anticancer drug-membrane interactions as a powerful strategy to improve cancer therapy. Biophysical techniques emerge, therefore, as essential tools to unveil such interactions.

Proof of pore formation and biophysical perturbations through a 2D amoxicillin-lipid membrane interaction approach.

Amoxicillin is a worldwide used antibiotic, and it is classified as a first-line drug against Helicobacter pylori gastric infections. However, the current treatment of these infections has several limitations, such as the side effects and the low therapeutic compliance. Amoxicillin has been associated with gastrointestinal and renal side effects, with higher toxicity when the pH is lower. By considering this association and the well-known pH gradient of the gastric mucosa, this work aims to evaluate the influence of pH on the toxicity of amoxicillin. For that purpose, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) monolayers were used since phosphatidylcholines are the most common phospholipid headgroup of biological membranes. To have insight of the effects of amoxicillin, different techniques were employed, namely, isotherm measurements, infrared reflection-absorption spectroscopy, grazing incident X-ray diffraction and Brewster angle microscopy. The monolayers of DPPC spread onto different buffer solutions (pH1.2, pH5 and pH7.4) showed different structural and packing properties. The interaction with amoxicillin also depended on the pH. At pH7.4, the highest effect was visualized at lower pressures, with partial restoration of the biophysical properties of the monolayer at 30 mN.m-1. A higher perturbation is shown at acidic pH, in which pores were visualized by Brewster angle microscopy. These perturbations may ultimately be related with amoxicillin toxicity.

The daunorubicin interplay with mimetic model membranes of cancer cells: A biophysical interpretation.

The present work aimed to study the interactions between the anticancer drug daunorubicin and lipid membrane mimetic models of cancer cells composed by their most representative classes of phospholipids, with different degrees of complexity. Regarding these anticancer drug-membrane interactions, several biophysical parameters were assessed using liposomes (LUVs) composed of different molar ratios of DMPC, DOPC, DPPS, DOPE and Chol. In this context, daunorubicin's membrane concentration was determined by calculating its partition coefficient (Kp) between liposomes and water using derivative UV/vis spectrophotometry at 37°C and pH6.3, a typical tumoral microenvironment. Characterization of the zeta potential of such model membranes, in both the absence and presence of the compound, was accomplished through Electrophoretic Light Scattering (ELS). Fluorescence quenching studies, which determine the location of the drug within the bilayer, were carried out using liposomes labelled with DPH and TMA-DPH, fluorescent probes with known membrane position. Temperature dependent steady-state anisotropy assays were also performed to measure the daunorubicin effect on the membranes' microviscosity. The overall results support that daunorubicin permeation depends on the phospholipid membrane composition and causes alterations in the biophysical properties of the bilayers, namely in the membrane fluidity. The interaction of daunorubicin with the studied phospholipids is mainly driven by electrostatic and hydrophobic interactions. These insights demonstrated that not only membranes can affect daunorubicin accumulation in cells but the compound can alter the properties of membranes. The changes produced by daunorubicin on the lipid structure may constitute an additional mechanism of action, which might lead to modifications in the location and, consequently, the activity of membrane signaling proteins.

Apo E-Functionalization of Solid Lipid Nanoparticles Enhances Brain Drug Delivery: Uptake Mechanism and Transport Pathways.

Several strategies have been implemented to enhance brain drug delivery, and herein solid lipid nanoparticles functionalized with apolipoprotein E were tested in hCMEC/D3 cell monolayers. The mean diameter of 160 nm, negative charge of -12 mV, and their lipophilic characteristics make these nanosystems suitable for brain delivery. Confocal images and flow cytometry data showed a cellular uptake increase of 1.8-fold for SLN-Palmitate-ApoE and 1.9-fold for SLN-DSPE-ApoE when compared with the non-functionalized SLNs. Clathrin-mediated endocytosis was distinguished as the preferential internalization pathway involved in cellular uptake and nanoparticles could cross the blood-brain barrier predominantly by a transcellular pathway. The understanding of the mechanisms involved in the transport of these nanosystems through the blood-brain barrier may potentiate their application on brain drug delivery.

Multiple Lipid Nanoparticles (MLN), a New Generation of Lipid Nanoparticles for Drug Delivery Systems: Lamivudine-MLN Experimental Design.

PURPOSE: An optimized methodology for the development of a new generation of lipid nanoparticles, the multiple lipid nanoparticles (MLN) is described. MLN have characteristics between nanostructured lipid carriers (NLC) and multiple emulsions (W/O/W), but without the outer aqueous phase. METHODS: The production is based on a hot homogenization method combined with high shear and ultrasonication. The antiretroviral agent lamivudine (3TC), was loaded in the MLN. For comparison purposes, NLC-3TC formulation was also developed and physico-chemically characterized by the same parameters as MLN-3TC. The development and optimization of MLN and NLC formulations were supported by a Quality by Design (QbD) approach. RESULTS: The MLN-3TC formulation exhibited a size of about 450 nm, polydispersity <0.3 and negative zeta potential > -20 mV. Furthermore, the morphology assessed by TEM showed a structure with multiples aqueous vacuoles. MLN-3TC was physically stable for at least 45 days, had low cytotoxicity and drug release studies showed a sustained and controlled release of 3TC under gastric and plasma-simulated conditions (at pH 7.4 for about 45 h). CONCLUSIONS: The optimized formulations present suitable profiles for oral administration. Overall, the results reveal that MLN present higher loading capacity and storage stability than NLC.

Effects of novel triple-stage antimalarial ionic liquids on lipid membrane models.

Primaquine-based ionic liquids, obtained by acid-base reaction between parent primaquine and cinnamic acids, were recently found as triple-stage antimalarial hits. These ionic compounds displayed significant activity against both liver- and blood-stage Plasmodium parasites, as well as against stage V P. falciparum parasites. Remarkably, blood-stage activity of the ionic liquids against both chloroquine-sensitive (3D7) and resistant (Dd2) P. falciparum strains was clearly superior to those of the respective covalent (amide) analogues and of parent primaquine. Having hypothesized that such behaviour might be ascribed to an enhanced ability of the ionic compounds to permeate into Plasmodium-infected erythrocytes, we have carried out a differential scanning calorimetry-based study of the interactions between the ionic liquids and membrane models. Results provide evidence, at the molecular level, that the primaquine-derived ionic liquids may contribute to an increased permeation of the parent drug into malaria-infected erythrocytes, which has relevant implications towards novel antimalarial approaches based on ionic liquids.