Machine Learning-Based Prediction of Reduction Potentials for PtIV Complexes.

Some of the well-known drawbacks of clinically approved PtII complexes can be overcome using six-coordinate PtIV complexes as inert prodrugs, which release the corresponding four-coordinate active PtII species upon reduction by cellular reducing agents. Therefore, the key factor of PtIV prodrug mechanism of action is their tendency to be reduced which, when the involved mechanism is of outer-sphere type, is measured by the value of the reduction potential. Machine learning (ML) models can be used to effectively capture intricate relationships within PtIV complex data, leading to highly accurate predictions of reduction potentials and other properties, and offering significant insights into their electrochemical behavior and potential applications. In this study, a machine learning-based approach for predicting the reduction potentials of PtIV complexes based on relevant molecular descriptors is presented. Leveraging a data set of experimentally determined reduction potentials and a diverse range of molecular descriptors, the proposed model demonstrates remarkable predictive accuracy (MSE = 0.016 V2, RMSE = 0.13 V, R2 = 0.92). Ab initio calculations and a set of different machine learning algorithms and feature engineering techniques have been employed to systematically explore the relationship between molecular structure and similarity and reduction potential. Specifically, it has been investigated whether the reduction potential of these compounds can be described by combining ML models across different combinations of constitutional, topological, and electronic molecular descriptors. Our results not only provide insights into the crucial factors influencing reduction potentials but also offer a rapid and effective tool for the rational design of PtIV complexes with tailored electrochemical properties for pharmaceutical applications. This approach has the potential to significantly expedite the development and screening of novel PtIV prodrug candidates. The analysis of principal components and key features extracted from the model highlights the significance of structural descriptors of the 2D Atom Pairs type and the lowest unoccupied molecular orbital energy. Specifically, with just 20 appropriately selected descriptors, a notable separation of complexes based on their reduction potential value is achieved.

DNA-based nanoscaffolds as vehicles for 5-fluoro-2'-deoxyuridine oligomers in colorectal cancer therapy.

Fluoropyrimidines, such as 5-fluorouracil (5-FU) and related prodrugs, are considered one of the most successful agents in the treatment of colorectal cancer, yet poor specificity and tumor cell resistance remain the major limiting bottlenecks. Here, we exploited for the first time the ability of two DNA nanoscaffolds, a DNA tetrahedron (Td) and rectangle DNA origami, to incorporate 5-fluoro-2'-deoxyuridine (FdUn) oligomers. In addition, cholesterol moieties were synthetically attached to Td and DNA origami staples to enhance cellular uptake. DNA nanostructures functionalized with FdUn exhibited an enhanced cytotoxicity and higher ability to trigger apoptosis in colorectal cancer cells relative to conventional 5-FU and FdU, especially having cholesterol as an internalization helper. The cholesterol content mostly correlates with the increase of the FdUn nanostructure cytotoxicity. DNA nanoscaffolds bearing FdUn were able to circumvent the low sensitivity of colorectal cancer cells towards 5-FU. Both DNA nanostructures attained a comparable cytotoxic effect yet Td displays higher antiproliferative action. The ability to reduce the proliferation of cancer cells is mainly related to the concentration of DNA nanostructures. The present work suggests that self-assembled DNA nanoparticles are privileged vehicles for delivering fluoropyrimidines, opening new avenues to the development of promising therapeutics for cancer treatment.

Fluorescence Enhancement of a Cationic Fluorene-Phenylene Conjugated Polyelectrolyte Induced by Nonionic n-Alkyl Polyoxyethylene Surfactants.

The modulation of conjugated polyelectrolyte fluorescence response by nonionic surfactants is dependent on the structures of the surfactant and polymer, polymer average molecular weight, and polyelectrolyte-surfactant interactions. In this paper, we study the effect of nonionic n-alkyl polyoxyethylene surfactants (CiEj) with different alkyl chain lengths (CiE5 with i = 6, 8, 10, and 12) and number of oxyethylene groups (C12Ej with j = 5, 7, and 9) on the photophysics and ionic conductivity of poly{[9,9-bis(6'-N,N,N-trimethylammonium)-hexyl]-2,7-fluorene-alt-1,4-phenylene}bromide (HTMA-PFP) in dimethyl sulfoxide-water 4% (v/v). Molecular dynamics simulations show that HTMA-PFP chains tend to approach as the simulation evolves. However, the minimum distance between the polymer centers of mass increases upon addition of the surfactant and grows with both the surfactant alkyl chain length and the number of oxyethylene groups, although there are no specific polymer-surfactant interactions. A significant increase in the polymer emission intensity has been observed at surfactant concentrations around their critical micelle concentrations (cmcs), which is attributed to polymer aggregate disruption. However, an increase in the solution conductivity for concentrations above the C12E5 cmc has only been observed for the HTMA-PFP/C12E5 system. The enhancement of fluorescence emission intensity and conductivity upon surfactant addition increases with polymer average molecular weights and seems to be controlled by the polymer-surfactant proximity, which is maximum for C10E5 and C12E5.

Expanding Transdermal Delivery with Lipid Nanoparticles: A New Drug-in-NLC-in-Adhesive Design.

A monolithic drug-in-NLC-in-adhesive transdermal patch, with a novel design, was developed for codelivery of olanzapine (OL) and simvastatin (SV). Nanostructured lipid carriers (NLC) and enhancers were used as passive strategies, while the pretreatment of the skin with Dermaroller was tested as an active approach. The formulation was optimized for composition in a quality by design basis, in terms of enhancer and adhesive, with focus on permeation behavior, adhesion properties, and cytotoxicity. Propylene glycol promoted the best permeation rate for both drugs, with enhancement ratios of 8.1 and 12.9 for OL and SV, respectively, relative to the corresponding Combo-NLC patch without enhancer. Molecular dynamics results provided a rationale for these observations. The adhesive type displayed an important role in skin permeation, reinforced by the presence of the enhancer. Finally, Dermaroller pretreatment did not promote a significant improvement in permeation, which highlights the role of the combination of NLC with chemical enhancer in the transdermal patch as the main driving force in the process. It is also observed that NLC are able to reduce cytotoxicity, especially that associated with SV. This work provides a promising in vitro-in silico basis for a future in vivo development.

Can lipid nanoparticles improve intestinal absorption?

Lipid nanoparticles and their multiple designs have been considered appealing nanocarrier systems. Bringing the benefits of these nanosystems together with conventional coating technology clearly results in product differentiation. This work aimed at developing an innovative solid dosage form for oral administration based on tableting nanostructured lipid carriers (NLC), coated with conventional polymer agents. NLC dispersions co-encapsulating olanzapine and simvastatin (Combo-NLC) were produced by high pressure homogenization, and evaluated in terms of scalability, drying procedure, tableting and performance from in vitro release, cytotoxicity and intestinal permeability stand points. Factorial design indicated that the scaling-up of the NLC production is clearly feasible. Spray-drying was the method selected to obtain dry particles, not only because it consists of a single step procedure, but also because it facilitates the coating process of NLC with different polymers. Modified NLC formulations with the polymers allowed obtaining distinct release mechanisms, comprising immediate, delayed and prolonged release. Sureteric:Combo-NLC provided a low cytotoxicity profile, along with a ca. 12-fold OL/3-fold SV higher intestinal permeability, compared to those obtained with commercial tablets. Such findings can be ascribed to drug protection and control over release promoted by NLC, supporting them as a versatile platform able to be modified according to the intended needs.

Starch-based Pickering emulsions for topical drug delivery: A QbD approach.

Pickering emulsions are stabilized by solid particles instead of surfactants and have been widely investigated in pharmaceutical and cosmetic fields since they present less adverse effects than the classical emulsions. A quality by design (QbD) approach was applied to the production of w/o emulsions stabilized by starch. A screening design was conducted to identify the critical variables of the formula and the process affecting the critical quality properties of the emulsion (droplet size distribution). The optimization was made by establishing the Design Space, adjusting the concentration of starch and the quantity of the internal aqueous phase. The emulsion production process was, in turn, adjusted by varying the time and speed of stirring, to ensure quality and minimum variability. The stability was also investigated, demonstrating that an increase in starch concentration improves the stability of the emulsion. Rheological and mechanical studies indicated that the viscosity of the emulsions was enhanced by the addition of starch and, to a higher extent, by the presence of different lipids. The developed formulations was considered non-irritant, by an in vitro assay using human cells from skin (Df and HaCat) with the cell viability higher than 90% and, with self-preserving properties. Finally, the QbD approach successfully built quality in Pickering emulsions, allowing the development of hydrophilic drug-loaded emulsions stabilized by starch with desired organoleptic and structural characteristics. The results obtained suggest that these systems are a promising vehicle to be used in products for topical administration.

Skin cancer and new treatment perspectives: a review.

Skin cancers are by far the most common malignancy of humans, particularly in the white population. The growing incidence of cutaneous malignancies has heralded the need for multiple treatment options. Although surgical modalities remain the mainstay of treatment, new research and fresh innovation are still required to reduce morbidity and mortality. Approaches for skin cancer may pass through new technological methods instead of new molecules. The first part of this paper provides a review of the state of the art regarding skin cancer disease as well as epidemiology data. Then, it describes the gold standards of the current recommended therapies worldwide and the actual needs of these patients. This is the first paper that highlights the novel and future therapeutic perspectives for the treatment of skin malignancies, new therapeutic agents and promising technological approaches, from nanotechnology to immunotherapy.

From molecular modelling to photophysics of neutral oligo- and polyfluorenes incorporated into phospholipid bilayers.

The combination of various experimental techniques with theoretical simulations has allowed elucidation of the mode of incorporation of fluorene based derivatives into phospholipid bilayers. Molecular dynamics (MD) simulations on a fully hydrated 1,2-dimyristoyl-sn-glycero-3-phosphatidylcholine (DMPC) bilayer, with benzene (B), biphenyl (BP), fluorene (F) and tri-(9,9-di-n-octylfluorenyl-2,7-diyl), TF, have provided insights into the topography of these molecules when they are present in the phospholipid bilayer, and suggest marked differences between the behavior of the small molecules and the oligomer. Further information on the interaction of neutral fluorenes within the phospholipid bilayer was obtained by an infrared (IR) spectroscopic study of films of DMPC and of the phospholipid with PFO deuterated specifically on its alkyl chains (DMPC-PFO-d34). This was complemented by measurements of the effect of F, TF and two neutral polymers: polyfluorene poly(9,9-di-n-octylfluorenyl-2,7-diyl), PFO, and poly(9,9-di-n-dodecylfluorenyl-2,7-diyl), PFD, on the phospholipid phase transition temperature using differential scanning calorimetry (DSC). Changes in liposome size upon addition of F and PFO were followed by dynamic light scattering. In addition, the spectroscopic properties of F, TF, PFO and PFD solubilised in DMPC liposomes (absorption, steady-state and time-resolved fluorescence) were compared with those of the same probes in typical organic solvents (chloroform, cyclohexane and ethanol). Combining the insight from MD simulations with the results at the molecular level from the various experimental techniques suggests that while the small molecules have a tendency to be located in the phospholipid head group region, the polymers are incorporated within the lipid bilayers, with the backbone predominantly orthogonal to the phospholipid alkyl chains and with interdigitation of them and the PFO alkyl chains.

A new perspective on correlated polyelectrolyte adsorption: positioning, conformation, and patterns.

This work focuses on multiple chain deposition, using a coarse-grained model. The phenomenon is assessed from a novel perspective which emphasizes the conformation and relative arrangement of the deposited chains. Variations in chain number and length are considered, and the surface charge in the different systems ranges from partially neutralized to reversed by backbone deposition. New tools are proposed for the analysis of these systems, in which focus is given to configuration-wise approaches that allow the interpretation of correlated multi-chain behavior. It is seen that adsorption occurs, with a minimal effect upon the bulk conformation, even when overcharging occurs. Also, chain ends create a lower electrostatic potential, which makes them both the least adsorbed region of the backbone, and the prevalent site of closer proximity with other chains. Additionally, adsorption into the most favorable region of the surface overrides, to a large degree, interchain repulsion.

Pseudomonas aeruginosa infection in cystic fibrosis lung disease and new perspectives of treatment: a review.

Cystic fibrosis (CF) is a complex inherited disease which affects many organs, including the pancreas and liver, gastrointestinal tract and reproductive system, sweat glands and, particularly, the respiratory system. Pseudomonas aeruginosa is the main cause of chronic airway infection. In order to reduce morbidity and mortality due to lung infection by P. aeruginosa, aerosol antibiotics have been used to achieve high local concentrations in the airways and to reduce systemic toxicity. In the course of this review, the current treatments to control CF lung infections by P. aeruginosa are presented. Some innovative aerosol formulations such as liposomes and microspheres are herein reviewed, which may improve the efficiency of anti-pseudomonal agents, and ensure patients' compliance to treatments, by reducing dosing frequency and/or drug dose, while maintaining therapeutic efficacy, preventing the occurrence of bacterial resistance and/or reducing adverse effects due to their controlled-release properties.

Co-encapsulating nanostructured lipid carriers for transdermal application: from experimental design to the molecular detail.

Co-encapsulation of drugs directed at commonly associated diseases provides a convenient means for administration, especially if transdermally delivered. In this work, a comprehensive study for the co-encapsulation of drugs with a differential lipophilicity, olanzapine and simvastatin, and their transdermal delivery in a formulation containing nanostructured lipid carriers (NLC) is presented. Focus is given to the evaluation of a strategy in which NLC and chemical permeation enhancers are combined. It comprises in vitro, in silico and cellular viability approaches. The optimization and rationalization of the systems are carried out using a two-step factorial design. It is shown that the external medium in the NLC dispersion strongly influences permeation. It is also seen that the use of NLC determines a synergistic effect with selected permeation enhancers, thus promoting marked flux enhancement ratios (48 and 21, respectively for olanzapine and simvastatin) relative to the drugs in solution. The developed formulations can be considered non-irritant. A correlation between enhancer positioning in a lipid bilayer, partially governed by a H-bonding phenomenon, and enhancement effect is suggested from molecular dynamics studies and experimental observations.

Nonrandom adsorption of polyelectrolyte chains on finite regularly charged surfaces.

Adsorption phenomena are relevant in a wide variety of subjects, from biophysics to technological applications. Different aspects, such as molecular recognition, multilayer deposition, and dynamics of polymer adsorption have been addressed. The methodologies used range from analytical and numerical methods to molecular dynamics or Monte Carlo simulations. In this work, a coarse-grained model is used to explore the adsorption of charged backbones to oppositely charged regions of a surface. These regions encompass those small enough to prevent complete adsorption, but extend to surfaces sufficiently large to promote adsorption with minimal effect on the three-dimensional conformation in bulk. Apart from the different surface areas explored, variations on the surface charge density, polyelectrolyte chain length, and chain stiffness were also considered. The degree of compaction of the polyelectrolyte, on adsorption, is different from that found in the bulk. Also, results indicate an nonuniform adsorption pattern on regularly charged surfaces.

On the use of big-bang method to generate low-energy structures of atomic clusters modeled with pair potentials of different ranges.

The efficiency of the so-called big-bang method for the optimization of atomic clusters is analysed in detail for Morse pair potentials with different ranges; here, we have used Morse potentials with four different ranges, from long- ρ = 3) to short-ranged ρ = 14) interactions. Specifically, we study the efficacy of the method in discovering low-energy structures, including the putative global minimum, as a function of the potential range and the cluster size. A new global minimum structure for long-ranged ρ = 3) Morse potential at the cluster size of n= 240 is reported. The present results are useful to assess the maximum cluster size for each type of interaction where the global minimum can be discovered with a limited number of big-bang trials.

Stepwise disproportionation in polyelectrolyte complexes.

Structural properties and the topology of polyelectrolyte complexes (PECs) formed in solution have been investigated under different conditions by Monte Carlo simulations using a coarse-grained model. The extension of individual polyions has been characterized by their radius of gyration, whereas the composition of the complexes has been investigated by their net charge and their internal topological structure by a novel analysis describing how the shorter polycations link to monomers of the longer polyanion. Conditions have been found at which the polyanion and a given number of polycations form distinguishable complexes differing in (i) the polyanion conformation and (ii) the fraction of polycations being in extended and collapsed states. Thus, at equilibrium, these PECs display a stepwise variation of the degree of intrachain disproportionation within the polyanion (also referred to as intrachain segregation), concomitant with the interchain disproportionation of the polycations, which is in agreement with previous theoretical predictions. The coexistence of the different polyelectrolyte complex structures appears, generally, at mixing ratios close to but different from charge equivalence and, as a consequence, broad polyelectrolyte size distributions are commonly obtained.

Polyelectrolyte condensation in bulk, at surfaces, and under confinement.

In this review we discuss recent results from computer simulations based on coarse-grained polyion models representing aqueous solutions of polyelectrolytes. The focus will be directed to the conformation of the polyions and, in particular, their condensation in bulk, induced by multivalent ions and oppositely charged polyelectrolytes, at responsive surfaces and under confinement.

Generation and characterization of low-energy structures in atomic clusters.

Factors relevant for controlling the structures determined in the local optimization of argon clusters are investigated. In particular, the role of volume and shape for the box where initial structures are generated is assessed. A thorough characterization of the optimization is also presented, based on a nearest-neighbor analysis, in clusters ranging from 30 to 55 atoms. This includes the assessment of the degree of preservation of aspects of the initial randomly generated structure in the final optimized counterpart, and the correlation between optimized energy and the number of nearest neighbors and average departure from the diatomic reference distance. The usefulness of this analysis to explore the energy landscape of atomic clusters is also highlighted.

Polyelectrolyte compaction by pH-responsive agents.

Compaction of negatively charged polyanions by polycations with different characteristics is investigated using Monte Carlo simulation in a coarse-grain model. Two different routes are tested and the results compared. In one, the polycation/polyanion charge ratio is varied by increasing the amount of polycations, keeping all the chain characteristics constant. In the other, the linear charge density of the polycations is altered but their number is kept constant. The set of systems in which the linear charge density changes is used as a model for a system comprising chains with different degrees of ionization under different pH conditions. In both cases, polycation/polyanion charge ratios ranging from 0.25 to 1.25 are addressed. The system with unitary charge ratio is common to both routes. It is seen that, although the overall trends followed by the two sets of systems are similar, marked differences can be discerned both for low charge ratios, and for the higher ones, where the systems are overcharged. Coexistence regimes are clearly detected in some of the systems. The results obtained computationally can be used to guide practical applications.

Structure of microemulsion-ABA triblock copolymer networks.

Structural equilibrium properties of transient networks formed by microemulsion droplets and ABA triblock copolymers in solution have been studied by Monte Carlo simulation. The droplets were represented by soft spheres, and the polymers were represented by junctions connected by harmonic bonds with an angular potential regulating the intrinsic chain stiffness. The interaction parameters were selected such that the end A-blocks were localized inside the droplets and the middle B-block in the continuous phase. The influence of (i) the polymer concentration, (ii) the polymer stiffness, and (iii) the contour length of the middle B-block on the formation and the structure of the microemulsion-polymer network were investigated using polymer end-to-end separation probability distribution functions, droplet radial distribution functions, droplet-droplet nearest-neighbor probability distribution functions, and network connectivity indicators. An increase of the polymer-droplet number ratio had a strong impact on the network formation. Under typical conditions and at an intermediate polymer-droplet number ratio, (i) the fraction of polymers forming bridges between droplets increased from essentially zero to unity and (ii) the fraction of polymers that were forming loops decreased as the ratio of the polymer end-to-end separation and the surface-to-surface separation between neighboring droplets for a hypothetical homogeneous droplet distribution was increased from 0.5 to 2. For long and flexible polymers, a mesoscopic segregation triggered by a depletion attraction between droplets appeared, and, furthermore, for sufficiently stiff chains, only bridge conformations occurred. The percolation probability could be represented as a function of the average droplet cluster size only, across all systems.

Stratum corneum hydration: phase transformations and mobility in stratum corneum, extracted lipids and isolated corneocytes.

The outermost layer of skin, stratum corneum (SC), functions as the major barrier to diffusion. SC has the architecture of dead keratin filled cells embedded in a lipid matrix. This work presents a detailed study of the hydration process in extracted SC lipids, isolated corneocytes and intact SC. Using isothermal sorption microcalorimetry and relaxation and wideline (1)H NMR, we study these systems at varying degrees of hydration/relative humidities (RH) at 25 degrees C. The basic findings are (i) there is a substantial swelling both of SC lipids, the corneocytes and the intact SC at high RH. At low RHs corneocytes take up more water than SC lipids do, while at high RHs swelling of SC lipids is more pronounced than that of corneocytes. (ii) Lipids in a fluid state are present in both extracted SC lipids and in the intact SC. (iii) The fraction of fluid lipids is lower at 1.4% water content than at 15% but remains virtually constant as the water content is further increased. (iv) Three exothermic phase transitions are detected in the SC lipids at RH=91-94%, and we speculate that the lipid re-organization is responsible for the hydration-induced variations in SC permeability. (v) The hydration causes swelling in the corneocytes, while it does not affect the mobility of solid components (keratin filaments).

Interaction of omeprazole with a methylated derivative of beta-cyclodextrin: phase solubility, NMR spectroscopy and molecular simulation.

PURPOSE: Cyclodextrins are known to be good solubility enhancers for several drugs, improving bioavailability when incorporated in pharmaceutical formulations. In this work we intend to assess and characterize the formation of inclusion complexes between omeprazole (OME) and a methylated derivative of beta-cyclodextrin, methyl-beta-cyclodextrin (MbetaCD). A comparison with results obtained from the most commonly used natural cyclodextrin, beta-cyclodextrin (betaCD) is also presented in most cases. MATERIALS AND METHODS: The interaction of OME with the mentioned cyclodextrins in aqueous solutions was studied by phase solubility studies, 1D (1)H and 2D rotating frame nuclear overhauser effect NMR spectroscopy (ROESY) and Molecular Dynamics. RESULTS: The solubility of OME was significantly increased by formation of inclusion complexes with each cyclodextrin. Phase solubility studies and continuous variation plots revealed that OME forms an inclusion complex in a stoichiometry of 1:1 with both cyclodextrins. (1)H NMR and ROESY spectra of the inclusion complexes indicated that the benzimidazole moiety is included within the cyclodextrins cavities. Molecular dynamics showed that OME is more deeply included in the MbetaCD than in betaCD cavity, in agreement with a larger apparent stability constant (K (S)) obtained for the inclusion complex with MbetaCD. CONCLUSIONS: MbetaCD proved to be an efficient enhancer of OME solubility, thus possessing characteristics for being an useful excipient in pharmaceutical formulations of this drug.