Carbohydrate Chronicles

This podcast episode is about the key application of cyclodextrins: solubility enhancement. Cyclodextrins (CDs) are important functional excipients in pharmaceuticals, primarily recognized for their ability to solubilize poorly water-soluble drugs. They are cyclic oligosaccharides derived from starch, shaped like a truncated cone or torus. The exterior of the cone is hydrophilic, while its central cavity is relatively lipophilic, allowing it to interact with hydrophobic guest molecules.Here's an overview of their solubilization properties:Mechanism of Solubilization: The most prominent mechanism involves the formation of non-covalent, dynamic inclusion complexes in solution, where a drug molecule (guest) enters the lipophilic cavity of the cyclodextrin (host). Beyond this, CDs can also contribute to solubilization through the formation of non-inclusion based complexes, the creation of aggregates and related domains, and their capacity to form and stabilize supersaturated drug solutions.Impact on Drug Properties:Types of Cyclodextrins Used: The most commonly used cyclodextrins for pharmaceutical applications are α-cyclodextrin (αCD), β-cyclodextrin (βCD), and γ-cyclodextrin (γCD), along with some of their derivatives. Derivatives like hydroxypropyl-β-cyclodextrin (HPβCD) and sulfobutylether-β-cyclodextrin (SBEβCD) are particularly well-studied and have advanced to market.Complex Stoichiometry and Challenges: While a 1:1 drug/cyclodextrin complex (one drug molecule with one CD molecule) is the most common stoichiometry, it has become clear that solubilizing effects often involve the formation of multiple inclusion and non-inclusion complexes. For natural cyclodextrins, a tendency to coprecipitate with the drug can limit their use, although using combinations of different cyclodextrins can help overcome this issue, sometimes showing additive or even synergistic solubilizing effects.These properties make cyclodextrins valuable tools in addressing the challenges of poorly water-soluble drug candidates in pharmaceutical development.

Step into the future of medicine and manufacturing, where a remarkable class of compounds called cyclodextrins (CDs) is transforming the landscape of 3D and 4D printing for critical biomedical and pharmaceutical applications.Imagine 3D printed objects that dynamically change shape in response to environmental cues like moisture or temperature – a concept known as 4D printing, vividly demonstrated by a shape-shifting flower with variable flexibility.These safe, sustainable, and highly versatile cyclodextrins enable homogeneous dispersion of challenging drugs in water-based mixtures, foster self-healing properties, and provide tunable architectures sensitive to a range of stimuli.Crucially, cyclodextrins are powering the shift towards personalized medicine, especially for pediatric patients, allowing for the Direct Powder Extrusion (DPE) 3D printing of customized dosage forms, like Mini-Tablets, that precisely deliver drugs such as budesonide with enhanced solubility and site-specific release to target conditions like eosinophilic colitis.Beyond printing, their applications extend to polymeric nanoparticles, one-dimensional nanostructures (nanofibers), and hydrogels for advanced drug delivery, tissue engineering, and wound healing, underscoring their profound impact on healthcare innovation.

Carbohydrate chemistry, the final frontier. These ubiquitous building blocks of life are still the most challenging biomolecules to manipulate due to their structural diversity and complexity. A realm where only the bravest creative chemists can go, to deeply understand their biological importance, explore and embrace their therapeutic value. The use of carbohydrates as actives is an emerging field with a vast potential in several areas like cancer treatment, rare diseases or infections. Our guest today is László Somsák, Professor of Organic Chemistry at the University of Debrecen, Expert in the synthesis of glycomimetics and biologically active carbohydrates. László has been working at Debrecen University for exactly 40 years now, with a main research interest in designing novel synthetic routes to create carbohydrates, and discover glycomimetics, glycopeptidomimetics, and lectin inhibitors. He is a board member of nearly all local and international carbohydrate organizations and serves in the editorial board of the prestigious journal, CarboHydrate Research. He has almost 400 publications available on the topic.

For decades, scientists lived in a paradigm that cyclodextrins are useful excipients and additives with numerous applications and that’s it. The pioneers came and broke these chains, releasing the true potential of these molecules. First Sugammadex was discovered (which is now a blockbuster drug), and later long known cyclodextrins were re-purposed as active ingredients for various therapeutic indications. Some of these developments are now in phase III and II clinical trials for a rare genetic indication and Alzheimer’s disease. Research started to flourish both in the academia and industry, and companies like Cyclarity Therapeutics were incorporated focusing on cyclodextrin-based drug discovery and development. Today, our guest is Dr Matthew ‘Oki’ O’Connor, founder and co-CEO of Cyclarity Tx. Oki is a true longevity warrior, who dedicated all his professional career to this research area. After finishing his studies, Oki almost immediately joined SENS Research Foundation as head of research developing, promoting, and ensuring widespread access to therapies that cure and prevent the diseases and disabilities of aging which he left for Cyclarity eventually. He is also a board member of the Longevity Biotech Fellowship and Senior Reviewer of Vitadao, a decentralized collective funding initiative for early-stage longevity research.

In earlier episodes, we have touched the topic of cyclodextrin based drug delivery and even nanotechnology, yet today, with our guest, Erem Bilensoy, we are taking a deep dive. As we will hear today, cyclodextrins are not only capable of solubilizing and stabilizing actives, but in good hands also to remove toxic molecules from the body, enhance cellular delivery, compose targeted drug delivery systems and much more. The possibilities are truly infinite. Welcome Erem Bilensoy, Professor of Pharmaceutical Technology at Hacettepe University and Owner and CSO at BioGalenica. Erem’s main research related not only to cyclodextrins but pharmaceutical technology and nanoparticle based drug delivery in general. He has authored close to 100 papers and 15 book chapters. Apart from the academic career, industry has also been present in his life, in 2021 she founded her company BioGalenica and she is the president of the European Federation for Pharmaceutical Sciences EUFEPS. Her current research interests include targeted nanoparticles in cancer therapy, cholesterol-targeted nanoparticles to overcome multidrug drug resistance and enhance cellular delivery, applications of proteomics, metabolomics and lipidomics to develop nanomedicines.

Carbohydrates are molecules expressed on the surface of nearly all living cells, and their interaction with carbohydrate-binding proteins is critical to many immunobiological processes. Accordingly, carbohydrates are utilized as antigens in many licensed vaccines against bacterial pathogens. More recently, they have also been considered as adjuvants. Our Guest today, Luigi Lay, Professor of Chemistry at the University of Milan is specialized in advanced glyco-nanomedicine and carbohydrate-based vaccines and will help us understand how carbohydrates could be used as building blocks, targetors and further components of these complex systems. Luigi has been working with carbohydrates for a very impressive 30+ years, dealing with all major aspects, such as synthesis, analysis, evaluation of biological role, later glycoconjugates leading to nanotechnology and vaccines. He has almost 100 papers in the field and the PI and leader of several international consortia dealing with glycoscience.

Glycoscience is the study of carbohydrates (sugars) and their roles in biology. Today, we are focusing on lectins. Lectins are carbohydrate-binding proteins that are highly specific for sugar groups that are part of other molecules, so cause agglutination of particular cells or precipitation of glycoconjugates and polysaccharides. Lectins have a role in recognition at the cellular and molecular level and play numerous roles in biological recognition phenomena involving cells, carbohydrates, and proteins. Lectins also mediate attachment and binding of bacteria, viruses, and fungi to their intended targets. Our guest today is Anne Imberty, senior researcher at CNRS Grenoble, whose present research projects are centered on lectins from opportunistic bacteria that are involved in the first steps of infection. Structural characterization of these lectins and of their interaction with human glycoconjugates is opening the route for the design of glycocompounds with anti-bacterial activities. Anne Imberty has decades of experience in Glycobiology, she worked at different institutions of CNRS (Grenoble, Nantes, Paris) also at University of Toronto. She is the author of over 300 papers, leads diverse fields of research teams in glycoscience, actively participates in education and spreading knowledge.

Designing novel sugars and understanding how they work is an extremely challenging task. Accordingly, carbohydrate chemistry and supramolecular carbohydrate chemistry require devotion, persistence and creativity. José Manuel Garcia Fernandez, professor at University of Seville is working on such challenging innovations and discoveries around the uses of novel sugars for innovative applications. José will guide us into the world of cyclodextrin and carbohydrate chemistry, unravel a few mysteries and point out challenges and possibilities of the future from a chemistry point of view.

Glycoscience is the study of carbohydrates (sugars) and their roles in biology. Glycans play critical roles in many biological processes such as cell signaling, cell adhesion, immune response, and protein folding, among others. Glycan analysis and characterization is an increasingly important area for biopharma as understanding glycan profiles helps in the development of new therapeutic agents. It is also important for the creation of biobetters when innovator molecules fall out of patent. Structural analysis of glycans and complex carbohydrates, in particular that of lipopolisaccharides and glycoconjugates is the expertise of our guest today, Anthony Molinaro, Professor of Organic Chemistry at University of Napoli.