Solid Lipid Nanoparticles Encapsulating a Benzoxanthene Derivative in a Model of the Human Blood-Brain Barrier: Modulation of Angiogenic Parameters and Inflammation in Vascular Endothelial Growth Factor-Stimulated Angiogenesis.

Lignans, a class of secondary metabolites found in plants, along with their derivatives, exhibit diverse pharmacological activities, including antioxidant, antimicrobial, anti-inflammatory, and antiangiogenic ones. Angiogenesis, the formation of new blood vessels from pre-existing ones, is a crucial process for cancer growth and development. Several studies have elucidated the synergistic relationship between angiogenesis and inflammation in various inflammatory diseases, highlighting a correlation between inflammation and vascular endothelial growth factor (VEGF)-induced angiogenesis. Thus, the identification of novel molecules capable of modulating VEGF effects presents promising prospects for developing therapies aimed at stabilizing, reversing, or even arresting disease progression. Lignans often suffer from low aqueous solubility and, for their use, encapsulation in a delivery system is needed. In this research, a bioinspired benzoxantene has been encapsulated in solid lipid nanoparticles that have been characterized for their pharmacotechnical properties and their thermotropic behavior. The effects of these encapsulated nanoparticles on angiogenic parameters and inflammation in VEGF-induced angiogenesis were evaluated using human brain microvascular endothelial cells (HBMECs) as a human blood-brain barrier model.

Development of Solid Lipid Nanoparticles as Dry Powder: Characterization and Formulation Considerations.

Solid lipid nanoparticles (SLNs) are lipid-based colloidal systems used for the delivery of active compounds. Although SLNs have many benefits, they show important issues due to physical and chemical instability phenomena during storage. For these reasons, it is highly desirable to have a dried SLN formulation available. Therefore, the aim of the project was to identify suitable methods to obtain a dry powder formulation from an SLN suspension. The nanoparticle suspension was dried using both freeze- and spray-drying techniques. The suitability of these methods in obtaining SLN dry powders was evaluated from the analyses of nanotechnological parameters, system morphology and thermal behavior using differential scanning calorimetry. Results pointed out that both drying techniques, although at different yields, were able to produce an SLN dry powder suitable for pharmaceutical applications. Noteworthily, the freeze-drying of SLNs under optimized conditions led to a dry powder endowed with good reconstitution properties and technological parameters similar to the starting conditions. Moreover, freeze-thaw cycles were carried out as a pretest to study the protective effect of different cryoprotectants (e.g., glucose and mannitol with a concentration ranging from 1% to 10% w/v). Glucose proved to be the most effective in preventing particle growth during freezing, thawing, and freeze-drying processes; in particular, the optimum concentration of glucose was 1% w/v.

Design of Nanotechnological Carriers for Ocular Delivery of Mangiferin: Preformulation Study.

(1) Background: Mangiferin (MGN) is a natural compound, showing anti-inflammatory and antioxidant activities for the potential treatment of eye diseases. The poor physicochemical features of MGN (low solubility and high instability) justify its nanoencapsulation into nanostructured lipid carriers (NLC) to improve its ocular bioavailability. (2) Methods: Firstly, MGN-NLC were prepared by the high shear homogenization coupled with the ultrasound (HSH-US) method. Finally, unloaded and MGN-loaded NLC were analyzed in terms of ocular tolerance. (3) Results: MGN-NLC showed good technological parameters suitable for ocular administration (particle size below 200 nm). The ORAC assay was performed to quantify the antioxidant activity of MGN, showing that the antioxidant activity of MGN-NLC (6494 ± 186 µM TE/g) was higher than that of the free compound (3521 ± 271 µM TE/g). This confirmed that the encapsulation of the drug was able to preserve and increase its activity. In ovo studies (HET-CAM) revealed that the formulation can be considered nonirritant. (4) Conclusions: Therefore, NLC systems are a promising approach for the ocular delivery of MGN.

Benzo[k,l]xanthene Lignan-Loaded Solid Lipid Nanoparticles for Topical Application: A Preliminary Study.

Skin is the first human barrier that is daily exposed to a broad spectrum of physical and chemical agents, which can increase reactive oxygen species (ROS) and lead to the formation of topical disorders. Antioxidant molecules, such as benzo[k,l]xanthene lignans (BXL), are ideal candidates to eliminate or minimize the effects of ROS. Herein, we aimed to formulate BXL-loaded solid lipid nanoparticles (SLN-BXL) to improve the bioavailability and interaction with the skin, and also to investigate the protective impact against intracellular ROS generation in HFF-1 in comparison with the drug-free situation. SLN-BXL were formulated using the PIT/ultrasonication method, and then were subjected to physicochemical characterizations, i.e., average size, zeta potential (ZP), polydispersity index (PDI), encapsulation efficiency (%EE), thermotropic behavior, and interaction with a biomembrane model. The results show a mean size around 200 nm, PDI of 0.2, and zeta potential of about -28 mV, with values almost unchanged over a period of three months, while the EE% is ≈70%. Moreover, SLN-BXL are able to deeply interact with the biomembrane model, and to achieve a double-action release in mildly hydrophobic matrices; the results of the in vitro experiments confirm that SLN-BXL are cell-safe and capable of attenuating the IL-2-induced high ROS levels. In conclusion, based on our findings, the formulation can be proposed as a candidate for a preventive remedy against skin disorders induced by increased levels of ROS.

Calorimetric Evaluation of Glycyrrhetic Acid (GA)- and Stearyl Glycyrrhetinate (SG)-Loaded Solid Lipid Nanoparticle Interactions with a Model Biomembrane.

Glycyrrhetic acid (GA) and stearyl glycyrrhetinate (SG) are two interesting compounds from Glycyrrhiza glabra, showing numerous biological properties widely applied in the pharmaceutical and cosmetic fields. Despite these appreciable benefits, their potential therapeutic properties are strongly compromised due to unfavourable physical-chemical features. The strategy exploited in the present work was to develop solid lipid nanoparticles (SLNs) as carrier systems for GA and SG delivery. Both formulations loaded with GA and SG (GA-SLNs and SG-SLNs, respectively) were prepared by the high shear homogenization coupled to ultrasound (HSH-US) method, and we obtained good technological parameters. DSC was used to evaluate their thermotropic behaviour and ability to act as carriers for GA and SG. The study was conducted by means of a biomembrane model (multilamellar vesicles; MLVs) that simulated the interaction of the carriers with the cellular membrane. Unloaded and loaded SLNs were incubated with the biomembranes, and their interactions were evaluated over time through variations in their calorimetric curves. The results of these studies indicated that GA and SG interact differently with MLVs and SLNs; the interactions of SG-SLNs and GA-SLNs with the biomembrane model showed different variations of the MLVs calorimetric curve and suggest the potential use of SLNs as delivery systems for GA.

Curcumin Containing PEGylated Solid Lipid Nanoparticles for Systemic Administration: A Preliminary Study.

Curcumin (CUR) has a wide range of pharmacological properties, including anti-inflammatory and antioxidant activities, and it can be considered a good candidate for the potential treatment of central nervous system (CNS) pathologies, although its use in clinical practice is compromised due to its high lipophilicity. Solid lipid nanoparticles (SLNs) are well-known nanocarriers representing a consolidated approach for the delivery of lipophilic compounds, but their systemic use is limited due their short half-life. The formulation of stealth SLNs (pSLNs) could be a valid strategy to overcome this limit. Curcumin-loaded-pSLNs were prepared by the solvent evaporation method. Formulation was characterized for their mean size, zeta potential, size distribution, and morphology. Drug antioxidant activity was evaluated by Oxygen Radical Absorbance Capacity (ORAC) assay. Finally, the obtained formulations were analyzed in terms of long-term stability. Curcumin-loaded-pSLNs showed good technological parameters with a mean particle size below 200 nm, as confirmed by TEM images, and a zeta potential value around -30 mV, predicting good long-term stability. Differential Scanning Calorimetry (DSC) analysis confirmed that PEG micelles interacted with the SLN surface; this suggests the location of the PEG on the pSLN surface. Therefore, these preliminary studies suggest that the produced formulation could be regarded as a promising carrier for the systemic administration.

Interaction of α-Hexylcinnamaldehyde with a Biomembrane Model: A Possible MDR Reversal Mechanism.

The ability of the naturally derived compound α-hexylcinnamaldehyde (1) to interact with biomembranes and to modulate their permeability has been investigated as a strategy to reverse multidrug resistance (MDR) in cancer cells. Dimyristoylphosphatidylcholine (DMPC) multilamellar vesicles (MLVs) were used as biomembrane models, and differential scanning calorimetry was applied to measure the effect of 1 on the thermotropic behavior of DMPC MLVs. The effect of an aqueous medium or a lipid carrier on the uptake of 1 by the biomembrane was also characterized. Furthermore, taking into account that MDR is strictly regulated by redox signaling, the pro-oxidant and/or antioxidant effects of 1 were evaluated by the crocin-bleaching assay, in both hydrophilic and lipophilic environments. Compound 1 was uniformly distributed in the phospholipid bilayers and deeply interacted with DMPC MLVs, intercalating among the phospholipid acyl chains and thus decreasing their cooperativity. The lipophilic medium allowed the absorption of 1 into the phospholipid membrane. In the crocin-bleaching assay, the substance produced no pro-oxidant effects in both hydrophilic and lipophilic environments; conversely, a significant inhibition of AAPH-induced oxidation was exerted in hydrophilic medium. These results suggest a possible role of 1 as a chemopreventive and chemosensitizing agent for fighting cancer.

α-Hexylcinnamaldehyde inhibits the genotoxicity of environmental pollutants in the bacterial reverse mutation assay.

The antimutagenicity of α-hexylcinnamaldehyde (1), a semisynthetic and more stable derivative of cinnamaldehyde, was evaluated against common environmental pollutants in the bacterial reverse mutation assay. The pre-, co-, and post-treatment protocols were applied to assess the involvement of desmutagenic and/or bioantimutagenic mechanisms. Compound 1 (9-900 µM) produced a strong antimutagenicity (>40% inhibition) in the Salmonella typhimurium TA98 strain against the nitroarenes 2-nitrofluorene and 1-nitropyrene in almost all experimental conditions. A strong inhibition was also reached against the nitroarene 1,8-dinitropyrene and the arylamine 2-aminoanthracene in the cotreatment at the highest concentrations tested. In order to evaluate if an inhibition of bacterial nitroreductase (NR) and O-acetyltransferase (OAT) could be involved in the antimutagenicity of 1 against nitroarenes, the substance was further tested against 1-nitropyrene (activated by both NR and OAT) in TA98NR and TA98 1,8-DNP strains (lacking the NR and OAT enzymes, respectively). Although both desmutagenic and bioantimutagenic mechanisms appear mostly involved in the antimutagenicity of 1, based on data obtained in the TA98NR strain, applying the pretreatment protocol, compound 1 seems to act as an inhibitor of the OAT-mediated mutagen bioactivation. These results provide justification for further studies on 1 as a possible chemopreventive agent.

Effect of resveratrol-related stilbenoids on biomembrane models.

The interactions of the two resveratrol analogues 2-hydroxy-3,5,3',5'-tetramethoxystilbene (4) and 2-hydroxy-3,5,3',4'-tetramethoxystilbene (5) with model biomembranes were studied. The aim of this investigation was to highlight possible differences in the interactions with such biomembranes related to the minimal structural differences between these isomeric stilbenoids. In particular, different experiments on stilbenoid/biomembrane model systems using both differential scanning calorimetry (DSC) and Langmuir-Blodgett techniques were carried out to evaluate stilbenoid/multilamellar vesicle and stilbenoid/phospholipid monolayer interactions, respectively. Dimyristoylphosphatidylcholine was used as constituent of the biomembrane models and permitted the experiments to be carried out at 37 °C, close to body temperature. Kinetic studies were also run by DSC to evaluate the uptake of the resveratrol derivatives by the biomembrane model in an aqueous medium and when transported by a lipophilic carrier. The results indicated that both of the resveratrol analogues influenced the behavior of multilamellar vesicles and monolayers, biomembrane models, with 4 producing a larger effect than 5. These results are useful for better understanding the mechanism of action of these compounds. Moreover, the kinetic results could be of importance for future design of lipophilic delivery systems for these stilbenoids.

Genotoxicity assessment of ß-caryophyllene oxide.

ß-caryophyllene oxide is a biciclic sesquiterpene, occurring naturally in essential oils from various medicinal and edible plants and used as a flavouring agent. Due to its potential hazardous chemical structure, the European Food Safety Authority reported to be pending a safety assessment for this compound. Here, this flavouring agent was tested for its mutagenic effect in the Ames test and micronucleus assay. Furthermore, considering that the penetration of a substance through phospholipid bilayers is determinant for its activity, the ability of ß-caryophyllene oxide to be absorbed into cells was evaluated by differential scanning calorimetry (DSC) using multilamellar vesicles of dimyristoylphosphatidylcholine as a biomembrane model. ß-caryophyllene oxide was found to be devoid of mutagenic effect, both at gene level (frameshift or base-substitution mutations), and on chromosome (clastogenicity and aneuploidogenicity). Results of DSC analysis highlighted that the substance was strongly absorbed through the membrane bilayer. Present results show that ß-caryophyllene oxide, although absorbed through cell membranes and in spite of its potentially reactive chemical structure, is devoid of genotoxic effects, inducing neither point mutations nor chromosomal damages. These negative genotoxic findings will be critical to the safety assessment of ß-caryophyllene oxide as used as a flavouring/fragrance ingredient.

Nanostructured Lipid Carriers Aimed to the Ocular Delivery of Mangiferin: In Vitro Evidence.

Although mangiferin (MGN) is a natural antioxidant that could be a good candidate for the treatment of ocular diseases, its use in ophthalmology is strongly compromised due to its high lipophilicity. Its encapsulation in nanostructured lipid carriers (NLC) seems to be an interesting strategy for improving its ocular bioavailability. As reported in our previous work, MGN-NLC showed high ocular compatibility and fulfilled the nanotechnological requirements needed for ocular delivery. The aim of the present work was to investigate, in vitro and ex vivo, the capability of MGN-NLC to act as a potential drug delivery system for MGN ocular administration. The data obtained in vitro on arising retinal pigment epithelium cells (ARPE-19) did not show cytotoxic effects for blank NLC and MGN-NLC; likewise, MGN-NLC showed the maintenance of the antioxidant role of MGN by mitigating ROS (Reactive Oxygen Species) formation and GSH (glutathione) depletion induced by H2O2. In addition, the capacity of MGN-released to permeate through and accumulate into the ocular tissues was confirmed ex vivo using bovine corneas. Finally, the NLC suspension has been formulated as a freeze-dried powder using mannitol at a concentration of 3% (w/v) in order to optimize its storage for long periods of time. All this evidence suggests a potential application of MGN-NLC in the treatment of oxidative stress-related ocular diseases.

Ethyl Protocatechuate Encapsulation in Solid Lipid Nanoparticles: Assessment of Pharmacotechnical Parameters and Preliminary In Vitro Evaluation for Colorectal Cancer Treatment.

Colorectal cancer is one of the most diffused tumoral diseases. Since most medicaments employed for its treatment are debilitating, the use of naturally derived products, which can be effective against the mutated cells and, in addition, can reduce most inflammatory-related effects, could be extremely beneficial for the continued treatment of this disease. In this research, ethyl protocatechuate (PCAEE), a protocatechuic acid prodrug, was encapsulated in solid lipid nanoparticles (SLN) (prepared without and with Tween 80), which were characterized in terms of size, polydispersity index (PDI), zeta potential and thermotropic behavior. Encapsulation efficiency, release profile and interaction with a model of biomembrane were also assessed. The nanoparticles were tested in vitro on both healthy cells and on a model of tumoral cells. SLN prepared with Tween 80 was promising in terms of physicochemical properties (z-average of 190 nm, PDI 0.150 and zeta potential around -20 mV) and encapsulation efficiency (56%); they showed a desirable release profile, demonstrated an ability to penetrate and release the encapsulated PCAEE into a biomembrane model and were nontoxic on healthy cells. In addition, they caused a greater dose-dependent decrease in the viability of CaCo-2 cells than PCAEE alone. In conclusion, the formulation could be proposed for further studies to assess its suitability for the treatment of colorectal cancer.

Correction: Santonocito et al. Astaxanthin-Loaded Stealth Lipid Nanoparticles (AST-SSLN) as Potential Carriers for the Treatment of Alzheimer's Disease: Formulation Development and Optimization. Nanomaterials 2021, 11, 391.

In the original publication [...].

Lipid Nanoparticles Loading Steroidal Alkaloids of Tomatoes Affect Neuroblastoma Cell Viability in an In Vitro Model.

Tomato by-products represent a good source of phytochemical compounds with health properties, such as the steroidal glycoalkaloid α-tomatine (α-TM) and its aglycone tomatidine (TD). Both molecules have numerous beneficial properties, such as potential anticancer activity. Unfortunately, their therapeutic application is limited due to stability and bioavailability issues. Therefore, a valid strategy seems to be their encapsulation into Solid Lipid Nanoparticles (SLN). The nanoformulations containing α-TM (α-TM-SLN) and TD (TD-SLN) were prepared by solvent-diffusion technique and subsequently characterized in terms of technological parameters (particle size, polydispersity index, zeta potential, microscopy, and calorimetric studies). To assess the effect of α-TM and TD on the percentage of cellular viability in Olfactory Ensheathing Cells (OECs), a peculiar glial cell type of the olfactory system used as normal cells, and in SH-SY5Y, a neuroblastoma cancer cell line, an MTT test was performed. In addition, the effects of empty, α-TM-SLN, and TD-SLN were tested. Our results show that the treatment of OECs with blank-SLN, free α-TM (0.25 µg/mL), and TD (0.50 µg/mL) did not induce any significant change in the percentage of cell viability when compared with the control. In contrast, in SH-SY5Y-treated cells, a significant decrease in the percentage of cell viability when compared with the control was found. In particular, the effect appeared more evident when SH-SY5Y cells were exposed to α-TM-SLN and TD-SLN. No significant effect in blank-SLN-treated SH-SY5T cells was observed. Therefore, SLN is a promising approach for the delivery of α-TM and TD.

Idebenone loaded solid lipid nanoparticles interact with biomembrane models: calorimetric evidence.

The knowledge of the interactions between solid lipid nanoparticles (SLN) and cell membranes is important to develop effective carrier systems for drug delivery applications. Loading idebenone (IDE), an antioxidant drug useful in the treatment of neurodegenerative diseases, into SLN improves IDE antioxidant activity in in vitro biological studies, but the mechanism by which IDE permeation through the blood-brain barrier (BBB) occurs are still unclear. Therefore, in this research, unloaded and IDE loaded SLN interaction with biomembrane models, consisting of dimyristoylphosphatidylcholine multilamellar vesicles (MLV), were studied by differential scanning calorimetry (DSC). In the experiments performed, unloaded and IDE loaded SLN where incubated with the biomembrane models and their interactions were evaluated through the variations in their calorimetric curves. The results of our DSC studies indicated that the SLN under investigation were able to go inside the phospholipid bilayers with a likely localization in the outer bilayers of the MLV from where they moved toward the inner layers by increasing the contact time between SLN and MLV. Furthermore, IDE loaded SLN were able to release IDE into the biomembrane model, thus facilitating IDE penetration into the bilayers while free IDE showed only a low ability to interact with this model of biomembranes. Our results suggest that these SLN could be regarded as a promising drug delivery system to improve IDE bioavailability and antioxidant activity.

Anticlastogenic effect in human lymphocytes by the sodium salt of 3,4-secoisopimar-4(18),7,15-trien-3-oic acid.

The ability of the sodium salt of 3,4-secoisopimar-4(18),7,15-trien-3-oic acid (1), a diterpenoid obtained from Salvia cinnabarina, to inhibit the genotoxic effect of ethyl methanesulfonate (a clastogenic agent) and colcemid (an aneugenic agent), was studied using a micronucleus assay on cultured human lymphocytes. Cells were treated with 1 before (pretreatment), during (co-treatment), and after (post-treatment) treatment with the mutagens, in order to investigate the type of antimutagenic activity (desmutagenic or bioantimutagenic) manifested. In the range of concentrations tested (0.3-330 µM) 1 reduced significantly the frequency of micronuclei induced by ethyl methanesulfonate, in both pre- and co-treatment protocols (up to 74% and 70% of reduction, respectively), showing an anticlastogenic activity. Conversely, 1 did not inhibit the effect of colcemid in all treatments. The nuclear division index value of lymphocytes was not affected by treatment with 1, thus demonstrating that the anticlastogenic effect of 1 was not due to a cytotoxic effect. On the basis of the results obtained, it can be hypothesized that 1 exerts its anticlastogenic activity against ethyl methanesulfonate by a desmutagenic mechanism, possibly by chemical inactivation of the mutagen.

Effect of Protocatechuic Acid Ethyl Ester on Biomembrane Models: Multilamellar Vesicles and Monolayers.

The interactions of drugs with cell membranes are of primary importance for several processes involved in drugs activity. However, these interactions are very difficult to study due to the complexity of biological membranes. Lipid model membranes have been developed and used to gain insight into drug-membrane interactions. In this study, the interaction of protocatechuic acid ethyl ester, showing radical-scavenging activity, antimicrobial, antitumor and anti-inflammatory effects, with model membranes constituted by multilamellar vesicles and monolayers made of DMPC and DSPC, has been studied. Differential scanning calorimetry and Langmuir-Blodgett techniques have been used. Protocatechuic acid ethyl ester interacted both with MLV and monolayers. However, a stronger interaction of the drug with DMPC-based model membranes has been obtained. The finding of this study could help to understand the protocatechuic acid ethyl ester action mechanism.

Characterization and Interaction with Biomembrane Model of Benzo[k,l]xanthene Lignan Loaded Solid Lipid Nanoparticles.

Benzo[k,l]xanthene lignans are a group of rare natural products belonging to the class of polyphenols with promising biological activities and are studied as potential chemotherapeutic agents. The lipophilic character of a xanthene core makes these molecules difficult to be used in an aqueous medium, limiting their employment in studies for pharmaceutical applications. To overcome this problem, a drug-delivery system which is able to improve the stability and bioavailability of the compound can be used. In this study, a bioactive benzoxanthene lignan (BXL) has been included in SLN. Unloaded and BXL-loaded SLN have been prepared using the Phase Inversion Temperature method and characterized in terms of size, zeta potential, entrapment efficiency and stability. Differential scanning calorimetry was used to evaluate the thermotropic behavior and ability of SLN to act as carriers for BXL. A biomembrane model, represented by multilamellar vesicles, was used to simulate the interaction of the SLN with the cellular membrane. Unloaded and loaded SLN were incubated with the MLV, and their interactions were evaluated through variations in their calorimetric curves. The results obtained suggest that SLN could be used as a delivery system for BXL.

A Thermodynamic Study on the Interaction between RH-23 Peptide and DMPC-Based Biomembrane Models.

Investigation of the interaction between drugs and biomembrane models, as a strategy to study and eventually improve drug/substrate interactions, is a crucial factor in preliminary screening. Synthesized peptides represent a source of potential anticancer and theragnostic drugs. In this study, we investigated the interaction of a novel synthesized peptide, called RH-23, with a simplified dimyristoylphosphatidylcholine (DMPC) model of the cellular membrane. The interaction of RH-23 with DMPC, organized either in multilamellar vesicles (MLVs) and in Langmuir-Blodgett (LB) monolayers, was assessed using thermodynamic techniques, namely differential scanning calorimetry (DSC) and LB. The calorimetric evaluations showed that RH-23 inserted into MLVs, causing a stabilization of the phospholipid gel phase that increased with the molar fraction of RH-23. Interplay with LB monolayers revealed that RH-23 interacted with DMPC molecules. This work represents the first experimental thermodynamic study on the interaction between RH-23 and a simplified model of the lipid membrane, thus providing a basis for further evaluations of the effect of RH-23 on biological membranes and its therapeutic/diagnostic potential.

Interaction of Lipophilic Cytarabine Derivatives with Biomembrane Model at the Air/Water Interface.

Cell membrane models are useful for obtaining molecular-level information on the interaction of biologically active molecules whose activity is believed to depend also on their effects on the membrane. Cytarabine was conjugated with fatty acids to improve the drug lipophilicity and the interaction with the biomembrane model. Cytarabine was conjugated with fatty acids of different lengths to form the trimyristoyl cytarabine and the tristearoyl cytarabine derivatives. Their interaction with biomembrane models constituted by dimyristoylphosphatidylcholine (DMPC) monolayers was studied by employing the Langmuir-Blodgett technique. DMPC/cytarabine, DMPC/trimyristoyl cytarabine and DMPC/tristearoyl cytarabine mixed monolayers at increasing molar fractions of the compound were prepared and placed on the subphase. The mean molecular area/surface pressure isotherms were recorded at 37 °C. Between the molecules of DMPC and those of cytarabine or prodrugs, repulsive forces act. However, these forces are very weak between DMPC and cytarabine and stronger between DMPC and the cytarabine derivatives, thus avoiding the expulsion of the compounds at higher surface pressure and modifying the stability of the mixed monolayer. The fatty acid moieties could then modulate the affinity of cytarabine for biomembranes.