Posted by Thiolated oligomers and polymers, also known as thiomers, are valuable tools for non-parenteral drug delivery.1-3 Due to the cysteine-rich segments in mucosal glycoproteins, thiomers form stable disulfide bonds with the mucus gel layer through a simple oxidation, resulting in a prolonged mucosal residence time for these excipients.4, 5 As a consequence, stronger local effect and higher uptake into the systemic circulation of the delivered drug can be reached. Thiolation is especially important for oligo- and polysaccharide-based drug delivery systems because most of these natural polymers serve as effective drug carriers; however, they show minimal interaction with the mucus layer.
One of the key factors in mucoadhesion is the degree of thiolation of selected oligo- and polysaccharides; the more thiol groups present, the stronger their mucoadhesive properties.6 Most commercially applied thiolation methods, such as oxidation followed by reductive amination or halogenation and a subsequent reaction with thiourea, yield only a low degree of thiolation. Our group has recently developed a novel and effective thiolation method that can achieve even per-thiolation of β-cyclodextrin (β-CD).7, 8 This reaction involves the thiolation of the hydroxyl groups of anhydroglucose repeats with phosphorus pentasulfide in sulfolane at elevated temperatures. In case of per-thiolated β-CD, an 89-fold increase in in vitro mucoadhesion was observed, and in vivo studies also showed that more than 60% of the thiomers remained in the gastrointestinal tract after 8 hours, while no native β-CD was present there anymore. Since both native and modified β-CDs have low solubility in water,7, 8 and starch-degrading enzymes, such as α-amylase, do not digest these CDs, we can take a step back and investigate the thiolation of starch, the parent polymer for β-CD.
Corn starch was thiolated using the method described above, resulting in a high degree of thiolation, approximately 40%.9 The acid dissociation constant (pKa), which measures the stability of the sulfhydryl moieties, was similar for both CD and starch, ranging from 7.75 to 8.20, close to the value for cysteine. The safety studies revealed the first significant differences between the two thiolated carbohydrates. Although both products displayed good cell viability on the Caco-2 cell line, the membrane-damaging effect of β-CD had a significantly larger impact, likely due to this oligosaccharide’s ability to extract cholesterol.
The mucoadhesive properties of various thiomers can be compared if their degrees of thiolation fall within the same range. When we compare β-CD and starch under these criteria,8, 9 we observe only minor differences between the two, with thiolated starch showing a slightly better enhancement of mucoadhesive properties. This difference likely arises from the distinct solution behavior of the two parental and thiolated macromolecules in an aqueous environment. While native and thiolated β-CD exhibit low water solubility, starch forms a gel in water—a property that, although slightly diminished, remains evident after thiolation.
When comparing thiolated β-CD to its parent polysaccharide, starch, the synthesis procedure reveals similar optimal conditions. However, slight differences in the product properties are evident, influenced by the advantages and disadvantages of the native macromolecules. The primary reason for using CDs in drug delivery—their ability to form host-guest complexes—is an almost unbeatable advantage, combined with the fact that β-CD is currently the only polymer that can be per-thiolated. On the other hand, starch can be hydrated to form a physical hydrogel even after thiolation, which is beneficial for drug delivery systems.
References:
(1) Bonengel, S.; Bernkop-Schnürch, A. Thiomers–from bench to market. J Control Release 2014, 195, 120-129. https://doi.org/10.1016/j.jconrel.2014.06.047
(2) Leichner, C.; Jelkmann, M.; Bernkop-Schnürch, A. Thiolated polymers: Bioinspired polymers utilizing one of the most important bridging structures in nature. Adv Drug Deliv Rev 2019, 151-152, 191-221. https://doi.org/10.1016/j.addr.2019.04.007
(3) Mfoafo, K.; Mittal, R.; Eshraghi, A.; Omidi, Y.; Omidian, H. Thiolated polymers: An overview of mucoadhesive properties and their potential in drug delivery via mucosal tissues. Journal of Drug Delivery Science and Technology 2023, 85, 104596. DOI: https://doi.org/10.1016/j.jddst.2023.104596.
(4) Kali, G.; Knoll, P.; Bernkop-Schnürch, A. Emerging technologies to increase gastrointestinal transit times of drug delivery systems. Journal of Controlled Release 2022, 346, 289-299. DOI: https://doi.org/10.1016/j.jconrel.2022.04.016.
(5) Kali, G.; Haddadzadegan, S.; Bernkop-Schnürch, A. Cyclodextrins and derivatives in drug delivery: New developments, relevant clinical trials, and advanced products. Carbohydrate Polymers 2024, 324, 121500. DOI: https://doi.org/10.1016/j.carbpol.2023.121500.
(6) Roldo, M.; Hornof, M.; Caliceti, P.; Bernkop-Schnürch, A. Mucoadhesive thiolated chitosans as platforms for oral controlled drug delivery: synthesis and in vitro evaluation. Eur J Pharm Biopharm 2004, 57 (1), 115-121. https://doi.org/10.1016/s0939-6411(03)00157-7
(7) Kali, G.; Haddadzadegan, S.; Laffleur, F.; Bernkop-Schnürch, A. Per-thiolated cyclodextrins: Nanosized drug carriers providing a prolonged gastrointestinal residence time. Carbohydrate Polymers 2022, 120275. https://doi.org/10.1016/j.carbpol.2022.120275
(8) Kali, G.; Taha, A. M. M. M.; Campanella, E.; Truszkowska, M.; Haddadzadegan, S.; Denora, N.; Bernkop-Schnürch, A. Enhanced Mucoadhesion of Thiolated β-Cyclodextrin by S-Protection with 2-Mercaptoethanesulfonic Acid. ACS Omega 2024, 9 (5), 5819-5828. https://doi.org/10.1021/acsomega.3c08836
(9) Davoudi, Z.; Kali, G.; Braun, D.; Azizi, M. H.; Bernkop-Schnürch, A. Highly thiolated corn starch for enhanced mucoadhesion and permeation. International Journal of Pharmaceutics 2025, 680, 125798. DOI: https://doi.org/10.1016/j.ijpharm.2025.125798.