Click synthesis of dendronized malonates for the preparation of amphiphilic dendro[60]fullerenes.

Fullerene C60 and its malonate derivatives, produced via the Bingel-Hirsch reaction, have displayed promising properties against various diseases. These molecules have great therapeutic potential, but their broad use has been limited due to poor aqueous solubility and toxicity caused by accumulation. In this study, we synthesized new malonates and malonamides attached to first- and second-generation polyester dendrons using click chemistry (CuAAC). These dendrons were then linked at C60 through the Bingel-Hirsch reaction, resulting in an amphiphilic system that retains the hydrophobic nature of C60. The dendronized malonate derivatives showed good reaction yields for the Bingel-Hirsch mono-adducts and were easier to work with than the corresponding malonamides. However, the malonamide derivatives, which were obtained through a multistep reaction sequence, showed moderate yields in the Bingel-Hirsch reaction. Surprisingly, removing acetonide protecting groups from dendritic architectures was more challenging than anticipated, likely due to product decomposition. Only the corresponding free malonate derivatives 25 and 26 were obtained, but in a low yield due to decomposition under the reaction conditions. Meanwhile, it was not possible to obtain the corresponding malonamide derivatives 27 and 28. Currently, efforts are being made to improve the production of the desired molecules and to design new synthesis routes that allow direct access to the desired poly-hydroxylated derivatives. These derivatives will be evaluated as multitarget ligands against Alzheimer's disease, through their use as inhibitors of amyloid ß-peptide aggregation, acetylcholinesterase modulators, and antioxidants.

ß-cyclodextrin dendritic derivatives as permeation mediators to enhance the in vitro albendazole cysticidal activity by the improvement of the diffusion component.

The improvement of permeation of drugs across parasites' membranes to promote their diffusion component represents a challenge to achieve better therapeutic effects, including the avoidance of drug resistance. In the context of medicinal chemistry, suitable structural modifications can be made, either on a drug or a nanocarrier, to trigger different mechanisms that promote the influx across membranes. This study aimed to demonstrate the potential of a set of dendritic derivatives of ß-cyclodextrin (m2G, h2G, and m3G) as nanocarriers, based on their physicochemical and biological behavior in terms of (i) stability, monitored by 1H NMR at pH 7 for seven days, (ii) ability to complex, and subsequently release around 50-80% of the cargo molecule (albendazole) in a biphasic medium and (iii) the absence of in vitro cysticidal effect in cysticercus cultures. The albendazole/nanocarrier inclusion complexes (ICs) were proved in the T. crassiceps model. According to the EC50 values related to the cysticidal activity of albendazole, either free or complexed, the potency of this drug in the ICs experienced a significant increase, which may be attributed to the enhancement of its solubility but also to a better permeation mediated by the amphiphilic dendritic moieties, which ultimately positively impacts the diffusion of this drug through the tegument of the cysticerci. Additional considerations akin to synthetic ease of the dendritic nanocarriers, and production cost, along with the obtained outcomes, allowed us to place m2G followed by m3G as the best options to be considered for further in vivo assays.

Exploring In Vitro Biological Cellular Responses of Pegylated ß-Cyclodextrins.

ßCDPEG5 and ßCDPEG2 are two derivatives comprising seven PEG linear chains of 5 and 2 kDa, respectively, conjugated to ßCD. As ßCDPEGs display different physicochemical properties than their precursors, they could also trigger distinct cellular responses. To investigate the biological behavior of ßCDPEGs in comparison to their parent compounds, we performed broad toxicological assays on RAW 264.7 macrophages, MC3T3-E1 osteoblasts, and MDCK cells. By analyzing ROS and NO2- overproduction in macrophages, we found that ßCDPEGs induced a moderate stress response without affecting cell viability. Although MC3T3-E1 osteoblasts were more sensitive than MDCK cells to ßCDPEGs and the parent compounds, a similar pattern was observed: the effect of ßCDPEG5 on cell viability and cell cycle progression was larger than that of ßCDPEG2; PEG2 affected cell viability and cell cycle more than ßCDPEG2; cell post-treatment recovery was favorable in all cases, and the compounds had similar behaviors regarding ROS generation. The effect on MDCK cell migration followed a similar pattern. In contrast, for osteoblasts, the interference of ßCDPEG5 with cell migration was smaller than that of ßCDPEG2; likewise, the effect of PEG2 was shorter than its conjugate. Overall, the covalent conjugation of ßCD and PEGs, particularly to yield ßCDPEG2, improved the biocompatibility profile, evidencing that a favorable biological response can be tuned through a thoughtful combination of materials. Moreover, this is the first time that an in vitro evaluation of ßCD and PEG has been presented for MC3T3-E1 and MDCK cells, thus providing valuable knowledge for designing biocompatible nanomaterials constructed from ßCD and PEGs.

In vitro refolding of the structural protein VP1 of parvovirus B19 produces virus-like particles with functional VP1 unique region.

Virus-like particles (VLPs) from Parvovirus B19 (B19V) can be obtained by the self-assembly of the structural proteins VP1 and VP2. It is possible to produce B19V VLPs either from VP2 or a mixture of VP1 and VP2, through its heterologous expression in eukaryotic cells. The difference between VP1 and VP2 protein is a tract of 227 residues located at the N-terminal region of VP1, known as the VP1 unique region (VP1u). This region is critical for B19V infection, including tropism, cell internalization, and lysosomal scape through its phospholipase 2A activity. Herein, we report the in vitro self-assembly of VP1 to form VLPs. These species have phospholipase activity, suggesting that the phospholipase domain is correctly folded. Furthermore, VP1 and VP2 were co-assembled to produce hybrid VLPs which were able to bind and internalize in the non-permissive HepG2 cells, another evidence of the functionality of the in vitro refolded VP1u.

Click synthesis of novel dendronized curcumin and analogs. Strengthening of physicochemical properties toward biological applications.

Curcumin and its analogs, chalcones, and C5-monocarbonyl are molecules of great therapeutic potential, but their poor stability and hydrophobicity have hampered their extensive use in clinical trials. Therefore, significant efforts have been made in materials science to improve their physicochemical properties. In this study, we propose dendronization as a synthetic strategy to strengthen some physicochemical properties such as solubility and stability of curcumin and analogs, taking advantage of the click chemistry (CuAAC) to attach second-generation polyester dendrons to the unsaturated cores. The dendronization, with the subsequent formation of aromatic triazole groups as linkers, not only modified the solubility and stability of the molecular systems but also favored the diketo tautomeric form of curcumin, as demonstrated spectroscopically. This result is significant since the diketo tautomer, which preserves the antioxidant properties of curcumin, is the most biologically active form. The hydrophobic/hydrophilic balance, achieved after dendronization, allowed the solubilization of the chromophoric molecules in buffered solutions at relevant pH values (7.4 and 6.4). Furthermore, the stability of all molecules was also upgraded since UV-vis absorption spectra did not exhibit modified profiles after 7 days at physiologic pH. From photochemical stability experiments irradiating at 415 nm, the dendritic derivatives containing triazole linkers were more susceptible to being degraded. All derivatives exhibited emission properties according to the length of each conjugate fragment. Fluorescence experiments evidenced the role of dendrons in preventing emission quenching by aggregation and exhibited differentiated emission behavior depending on the linker type (triazole or ester) between the chromophoric core and the polyester dendrons.

Mono-Dendronized ß-Cyclodextrin Derivatives as Multitasking Containers for Curcumin. Impacting Its Solubility, Loading, and Tautomeric Form.

In this study, three mono-dendronized ß-cyclodextrin (ßCD) derivatives (ßCD-1G, ßCD-2G, and ßCD-3G) were used as multitasking containers of curcumin (CUR) to influence its aqueous solubility and tautomerism, both of which are related to its biological activity. We evaluated the relevant physicochemical properties of these containers associated with their potential hosting capacity. All mono-dendronized derivatives exhibited enhanced solubility in different solvents, including water, in comparison with native ßCD. Gas-phase geometry optimizations by density functional theory (DFT) confirmed that none of the dendrons blocked the passage of CUR into the ßCD cavity, and depending on the generation, different preorganization scenarios were promoted before complexation. Phase solubility diagrams showed that all the dendronized containers have superior performance for solubilizing CUR compared to native ßCD. We proved that coprecipitation is most efficient than lyophilization for forming inclusion complexes (ICs) with dendronized containers. Even though ßCD-3G with the largest 3G dendron exhibited the highest CUR loading, the complexation of CUR with ßCD-2G provided the supramolecular system that contains CUR preferentially in its diketo tautomer, which is known for its antioxidant activity.

Dendronization: A practical strategy to improve the performance of molecular systems used in biomedical applications.

Nanomedicine is an emerging area that largely influences the efficacy of various therapies through the rational design of new materials exhibiting more targeted behavior. The synthetic effort, the amount of used material, and the cost are critical parameters to bear in mind if the production of the designed material is intended to be scaled for their widespread use. Even though materials science offers diverse options for different types of therapies, it is a difficult task to meet all the parameters mentioned above. The dendronization appears as an insightful approach to incorporate all the known benefits of the dendritic architecture by the attachment of dendrons to therapeutic agents, but in a much more affordable manner in terms of synthetic effort, amount of material, and cost. As will be presented, the most common dendrons used for biomedical applications are polyamide, polyester, carbosilane, polyether, and glycol-type, which are bonded to biological active molecules (BAMs), or molecular nanoplatforms (MPs) by hydrolysable bonds. Also relevant is the fact that the incorporation of dendrons not larger than third generation (G3) is sufficient to improve essential properties of these molecular systems, such as aqueous solubility, stability, and cellular internalization, among others. The type of dendron and its location on the BAMs or MPs, similar to placing a Lego piece on a model, will be decisive for obtaining the desired properties.

Convergent click synthesis of macromolecular dendritic ß-cyclodextrin derivatives as non-conventional drug carriers: Albendazole as guest model.

From a materials science perspective, herein we present the design and synthesis of six macromolecular carbohydrate derivatives, obtained by combining the native cyclic oligosaccharide ßCD and dendritic poly(ester) moieties, coupled by CuAAc click reactions, in a convergent fashion. We envisioned two structural variables to promote the formation of inclusion complexes (ICs) with the anti-parasitic drug Albendazole, the degree of substitution on the ßCD (mono or hepta-substitution) and the dendritic generation (from first to third). In terms of synthetic effort and cost, the mono-substituted ßCD derivatives were obtained in more approachable experimental conditions in comparison to the ßCD dendrimers (hepta-substituted macrocycle). The six dendritic derivatives were more soluble in water and showed better complexation capacity than native ßCD. For both, mono and hepta-substituted ßCD, we observed that the amount of encapsulated ABZ increases when the dendron generation increases. Interestingly, different degrees of substitution (mono and hepta) lead comparable results of ABZ complexation. In conclusion, the encapsulation performance and the consequent solubility enhancement, make these molecular containers excellent materials to positively impact the therapeutic desirability of ABZ.

PEGylated ß-cyclodextrins: Click synthesis and in vitro biological insights.

We present three easily rationalized star-shaped PEGylated ß-cyclodextrin (ßCD) derivatives synthesized via conjugation of different molecular weight PEG chains (5000, 2000, and 550 Da) to the ßCD primary face by click chemistry (ßCD-PEG5000, ßCD-PEG2000, ßCD-PEG550 respectively). ßCDPEG systems are envisioned to further carry bioactive molecules, therefore, their interactions with biological interfaces must be determined at an early stage of development. Hence, the effect of ßCDPEGs chain length on cell viability was investigated. To this aim, three models were selected: Vero cells for their fibroblast-like features; HeLa cells that are commonly used for preliminary viability screening; and human peripheral monocytes which are macrophage precursors. Of the three pegylated derivatives, ßCD-PEG550 was the one that significantly affected HeLa cells and human monocytes viability. Despite the popularity of PEGylation approach, our results underscore the importance of careful and systematic PEGylated materials design for their future success in drug delivery systems.

Wetland plant species improve performance when inoculated with arbuscular mycorrhizal fungi: a meta-analysis of experimental pot studies.

The presence of arbuscular mycorrhizal fungi (AMF) in wetlands is widespread. Wetlands are transition ecosystems between aquatic and terrestrial systems, where shallow water stands or moves over the land surface. The presence of AMF in wetlands suggests that they are ecologically significant; however, their function is not yet clearly understood. With the aim of determining the overall magnitude and direction of AMF effect on wetland plants associated with them in pot assays, we conducted a meta-analysis of data extracted from 48 published studies. The AMF effect on their wetland hosts was estimated through different plant attributes reported in the studies including nutrient acquisition, photosynthetic activity, biomass production, and saline stress reduction. As the common metric, we calculated the standardized unbiased mean difference (Hedges' d) of wetland plant performance attributes in AMF-inoculated plants versus non-AMF-inoculated plants. Also, we examined a series of moderator variables regarding symbiont identity and experimental procedures that could influence the magnitude and direction of an AMF effect. Response patterns indicate that wetland plants significantly benefit from their association with AMF, even under flooded conditions. The beneficial AMF effect differed in magnitude depending on the plant attribute selected to estimate it in the published studies. The nature of these benefits depends on the identity of the host plant, phosphorus addition, and water availability in the soil where both symbionts develop. Our meta-analysis synthetizes the relationship of AMF with wetland plants in pot assays and suggests that AMF may be of comparable importance to wetland plants as to terrestrial plants.

Synthesis of a poly(ester) dendritic ß-cyclodextrin derivative by "click" chemistry: Combining the best of two worlds for complexation enhancement.

In spite of the progress in the cyclodextrins chemistry, the synthesis of monodisperse derivatives with a defined degree of substitution is still a challenge. In this work we present a novel dendritic material produced by combining ßCD and second generation poly(ester) dendrons. The selective attachment of dendrons in the seven positions of the ßCD-primary face was performed through a CuAAC click reaction, which along with a very simple work-up, allowed obtaining the monodisperse material in very high yields. The product showed a great aqueous solubility and an in vitro non-toxic profile. The enhanced complexation potential of the product was evidenced through the formation of an inclusion complex with albendazole, which presented a Kc = 29636.17 M-1. In this system, albendazole was 45 times more water-soluble in comparison to the complex albendazole-native ßCD. All these features make the dendritic material very attractive for further applications in the formulation and drug delivery fields.

A two-step synthetic strategy to obtain a water-soluble derivative of curcumin with improved antioxidant capacity and in vitro cytotoxicity in C6 glioma cells.

A novel water-soluble derivative of curcumin (Cur-[G-2]-OH) was designed and synthesized from accessible raw materials in only two steps with an overall yield of 80%. The modification of curcumin phenol groups with second-generation polyester dendrons (dendronization) as a strategy to achieve an optimal hydrophilic/hydrophobic balance allows the complete water solubilization of the new curcumin derivative (5mg/ml) at room temperature. The therapeutic potential of Cur-[G-2]-OH was investigated in terms of antioxidant capacity, intracellular uptake and cytotoxicity in both rat glioblastoma cells and normal human dermal fibroblasts. Although the phenolic groups of curcumin were locked by dendronization, Cur-[G-2]-OH exhibited antioxidant capacity in water that was even higher than curcumin in dimethylsulfoxide (DMSO). This compound showed a steady cellular uptake contrasted with curcumin, which has a saturation capture at high concentrations. Combined with improved stability, this property seems to allow the intracellular accumulation of Cur-[G-2]-OH. Furthermore, the new compound exhibited increased cytotoxicity in rat C6 glioma cells in a time- and concentration-dependent manner, whereas in normal human fibroblasts, its IC50 value was >600µM versus the IC50 of curcumin found between 100 and 200µM. Surprisingly, Cur-[G-2]-OH drives cell death of C6 cells by a different mechanism of apoptosis triggered by curcumin. Together, these results suggest that curcumin dendronization could promote molecular and cellular mechanisms that are different from those induced by curcumin, presumably due to structural factors and not only for improved water solubility.

DFT study of zinc, cadmium, mercury, copper, silver, and gold complexes of 21,23-dioxaporphyrin and one-dimensional arrays of those complexes.

Complexes of 21,23-dioxaporphyrin with neutral Zn, Cd, Hg, Cu, Ag, and Au atoms as well as some one-dimensional arrays of those complexes containing up to ten repeat units were modeled at the PBE/def2-TZVPP level of theory with D3 empirical dispersion correction. The binding energy between the metal atom and the macrocycle was found to vary from 90 kcal/mol for Cu to -14 kcal/mol for Hg. Strong charge transfer from the metal to the macrocycle accompanied complex formation. The complexes were able to form dimers and nanoarrays that were held together mostly by dispersion forces. Different types of dimers were studied: face-to-face (F) and two types of parallel-displaced ones. F dimers were calculated to be the lowest-energy structures for Cu and Ag systems. Nanoarray formation was studied for these complexes. The band gaps (Eg) of the nanoarrays were found to be smaller than 1 eV, and decreased slightly as the number of repeat units in the nanoaggregates increased. The ionization potentials and electron affinities were greatly affected by the number of repeat units due to the delocalization of polarons over the entire nanoarray. The polaron delocalization and the related reorganization energies depended to a considerable extent on the metal present in the complex. For the studied nanoarrays, the reorganization energies for hole and electron transport decreased linearly with 1/n, where n is the number of repeat units in the nanoaggregate; for an infinitely long chain, the reorganization energy was zero for electron transport and 0.03-0.04 eV for hole transport.

Multiconfigurational character of the ground states of polycyclic aromatic hydrocarbons. A systematic study.

A systematic study of the electronic structure of polycyclic hydrocarbons from naphthalene to a system containing 80 fused benzene has been carried out. Geometries were optimized for closed shell singlet, open shell singlet, triplet and multiplet states at B3LYP/cc-pVDZ level of theory, D1 (second order Møller-Plesset) and D1 (second-order approximate coupled-cluster) diagnostics have been calculated for studied molecules. Complete active space self-consistent field (10,10)/6-31G(d) single point energy calculations have been carried out for all optimized structures. Multireference character of the ground state becomes important when the number of atoms in the polycyclic hydrocarbon exceeds 40-50. At this point, D1 diagnostics reaches 0.04-0.05 and the squared configuration interaction expansion coefficient for dominant configuration drops to about 0.6. However, only for the three largest systems predominantly polyradicalic ground states have been detected. All other polycyclic hydrocarbons showing significant multiconfigurational character of singlet ground state have only two dominant configurations which are closed shell singlet and doubly excited singlet, respectively. Thus, small polycyclic hydrocarbons have mostly single reference singlet ground state, the medium size systems have notably multireference ground state (singlet or triplet) with only moderate polyradicalic character. The ground state of largest systems is singlet polyradical.

Impact of weed control on arbuscular mycorrhizal fungi in a tropical agroecosystem: a long-term experiment.

Cover crop species represent an affordable and effective weed control method in agroecosystems; nonetheless, the effect of its use on arbuscular mycorrhizal fungi (AMF) has been scantily studied. The goal of this study was to determine root colonization levels and AMF species richness in the rhizosphere of maize plants and weed species growing under different cover crop and weed control regimes in a long-term experiment. The treatment levels used were (1) cover of Mucuna deeringian (Muc), (2) "mulch" of Leucaena leucocephala (Leu), (3) "mulch" of Lysiloma latisiliquum (Lys), (4) herbicide (Her), (5) manual weeding (CD), (6) no weeding (SD), and (7) no maize and no weeding (B). A total of 18 species of AMF belonging to eight genera (Acaulospora, Ambispora, Claroideoglomus, Funneliformis, Glomus, Rhizophagus, Sclerocystis, and Scutellospora) were identified from trap cultures. Muc and Lys treatments had a positive impact on AMF species richness (11 and seven species, respectively), while Leu and B treatments on the other hand gave the lowest richness values (six species each). AMF colonization levels in roots of maize and weeds differed significantly between treatment levels. Overall, the use of cover crop species had a positive impact on AMF species richness as well as on the percentage of root colonized by AMF. These findings have important implications for the management of traditional agroecosystems and show that the use of cover crop species for weed control can result in a more diverse AMF community which should potentially increase crop production in the long run.

"Russian doll" complexes of [n]cycloparaphenylenes: a theoretical study.

The formation of "Russian doll" complexes consisting of [n]cycloparaphenylenes was predicted using quantum chemistry tools. The electronic structures of multiple inclusion complexes containing up to four macrocycles were explored at the M06-2X/6-31G* level of theory. The binding energy between the macrocycles increases from the center to the periphery of the complex and can be >60 kcal mol(-1) for macrocycles containing 14 and 19 repeating units. It has been demonstrated that additional electrostatic interactions originating from the asymmetric electron density distribution observed when comparing the concave and convex macrocycle sides are responsible for the high binding energies in these Russian doll complexes. Oxidation or reduction of the Russian doll complexes creates polarons that are delocalized across the complexes. In the case of polaron cations, most of the polarons are localized at the macrocycle with the smallest ionization potential; for polaron anions, the negative charge is localized across the outer rings of the complex. Because anion polarons are more delocalized than cation polarons, the relaxation energies of the polaron anions were found to be smaller than those of the polaron cations.

Solubilization and anticancer-activity enhancement of Methotrexate by novel dendrimeric nanodevices synthesized in one-step reaction.

The one-step synthesis of nanodevices based on PAMAM framework for targeted cancer therapy is described. Four water-soluble nanodevices (named fractions F1 to F4) were rightly separated by size discrimination, and characterized. From biological assays of cell growth inhibition percentage, the anticancer activity of Methotrexate (chemotherapeutic drug) as part of a nanodevice, generally increases over cancer cell lines and notably, in case of human lymphocytes, the cell growth inhibition percentage decreases drastically (more than 80%), thus, the nanodevices exhibited a favorable discrimination between healthy and diseased cells. From the characterization it can be conclude that the synthesized nanodevices provide a dual scenario of drug transportation: encapsulation and conjugation.

Geometric distortions on a three-coordinated T1 Cu site model as a potential strategy to modulate redox potential. A theoretical study.

A model of the three-coordinated T1 Cu site from Trametes versicolor was considered to evaluate the effect on redox potential of geometrical distortions in the copper coordination sphere. Systematic modifications of geometrical parameters (distances and angles) of the coordination sphere of the T1 Cu site were carried out within a density functional theory (DFT) framework, to evaluate their effects on electron affinity directly related to redox potential. The most promising result in terms of redox potential increment was distortion of the dihedral angle C(methylthiolate)-S-Cu-N(ImA) (ω), which can be rationalized as a decrease in the overlap of imidazole orbitals in the redox-active molecular orbital (ß-LUMO). This overlap is minimized when ω achieves the value of 10°, therefore, this conformation might have the highest redox potential. From the molecular orbital viewpoint, a parallelism was found between the effect caused by the presence of a fourth ligand and the distorted three-coordination, which could be extrapolated to spectroscopic properties. It was also found that solvation effects on the redox potentials during geometrical distortions produce a very similar tendency, independently of the polarity of the solvent.

Arbuscular mycorrhizal propagules in soils from a tropical forest and an abandoned cornfield in Quintana Roo, Mexico: visual comparison of most-probable-number estimates.

The present study was aimed at comparing the number of arbuscular mycorrhizal fungi (AMF) propagules found in soil from a mature tropical forest and that found in an abandoned cornfield in Noh-Bec Quintana Roo, Mexico, during three seasons. Agricultural practices can dramatically reduce the availability and viability of AMF propagules, and in this way delay the regeneration of tropical forests in abandoned agricultural areas. In addition, rainfall seasonality, which characterizes deciduous tropical forests, may strongly influence AMF propagules density. To compare AMF propagule numbers between sites and seasons (summer rainy, winter rainy and dry season), a "most probable number" (MPN) bioassay was conducted under greenhouse conditions employing Sorgum vulgare L. as host plant. Results showed an average value of 3.5 ± 0.41 propagules in 50 ml of soil for the mature forest while the abandoned cornfield had 15.4 ± 5.03 propagules in 50 ml of soil. Likelihood analysis showed no statistical differences in MPN of propagules between seasons within each site, or between sites, except for the summer rainy season for which soil from the abandoned cornfield had eight times as many propagules compared to soil from the mature forest site for this season. Propagules of arbuscular mycorrhizal fungi remained viable throughout the sampling seasons at both sites. Abandoned areas resulting from traditional slash and burn agriculture practices involving maize did not show a lower number of AMF propagules, which should allow the establishment of mycotrophic plants thus maintaining the AMF inoculum potential in these soils.

Synthesis of non-cytotoxic poly(ester-amine) dendrimers as potential solubility enhancers for drugs: methotrexate as a case study.

This study describes the synthesis of two new families of dendrimers based on the esterification of N-alkylated 3-amine-1-propanol with two different cores, adipic acid (1st and 2nd generations) and ethylenediamine (generation 1.5), both with carboxylic acid end groups, offering a wide variety of further modifications at the periphery. According to the cytotoxic evaluation of the dendrimers and their possible degradation products within cell lines, these materials could be considered as innocuous. In preliminary studies, the synthesized dendrimers proved to be potential enhancers of solubility of highly hydrophobic drugs, like methotrexate, widely used in chemotherapy.