The intranasal route has emerged as a promising alternative for the treatment of neurological
disorders, owing to its unique advantages, most notably the ability to deliver drugs directly from
the nasal cavity to the brain (nose-to-brain delivery). This approach bypasses the blood-brain
barrier and can enhance therapeutic efficacy.
In recent years, the potential of the nose-to-brain route to improve the management of
neurological disorders such as Alzheimer’s disease, epilepsy, and migraine has attracted
significant preclinical attention. The findings so far are encouraging, particularly when this route
is combined with nanosystem-based formulations, including solid lipid nanoparticles (SLN) and
nanostructured lipid carriers (NLC). Nevertheless, evidence supporting the clinical efficacy of the
nose-to-brain pathway remains limited, and further research is required before progressing to
clinical trials.

The Lamiaceae family is among the largest plant families, including more than 230 genera and 7,000 species. Many members of this family are well known for their aromatic and medicinal properties, attributed to their rich content of specialized metabolites. In Greece, the genera Sideritis, Stachys, and Salvia hold particular importance due to their traditional uses and their value as sources of bioactive compounds. This study aimed to investigate the phytochemical composition of selected Greek species belonging to these genera. Plant materials were extracted, and their chemical profiles were analyzed through several analytical techniques. The results revealed a high diversity of polyphenolic compounds, including mainly flavone 7-O-allosylglucosides and phenylethanoid glycosides in Sideritis and Stachys species, while flavone glycosides and depsides are present in Salvia species. Overall, the studied Greek species represent valuable sources of polyphenolic constituents with promising pharmacological activities and potential applications in pharmaceuticals, nutraceuticals, and cosmetic formulations.

The genus Plectranthus, belonging to the Lamiaceae family, has emerged as a valuable source of bioactive natural products, particularly abietane-type diterpenoids. These compounds, rooted in traditional medicinal practices, have gained attention for their diverse pharmacological properties and potential as drug leads. Abietanes isolated from Plectranthus species exhibit a wide range of biological activities, including antimicrobial, anti-inflammatory, and anticancer effects, making them attractive scaffolds for therapeutic development.This presentation highlights the translational journey of Plectranthus-derived abietanes from ethnobotanical relevance to preclinical evaluation. Notable examples include Parvifloron D from P. ecklonii and 7α-acetoxy-6β-hydroxyroyleanone from P. grandidentatus, both demonstrating significant bioactivity. A particular focus is placed on dibenzoylroyleanone (RoyBz), a patented abietane diterpenoid with selective activation of protein kinase C (PKC) and potent antiproliferative effects in colon cancer models. Mechanistic studies reveal that RoyBz induces apoptosis via a PKCδ-mediated mitochondrial pathway and disrupts cancer cell metabolism, underscoring its promise as a drug candidate.By integrating phytochemical profiling, pharmacological screening, and molecular investigations, this work reinforces the role of Plectranthus species as a rich source of novel therapeutic agents. It also emphasizes the importance of preserving traditional knowledge and validating it through modern scientific approaches to support sustainable drug discovery from natural products.

Crystallization is widely employed in the pharmaceutical industry, ranging from the early stages of drug discovery and formulation to the large-scale production of pharmaceuticals. The process involves the formation of a new crystalline solid phase and can target either a solute, e.g., small molecule or protein, or the solvent, e.g., freezing of water.

The crystallization of solutes assisted by functionalized surfaces will be first discussed. Self-assembled monolayers immobilized on glass can modify the nucleation kinetics of small molecules, i.e., aspirin, and macromolecules. The role of secondary interactions between the surface and the solute was investigated through thin-film crystallization and X-Ray diffraction. Modified surfaces can also promote the formation of unknown polymorphs, thus showing the potential of this technique during the early stages of drug discovery.

The crystallization of proteins will be successively described considering diffusion-dominated environments. The elimination of convection allows better control over crystallization, promotes reproducible crystal size, and reduces the risk of crystal breakage. The use of agarose and silica gels will be presented and their advantages and limitations described, together with strategies to overcome them.

Finally, a focus on solvent crystallization will be provided. Freeze-drying is selected as a case-study as the ice crystals’ morphology impacts the freeze-dried product morphology and, consequently, the drying rate, the residual moisture, and the reconstitution time. Freezing of unit doses in vials is a complex process, and the impact of thermal interactions among vials on ice crystallization and final product morphology will be discussed by comparing experimental data and mathematical modelling.

As new medications are used to treat COVID-19, many studies have reported that proteins such as spike, polymerase and proteases are prone to high levels of mutation that can create resistance to therapy over time. Thus, it becomes necessary to, not only target other viral proteins such as the non-structural proteins (NSP’s), but to also target the most conserved residues of these proteins. A synergistic combination of bioinformatics, computer-aided drug-design and in-vitro studies can feed into better understanding of SARS-CoV-2 (SC-2) and therefore help in the development of small molecule inhibitors against the NSP’s. As part of our initial anti-viral work, a pharmacophore study on NSP15 found a hit molecule (INS316) that made interactions with Ser293, Lys344 and Leu345 residues which are highly conserved across SC-2.

Our group was selected to enter an international challenge organized by CACHE to find inhibitors for the Mac1 domain of SC-2 NSP3. Our MSA alignment results of ~1 million NSP3 sequences indicated that the Mac1 domain is a highly conserved pocket that can be targeted for developing promising SC-2 inhibitors. We used a tiered screening workflow which included the use of volume/shape information of the binding pockets (fastROCS), use of in-house pharmacophore generation software (MoPBS/MOE) and performed docking in the binding pocket (FRED) to rank compounds for subsequent clustering and to identify hits that bind to these conserved pockets. The primary experimental validation results provided by CACHE found that two of our predicted hits show activity in HTRF and SPR assays.

Gliomas, particularly glioblastoma multiforme, are highly aggressive brain tumors characterized by poor prognosis, mainly due to the blood-brain barrier limiting drug delivery. The intranasal route has been identified as a promising strategy for bypassing this barrier. Silibinin (SLB) is a natural flavonoid that inhibits glioma cell growth and invasion while inducing apoptosis, highlighting its potential as a therapeutic agent for glioblastoma. Hyaluronic acid (HA), a naturally occurring glycosaminoglycan, is recognized for its mucoadhesive, biocompatible, and targeting properties, mainly through its interaction with the CD44 receptor and other proteins overexpressed in tumor cells. In this context, HA-based hybrid lipid/polymeric nanoparticles (LPNs) were developed using HA of varying molecular weights for the intranasal delivery of SLB targeted to glioma tumors. Formulations were produced using low-, medium-, and high molecular-weight hyaluronate salts.

LPNs were prepared using a nanoprecipitation method. Physicochemical characterization included measurements of particle size and stability over 30 days, surface charge (ζp), morphology (via Cryo-TEM), thermal properties (DSC and ITC), total drug content in dispersion (DC), and encapsulation efficiency (EE). Mucoadhesive and viscosity properties were assessed to determine the potential for adhesion to nasal mucosa. In-vitro SLB- release kinetics studies were carried out. Cytotoxicity assays and cellular uptake tests were performed in RPMI 2650 nasal epithelial cells and T98-G glioblastoma cells to evaluate the potential of HA-SLB-loaded LPNs for targeted glioma therapy via intranasal administration.

Blank LPNs had an average size of approximately 100 nm, while SLB-loaded LPNs measured about 160 nm. The LPNs exhibited a negative ζp around -44.4 mV, indicative of good colloidal stability and confirming the presence of HA on the surface. Cryo-TEM analysis revealed spherical particles with an internal multilayer bilayer structure and a well-defined membrane thickness. ITC and DSC analyses suggested increased stability and an amorphous state of SLB within the LPN matrix, particularly when using low molecular weight HA. The formulations demonstrated good physicochemical stability over 30 days. DC and EE in the dispersions were approximately 100% and 60%, respectively. In-vitro release studies indicated that LPNs achieved a higher SLB release (85%) compared to free SLB (20% in 1 hour), highlighting the influence of low molecular weight HA on nanoparticle performance. The LPNs showed appropriate viscosity and mucoadhesive properties for nasal administration, regardless of HA molecular weight. Cellular uptake studies in RPMI 2650 cells confirmed efficient internalization, while cytotoxicity assays in T98-G glioblastoma cells demonstrated promising therapeutic efficacy through significant glioma cell growth inhibition.

The findings highlight the fundamental role of hyaluronic acid molecular weight in optimizing hybrid nanoparticles (LNPs), demonstrating their strong potential for intranasal delivery of hydrophobic natural compounds to overcome limitations of conventional routes and enhance therapeutic efficacy in glioma treatment.

Peptides have traditionally been perceived as poor drug candidates due to unfavorable
characteristics mainly regarding their pharmacokinetic behavior, including plasma stability,
membrane permeability and circulation half-life. Nonetheless, in recent years, general strategies
to tackle those shortcomings have been established, and peptides are subsequently gaining
increasing interest as drugs due to their unique ability to combine the advantages of antibodies
and small molecules. Macrocyclic peptides are a special focus of drug development efforts due
to their ability to address so called ‘undruggable’ targets characterized by large and flat protein
surfaces lacking binding pockets. Especially in the field of complement therapeutics this has
resulted in two remarkable approvals of cyclic peptides, Pegcetacoplan and Zilucoplan. Both
are the first cyclic peptides reaching the market which have been de-novo evolved by display
methods.

Our group focuses on the development of cyclic peptides by using chemically modified phage
display and computational design, with special emphasis on complement modulation. In a
recent project we focused on the complement receptors CR3 and CR4. These members of the
β2-integrin family are involved in complement-dependent phagocytosis and leukocyte
adhesion, migration, and activation, thereby playing important roles in immune surveillance and
inflammation. The direct involvement of β2-integrin receptors in autoimmune, inflammatory,
and age-related diseases render them interesting drug targets, however their complex interplay
to a multitude of endogenous protein ligands is not well understood. By developing CR3-
targeting cyclic peptides, we aim to gain more insights in its ligand binding sites, and to
ultimately modulate leukocyte function. Phage display screening against CR3 αMI identified a
set of cyclic peptides with direct binding to the αMI domain and able to compete with
endogenous ligands. We conducted structure-activity relationship and plasma stability studies
and investigated modulating activities in functional adhesion assays.