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Thiomers – Universität Innsbruck

 

Thiomers.

 

Thiolated Polymers (Thiomers) – Mimicking the workhorses of our body

With the intention to improve the mucoadhesive properties of polymeric excipients by the likely most prominent bridging structure designed by nature – namely disulfide bonds - Andreas Bernkop-Schnürch invented and pioneered thiolated oligo- and polymers – designated thiomers (1). The covalent attachment of thiol groups to well-established oligo- and polymers such as cyclodextrins and polysaccharides opened the door to a new generation of auxiliary agents for medical and pharmaceutical use. Thiomers mimic proteins – the workhorses of our body – bearing also thiol groups because of cysteines in their amino acid sequence. In contrast to proteins, however, thiomers are less complex in their structure, less immunogenic, do not show additional unintended functions and are simple to manufacture. Furthermore, the degree of thiolation of many proteins is simply too low. The great potential of thiomers for life sciences might be described in the best way by the simple imagination of protein chemistry with and without cysteine. Like proteins thiomers form disulfide bonds with cysteine-rich subdomains of endogenous proteins and crosslink by the formation of intra- and interchain disulfide bonds. Due to the covalent attachment of thiol groups numerous features of well-established polymers can be substantially improved and new properties can be introduced (2). In particular, thiomers exhibit high in situ gelling properties by their disulfide crosslinking under physiological conditions. Hydrogels containing thiolated polysaccharides were shown to increase their viscosity over 10,000-fold within a few minutes (3). Because of this disulfide crosslinking well defined polymeric scaffolds facilitating cell adhesion can be generated. As thiomers from disulfide bonds with cysteine-rich subdomains of keratins and mucus glycoproteins, they exhibit comparatively high bio- and mucoadhesive properties. In fact, thiomers prolong the residence time of numerous drugs on mucosal membranes such as the ocular or gastrointestinal mucosa 10- to 100-fold (4,5). By directly or indirectly interacting with cysteine substructures of cellular membrane bound proteins, thiomers show permeation and cellular uptake enhancing as well as efflux pump inhibiting properties improving especially the oral bioavailability of many drugs tremendously (2,6). In addition, drugs bearing a thiol group can be attached to thiomers via disulfide bonds providing a sustained release in vivo via thiol/disulfide exchange reactions with enogenous thiols (7). Furthermore, thiomers display high binding properties for metals such as mercury, gold and nickel. As thiomers can also be used for the design of thiolated nanoparticles, they contributed essentially to the development of such drug delivery systems (6).

Although it takes in life sciences often several decades until new platform technologies reach their full potential, the benefit of thiomers has already been demonstrated in over twenty studies in humans/clinical trials (PDF). In fact, thiomers contribute already to society in form of numerous pharmaceutical and medical products improving the quality of life of millions of patients.

At the 4th Central European Symposium on Pharmaceutical Technology in Vienna 2001 Andreas Bernkop-Schnürch and his team introduced thiolated polysaccharides as new biopolymers for tissue engineering and regenerative medicine (8) resulting in numerous products such as Blafar (thiolated hyaluronic acid), Glycosil® (thiolated hyaluronan) or Heprasil® (thiolated heparin/thiolated hyaluronic acid) for this purpose.

In addition, thiomers are used as therapeutic polymers per se. They are for example used in eye drops for treatment of dry eye syndrome affecting 5 - 6% of the population and rising to 6 - 9.8% in post-menopausal women. The likely most important prerequisite for successful topical lubrication is a long residence time on the ocular surface. LacrimeraTM (thiolated chitosan) were the first eye drops containing a polymer showing in clinical trials a significant improvement in symptoms of dry eye syndrome (9).  Marketed under the slogan ‘Tears for dry eyes’ this product won the German Innovation Award in 2018. Moreover, adhesive hydrogels containing thiolated chitosan (e.g. Nidiesque®) have been marketed for dermal use to treat nickel allergy (10).

Further product developments focusing on injectable self-crosslinkable hydrogels for stem cell therapy (11), vitreous substitutes (12), adhesive wound dressings, ocular bandage gels for improving persistent corneal epithelial defects (13) or reepithelialization after photorefractive keratectomy (14), thiolated cyclodextrins as alternatives to aluminium salts for treatment of hyperhidrosis, eye drops providing a prolonged residence time of dexamethasone on the ocular surface (15) and oral formulations improving the bioavailability of BCS class 4 drugs (16) are in preclinical or clinical development. All these developments illustrate the huge variety and broadness in that the thiomer technology inspires academia and industry worldwide resulting in more and more products reaching the global market and the sheer endless possibilities for further pharmaceutical and medical applications.

  1. Bernkop-Schnürch, A. Mucoadhesive Polymers, Their Use and Their Production Method. Austria Patent AT269105T, 1998; and following patents worldwide
  2. Leichner et al. Thiolated polymers: Bioinspired polymers utilizing one of the most important bridging structures in nature. Adv Drug Deliv Rev. 2019; 151-152:191-221.
  3. Sakloetsakun et al. In situ gelling properties of chitosan-thioglycolic acid conjugate in the presence of oxidizing agents. Biomaterials. 2009;30(31):6151-7.
  4. Hornof et al. Mucoadhesive ocular insert based on thiolated poly(acrylic acid): development and in vivo evaluation in humans. J Control Release. 2003, 89(3):419-28.
  5. Kali et al. Per-thiolated cyclodextrins: Nanosized drug carriers providing a prolonged gastrointestinal residence time. Carbohydr Polym. 2023, 300:120275.
  6. Hock et al. Thiolated Nanoparticles for Biomedical Applications: Mimicking the Workhorses of Our Body. Adv Sci (Weinh). 2022, 9(1):e2102451.
  7. Shahnaz et al. Development and in vivo characterization of a novel peptide drug delivery system providing extended plasma half life. J Control Release, 2012, 157(3):375-82.
  8. Kast et al. Chitosan-thioglycolic acid conjugate: a new scaffold material for tissue engineering? Int J Pharm. 2003, 256 (1–2): 183–189.
  9. Lorenz et al. Long-term management of dry eye by once-daily use of Chitosan-N-Acetylcysteine (Lacrimera®) eye drops. J. Clin. Ophthalmol., 2 (2018) 47-54.
  10. Federer et al. Thiolated Chitosans: A Multi-talented Class of Polymers for Various Applications. Biomacromolecules. 2021, 22(1):24-56.
  11. Lee et al. Injectable Self-Crosslinkable Thiolated Hyaluronic Acid for Stem cell Therapy of Atopic Dermatitis. ACS Biomater Sci Eng. 2022 8(4):1613-1622.
  12. Hurst et al. Long-Term Biocompatibility of a Highly Viscously Thiol-Modified Cross-Linked Hyaluronate as a Novel Vitreous Body Substitute. Front Pharmacol. 2022, 13:817353.
  13. A Study of the KIO-201 (Ocular Bandage Gel) for Improving Persistent Corneal Epithelial Defects (2022) https://clinicaltrials.gov/ct2/show/NCT05436288?term=CMHA-S&draw=2&rank=1
  14. Durrie et al. Ability of a new crosslinked polymer ocular bandage gel to accelerate reepithelialization after photorefractive keratectomy. J Cataract Refract Surg. (2018) 44(3):369-375.
  15.  Grassiri et al., Thiolated Hydroxypropyl-β-cyclodextrin: A Potential Multifunctional Excipient for Ocular Drug Delivery. Int J Mol Sci. 2022 Feb 26;23(5):2612.
  16. Asim et al. Per-6-Thiolated Cyclodextrins: A Novel Type of Permeation Enhancing Excipients for BCS Class IV Drugs. ACS Appl Mater Interfaces. 2020 12(7):7942-7950.
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