In this study, we describe the stepwise synthesis and thorough structural elucidation of a newly designed thiadiazole-based hybrid molecule, referred to as compound 5. Its chemical framework was confirmed through an array of spectroscopic analyses, including [1]H and [13]C-NMR, infrared spectroscopy, and HRMS, ensuring a reliable structural validation. By using density functional theory optimized geometry and vibratinoal frequencies were computed. The Natural Bond orbital analysis confirmed the stability of this derivative. Molecular Electro Static potential used to identify electrophilic and nucleophilic area. The visual study of weak interactions NCI and RDG analysis carried out. The biological potential of compound 5 was then explored through in vitro cytotoxicity screening against three distinct human cancer cell lines: MCF-7 (breast carcinoma), A549 (lung carcinoma), and PC3 (prostate carcinoma). The MTT assay, with doxorubicin employed as the reference standard, demonstrated that compound 5 exerted measurable cytotoxicity, particularly against A549 lung cancer cells, yielding an IC50 of 25.12 µM, which highlights its moderate antitumor efficiency in comparison to the control drug. To complement the experimental findings, a comprehensive in silico investigation was performed. Molecular docking analyses revealed that thiadiazole 5 displayed a notable affinity toward the Tumor Necrosis Factor (TNF) binding site, reflected by a binding energy of -8.69 kcal/mol. Molecular dynamics (MD) simulations further substantiated the robustness of this interaction by confirming the long-term stability of the 5-TNF complex. Binding free energy calculations (MM-GBSA) corroborated these results, as ΔG_bind values consistently remained strongly negative throughout the simulation timeframe. In addition, PCA and RDF evaluations indicated a stable conformational behavior of compound 5, comparable or even superior to the reference molecule. Finally, free energy landscape mapping supported these observations by revealing energetically favorable and well-defined conformational states. Taken together, these experimental and theoretical insights suggest that compound 5 represents a promising scaffold for the development of new anticancer agents, with both structural stability and significant biological relevance.

Loading of the Doxorubicin (DOX) as an anticancer drug molecule on boron nitride (BN) nanosheets with different sizes, in the presence and absence of Folic Acid (FA) functional groups, are investigated using molecular dynamic simulations. The obtained results from these investigations revealed that the drug molecules are spontaneously adsorbed the carriers and form stable complexes. It is also shown that an increase the nanosheet leads to an enhancement in its capacity to adsorb the drugs. Furthermore, the conjugation of BN with the FA group not only improves the BN efficiency for the drug adsorption but also helps the drug-carrier complex to target the cancerous cells. Evaluation of interaction energies reveals that L-J interaction plays an essential role in the adsorption of the drug molecules on the BN. The radial distribution function (RDF) shows that the highest drug position probability is around 0.6 nm away from the BN surface. Atomic RDF analysis is in line with the interaction energy analysis and proved that π-π stacking contributes the most to this process. Hydrogen bond (HB) analysis also shows that, although limited, the columbic interaction can be helpful in the adsorption process. Moreover, the free energy (FE) surface is explored for a system containing a BN nanosheet, an FA group, and a DOX molecule through metadynamics simulations. The obtained results reveal that the lowest FE point located in coordinations d1 = 0.70 nm and d2 = 0.84 nm, and energetically reached -280.42 kJ/mol. It can be concluded from the FE calculations that while the FA is stuck on the substrate, DOX faces difficulty in the way it be adsorbed. In return, it will be hard for the molecule to be released from the BN surface through desorption processes in neutral pH because it faces an energy barrier with a height of ∼100 kJ/mol at 1.6 nm.

In this work, the effect of environment and additives on the self-assembly and delivery of doxorubicin (DOX) have been studied. A microfluidic system with better control over molecular interactions and high surface to volume ratio has superior performance in comparison to the bulk system. Moreover, carbon nanotube (CNT) and CNT-doped structures have a high surface area to incorporate the DOX molecules into a polymer and the presence of functional groups can influence the polymer-drug interactions. In this work, the interactions of DOX with both the polymeric complex and the nanotube structure have been investigated. For quantification of the interactions, H-bonding, gyration radius, root-mean-square deviation (RMSD), Gibbs free energy, radial distribution function (RDF), energy, and Solvent Accessible Surface Area (SASA) analyses have been performed. The most stable micelle-DOX interaction is attributed to the presence of BCN in the microfluidic system according to the gyration radius and RMSD. Meanwhile, for DOX-doped CNT interaction the phosphorus-doped CNT in the microfluidic system is more stable. The highest electrostatic interaction can be seen between polymeric micelles and DOX in the presence of BCN. For nanotube-drug interaction, phosphorus-doped carbon nanotubes in the microfluidic system have the largest electrostatic interaction with the DOX. RDF results show that in the microfluidic system, nanotube-DOX affinity is larger than that of nanotube-micelle.

The controlled delivery and release of drug molecules at specific targets increases the therapeutic efficacy of treatment. This paper presents a triple complex which is a new potential drug delivery system. Triple complex contains single-walled carbon nanotubes, Congo red, and doxorubicin. Nanotubes are built of a folded graphene layer providing a large surface for binding Congo red via "face-to-face" stacking which markedly increases the binding capacity of the carrier. Congo red is a compound that self-associates to form supramolecular ribbon-like structures, which are able to bind some drugs by intercalation. The nanotube-Congo red complex can bind the model drug doxorubicin. Thus, a new triple carrier system was obtained. The aim of this paper is to present studies on the controlled release of a model anticancer drug from a triple carrier system through pH changes. The specific aim of the study was to model the structure of the obtained experimental systems and to compare the changes in the average energy of interaction between its components induced by pH changes. The studies also aimed to compare the intensity of pH-dependent changes in hydrodynamic diameters of individual components of the triple carrier system. The effect of pH changes on the stability of the analyzed systems was examined using the molecular modeling method and dynamic light scattering. The decrease in pH influenced the structure and stability of the analyzed triple systems and ensured efficient drug release. The changes in hydrodynamic diameters of the obtained fractions were examined with the use of dynamic light scattering and were confirmed by computer simulation methods. The formulation presented in this paper shows potential for a therapeutic application owing to its high drug binding capacity and pH-dependent release. This ensures prolonged local action of the drug. The results reveal that the studied complex fulfills the basic requirements for its potential use as drug carrier, thus reducing side effects and enhancing pharmacological efficacy of drugs.

The self-assembly behaviour of dual-responsive block copolymers and their ability to solubilize the anticancer drug doxorubicin (DOX) has been investigated using all-atom molecular dynamics (MD) simulations, MARTINI coarse-grained (CG) force field simulation and Scheutjens-Fleer self-consistent field (SCF) computations. These diblock copolymers, composed of poly{γ-2-[2-(2-methoxyethoxy)ethoxy]ethoxy-ε-caprolactone} (PMEEECL) and poly(β-amino ester) (PAE) are dual-responsive: the PMEEECL block is thermoresponsive (becomes insoluble above a certain temperature), while the PAE block is pH-responsive (becomes soluble below a certain pH). Three MEEECL20-AE M compositions with M = 5, 10, and 15, have been studied. All-atom MD simulations have been performed to calculate the coil-to-globule transition temperature (T cg) of these copolymers and finding appropriate CG mapping for both PMEEECL-PAE and DOX. The output of the MARTINI CG simulations is in agreement with SCF predictions. The results show that DOX is solubilized with high efficiency (75-80%) at different concentrations inside the PMEEECL-PAE micelles, although, interestingly, the loading efficiency is reduced by increasing the drug concentration. The non-bonded interaction energy and the RDF between DOX and water beads confirm this result. Finally, MD simulations and SCF computations reveal that the responsive behaviour of PMEEECL-PAE self-assembled structures take place at temperature and pH ranges appropriate for drug delivery.

Star-shaped polymers have received significant attention and have been widely developed for prospective applications in drug delivery owing to their topological structure and unique physiochemical characteristics. The anticancer drug doxorubicin (DOX) was used as a model drug, and four/six-arm star-shaped block polymeric micelles were employed as the carriers. The dissipative particle dynamics (DPD) method was adopted to simulate the formation of micelles, the effects of the hydrophobic/hydrophilic block ratio on the micellar structure and drug-loading performance, the effect of the drug loading content on the micellar morphology, and the effect of the pH-sensitive block ratio on the drug release properties. Under neutral conditions (pH = 7.4), increasing the hydrophobic block ratio reduces the stability of the micelle structure but could improve its drug loading performance. Increasing the pH-sensitive block (DEAEMA) ratio is beneficial to the drug loading performance of the mikto-arm star-shaped polymeric micelles and is detrimental to the drug loading performance of the herto-arm star-shaped polymeric micelles. After comparing the structural changes, radial distribution function (RDF) and mean square displacement (MSD) of the polymeric micelles with different pH-sensitive block ratios under weakly acidic conditions (pH = 5.0), the drug release properties of the drug-loaded micelles were systematically analysed. The results showed that the higher the proportion of the pH-sensitive block in the polymeric micelles, the better their pH-response performance, and the looser the structure of the micelles during the release process. A too high or too low ratio of pH-sensitive blocks in the polymeric micelles was detrimental to drug release performance. This study could provide theoretical support for the structural design and development of novel functional block polymers.

The anthracyclines are an important group of antitumour drugs: the best known anthracyclines are doxorubicin (Adriamycin) and epirubicin (Pharmorubicin), both of which are very active against a wide range of solid tumours and haematological malignancies. They are marketed as lyophilized formulations that need to be reconstituted for administration with water for injections or sodium chloride injection. With the aim of reducing the risks of contamination during reconstitution (spillage, spray formation, etc.) and of enhancing the rate of dissolution (that is otherwise slow because of the formation of conglomerates and gelatinous masses), a new formulation (rapid dissolution formula, RDF) containing parabens (hydroxybenzoate esters) as anti-aggregants has been developed; the formulation is a freeze-dried product and is characterized by a practically instantaneous and complete reconstitution. A valid estimate of the completeness of dissolution has been objectively achieved by means of an instrument (Galai CIS-1) that acts both as a particle sizer and a shape analyser; the instrument is equipped with a rotating laser system that defines a toroidal-cylindrical space inside the solution in which every moving particle is measured and, at the same time, visualized on a monitor by an electronically driven video microscope. The instrument has been applied with very satisfactory results to the visualization of the reconstitutional behaviour of commercial lots of Adriamycin and Pharmorubicin lyophilized products, reconstituted at a concentration of 2 mg ml-1 with sodium chloride injection.