Ceftriaxone (CTX) a third-generation cephalosporin, is a broad-spectrum antibiotic that can be used by intramuscular or intravenous routes to treat various types of infection. However, CTX has poor cellular penetration and poor diffusion due to its high molecular weight and high hydrophilicity. To address these problems, we propose an innovative nanotherapy based on the encapsulation of CTX in a nanostructured lipid carrier. Usually, several attempts must be done, on a trial-and-error basis, until a formulation that guarantees high drug encapsulation and suitable physicochemical properties is found. Machine Learning (ML) has recently stirred great interest as a tool to model and predict the nanoparticles biological activity. Herein, for the first time, the use of ML for the optimization of a nanoformulation is explored. Several variables were optimized simultaneously, namely the amount of solid lipid, the percentage of liquid lipid, the surfactant solution, the water volume, the sonication amplitude, and the sonication time. To define the best nanoformulation, three different outcomes were considered: encapsulation efficiency of CTX, size of the nanoparticles and their zeta potential. Our ML approach was able to find, with a low number of experiments, the conditions that provided formulations with the highest encapsulation efficiency of CTX and nanoparticles with suitable size and adequate zeta potential. Besides the impressive acceleration of the optimization process that was achieved, the optimization guided by our ML model also provided insights over the optimization of other nanoformulations.

Melanoma is one of the most dangerous skin cancers, with a high mortality rate and an incidence that has increased radically in the past few years. This has led to a huge demand for new more effective forms of treatment. Nanoemulsions have been investigated as potential drug delivery vehicles to target cancer cells, since they are a promising alternative to increase the solubility and skin permeation and retention of hydrophobic drugs.

The purpose of this work was to incorporate miconazole, a hydrophobic antifungal drug with potential anticancer activity, in an oil-in-water (O/W) nanoemulsion for topical administration for the treatment of melanoma. Seventeen O/W nanoemulsions were prepared by spontaneous emulsification. The preconcentrate was constituted by Plurol® Diisostearique, Transcutol® HP and Kolliphor® RH 40, while the aqueous phase was water. A visual examination was performed to confirm the absence of phase separation or heterogeneity. Then an analysis using dynamic light scattering (Zetasizer Nano ZS apparatus) followed, to determine droplet size and polydispersity index (PDI). Nanoemulsions with a PDI below 0.300 and droplet size between 100 – 200 nm were selected for solubility assays. After drug incorporation, at 5 mg/mL, only one out of the seventeen nanoemulsions showed characteristics within the intended parameters.

In conclusion, this study showed that the incorporation of miconazole in nanoemulsions allows to greatly increase its solubility when compared to water (up to 6550 times). Future studies will include determination of viscosity, stability, in vitro drug release, ex vivo drug permeation and in vitro cytotoxicity in melanoma cells.

The intranasal route has been suggested as a promising alternative to improve drug delivery to the central nervous system, as it can transport drugs from the nose directly to the brain, avoiding the need to cross the blood-brain barrier and, therefore, can represent an effective strategy in the treatment of neurodegenerative diseases. Natural compounds, existent in marine microorganisms, can be used in the management of neurodegenerative diseases due to their remarkable antioxidant activity that reduces the oxidative stress associated with the development of these diseases. The objective of this work was to prepare solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) for nose-to-brain delivery loaded with 1000 µg/mL of two natural antioxidants, in particular antioxidant extract and pure antioxidant. On the day of the production, all formulations had a particle size, polydispersity index and zeta potential suitable for nose-to-brain administration. In addition, all formulations showed high encapsulation efficiency of the tested natural antioxidants. Six months after storage at 20.0 ± 0.5 ◦C, in the case of SLN and NLC with antioxidant extract, and one month after storage, in the case of SLN and NLC with pure antioxidant, the characterization parameters underwent only slight changes. Biocompatibility studies in human neuronal cells SH-SY5Y, showed that the developed formulations are safe at least at concentrations up to 100 µg/mL. The results of this study highlighted the potential of using lipid nanoparticles loaded with natural antioxidants in the managment of neurodegenrative diseases, although more experiments are needed to confirm this evidence.

This study was aimed at building a robust quantitative structure–activity relationship
(QSAR) to predict the anti-proliferate activity of 1,3,4-thiadiazole derivatives against the A549
lung cancer cell lines. The semi-empirical PM7 parametrization approach was used to optimize
the complete set of 1,3,4-thiadiazole derivatives and various classes of molecular descriptors
have been calculated. We built models using Fisher score and the best subset selection for
feature selection, and the final model was developed using the multiple linear regression
technique, all in accordance with the rigorous Organization for Economic Co-operation and
Development (OECD) requirements. Furthermore, various internationally agreed severe
validation parameters were used to validate the model. Overall, our established model for quick
prediction should be relevant to new, untested, or not yet produced compounds that fall within
the applicability domain (AD) of the model. The drug-likeness properties of the 10 compounds
with the greatest activity value were also calculated using Lipinski's rule properties.
Keywords: QSAR, Thiadiazole derivatives, A549, PM7, OECD

Alzheimer’s Disease (AD) and other dementias are ranked by the WHO as the World’s 7^th leading cause of death. Aiming to respond to this international public health priority, the Carbohydrate Chemistry Group of CQE-IMS has been dedicated to uncovering the AD-modifying potential of carbohydrate-based molecules. In this communication, the rational design, synthesis, and biological evaluation of C-glucosyl flavone analogs with neuroprotective activity against H₂O₂- and Aβ-induced cell death are explored. Furthermore, based on the well-established role of the binding between PrP^C and Aβ oligomers (Aβo) for Tau hyperphosphorylation in the brain, the structural optimization process leading up to the discovery of N-methylpiperazinyl flavones and their C-glucosyl derivatives as protein-protein interaction inhibitors (PPII) against PrP^C-Aβo is also presented. Importantly, because many planar lipophilic polyphenols such as the ones we have developed are Pan-Assay Interference CompoundS (PAINS), we were also interested in clarifying their ability to alter cell membrane properties in a non-specific manner. Our results show, for the first time, that well-known membrane disruptors such as resveratrol and genistein cease to reduce the membrane dipole potential when linked to a glucosyl moiety through a C-C bond, suggesting that our C-glucosides should not raise concerns regarding membrane-related PAINS-type behavior. This communication ultimately highlights the promising neuroprotective and PPII activity of C-glucosyl flavones and corresponding aglycones in the context of AD, while exploring the role of the sugar moiety in favorably tuning aglycone bioactivity, cytotoxicity, and unspecific membrane-modifying effects.

Podophyllotoxin (PTOX), one of the most important natural medicinal compounds, has anticancer properties. Its effective medicinal derivatives, such as etoposide and teniposide, have been approved by the FDA for cancer treatment. This compound is found as a specialized metabolite in the Linum album Kotschy ex Boiss., belonging to the Linaceae family. PTOX is the major aryltetralin lignans resulting from the shikimic acid/phenylpropanoid pathway and accumulates in the shoot and roots of L. album. PTOX play a necessary role in plant defense systems, protecting against abiotic and biotic stresses and helping their adaptation to adverse environmental conditions. Therefore, the content of specialized metabolites increases under stress. In this study, the content of PTOX under stressful conditions (potassium deficiency stress at two-time points of 12 and 48 hours) was examined using HPLC in a completely randomized design with three replications. The results of HPLC showed that the content of PTOX first decreased in 12 hours, while after 48 hours of treatment compared with the control plants, it showed a significant increase with the value of 135.8 in the shoot. In the root, the results were consistent with the results of the aerial parts, and the amount increased significantly after 48 hours. In general, the results show that L. album as a suitable natural source for PTOX has great potential to generate Large-scale products for commercial and pharmaceutical purposes.

Multiwalled carbon nanotubes (MWCNTs) have gained a lot of multidisciplinary attention and biomedical applications such as drug delivery, because of their distinct physicochemical characteristics. Even though MWCNTs are not used because of low dispersibility in aqueous or non-aqueous medium. Functionalizing MWCNTs is an attractive way to overcome this drawback, it improves biocompatibility and promotes ligand attachment for targeted drug delivery. However, most functionalization techniques include hazardous procedures and costly chemicals. The current study uses a straightforward, economically advantageous method to functionalize MWCNTs with lysine through 1,3-dipolar cycloaddition for enhanced dispersibility and to offer a ligand anchoring ε-amino group for targeted delivery to breast cancer. MWCNTs had been functionalized with lysine and sugar moieties ligands (galactose/mannose) to create efficient nanocarriers that can bind to lectin receptors in MDA-MB-231 or MCF-7 cancer cells. Doxorubicin (Dox) was loaded into the ligands conjugated MWCNTs. In comparison to pristine MWCNTs, 1,3-lysinated MWCNTs conjugated with ligands demonstrated enhanced dispersion in an aqueous medium and greater drug loading capacity. Drug release studies in pH 7.4 were 20% only & in pH 5.0 was around 75%. Dox-loaded MWCNTs provided pH-dependent releases and enhanced Dox accumulation inside the cancer cells, as evidenced by higher inhibition of MDA-MB-231 or MCF-7 compared to plain Dox, and unloaded Dox MWCNTs nanoformulations provided negligible cytotoxicity. Based on the results, MWCNTs functionalized with lysine by 1,3-dipolar cycloaddition offer promising nontoxic nanoplatforms with improved aqueous dispersibility and potential for conjugation with ligands for targeted delivery of Dox to breast cancer cells.

Colorectal cancer (CRC) is an important cause of global morbidity and mortality. CRC harboring KRAS mutations accounts for 40% of all CRCs and is resistant to available EGFR inhibitors. Specific targeting of KRAS hotspot mutations is very difficult to achieve, highlighting the need of developing new specific target drugs. In this work, we aimed to evaluate the in vitro anticancer effects and explore the preclinical in vivo “proof of concept” for KRAS-mutated CRC therapy of a new family of ruthenium-cyclopentadienyl complexes.

CRC-derived cell lines with KRAS wild-type and different hotspot mutations were used to determine the phenotypic alterations induced by the complexes. A xenografted CRC mice model was used to determine in vivo toxicity and anti-tumor growth effect.

Our results revealed that Ru complexes are more cytotoxic for CRC cells, decreasing proliferation and inducing apoptosis. Studies with the PMC79 compound showed a decrease in the expression levels of KRAS, ERK and AKT proteins only in CRC-derived cells with KRAS mutation. In the in vivo therapeutical study, tumors treated with PMC79 had a much higher level of necrosis. Furthermore, the expression levels of KRAS, ERK and AKT proteins were also decreased in this model.

Overall, PMC79 has a noticeable effect inhibiting KRAS on CRC cells harboring KRAS mutation and not on CRC cells with KRAS wild type. This new Ru agent is a promising new drug for CRC therapy, suggesting to be a specific and a potential “magic bullet” for CRCs harboring mutated KRAS.

Molecules containing the pyrazole nucleus are widely reported as promising candidates to develop new antimicrobial compounds against multidrug resistant (MDR) bacteria no longer inhibited by available antibiotics. Recently, aiming at improving the too high minimum inhibitory concentrations (MICs) of a pyrazole hydrochloride salt (CB1H), CB1H-loaded nanoparticles (CB1H-P7 NPs) were prepared using a potent cationic bactericidal macromolecule (P7) as polymer matrix. Here, CB1H-P7 NPs have been successfully tested on several MDR clinically relevant isolates of Gram-positive and Gram-negative species. CB1H-P7 NPs displayed very low MICs, often 2-fold lower than those of P7 (0.6-4.8 μM vs. 1.2-9.3 μM) [2]. Upon complexation, the antibacterial effects of pristine CB1H were improved by 2-16.4-fold, and, unexpectedly, also the already potent activity shown by P7, when administered alone, was improved by 2-8 times after complexation. Time-killing experiments have established that CB1H-P7 NPs possess rapid bactericidal effects against representative strains of both Gram-positive and Gram-negative species, such as methicillin-resistant Staphylococcus aureus, MDR Pseudomonas aeruginosa, including a colistin-resistant isolate, carbapenemases-producing Escherichia coli and Klebsiella pneumoniae. Selectivity indices up to 2.4, determined by cytotoxicity experiments on human keratinocytes (HaCaT), suggested that CB1H-P7 NPs could be promising for therapeutic uses in the treatment of infections sustained by most isolates, including MDR strains, tested in this study.

Nitrogen-containing heterocycles can have several applications in the pharmaceutical industry, since they contain a wide spectrum of biological activities. Imidazolidinones have shown activity against leukemia, lung cancer and metabolic disorders. These cyclic urea frameworks can be obtained through transition-metal-catalyzed intermolecular cycloaddition using an aziridine moiety as starting material. These reactions often provide effective one-step procedures that result in heterocyclic derivatives, that are challenging to access through conventional approaches.

We have previously described the photoreaction of butyl pyridinium salt into the corresponding bicyclic aziridine under continuous-flow. Additionally, we reported that palladium-catalyzed ring opening of bicyclic aziridines with active methylenes thought a new S_N2’ selectivity. In this study, is presented the reaction between bicyclic aziridines and several isocyanates, in the presence of Pd(0)-catalyst. The reactions proceed through ring opening of the aziridine moiety, with the formation of the π-allylpalladium complex, followed by cyclization via nucleophilic addition of nitrogen to the isocyanate, affording regioselectively imidazolidinones.