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Abstract

Mucosal drug delivery systems have gained significant attention as effective alternatives to conventional oral and parenteral routes, primarily due to their ability to enhance drug absorption and improve site-specific therapeutic outcomes. However, traditional mucoadhesive polymers often rely on weak physical interactions with mucin glycoproteins, resulting in limited residence time and reduced drug delivery efficiency. Thiolated polymers (thiomers) have emerged as a promising class of mucoadhesive materials designed to overcome these limitations. These polymers contain thiol (–SH) groups capable of forming strong covalent disulfide bonds with cysteine-rich domains of mucin, thereby significantly enhancing mucoadhesion and retention at mucosal surfaces. This review critically examines recent advances in the design, synthesis, characterization, and pharmaceutical applications of thiolated polymers in drug delivery. Relevant studies were systematically analyzed from major scientific databases, focusing on polymer chemistry, degree of thiolation, physicochemical properties, biological performance, and therapeutic applications. Thiomers also exhibit redox-responsive behavior, enabling in situ gel formation and controlled drug release under physiological conditions. These systems have been investigated for multiple administration routes, including oral, buccal, nasal, ocular, vaginal, and gastroretentive drug delivery. Despite their promising potential, challenges such as oxidative instability of thiol groups remain, although recent strategies involving molecular protection and optimized storage conditions have improved stability. Overall, thiolated polymers represent versatile and advanced platforms for mucosal drug delivery due to their strong mucoadhesive properties and enhanced therapeutic performance.

Keywords

Thiolated Polymers Thiomers Mucoadhesion Disulfide Bonds Permeation Enhancement Redox Responsive Delivery

Introduction

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Drug delivery through mucus lined surfaces now reaches areas like the mouth, nose, eyes, reproductive tract, and gut more effectively than before. Thanks to these methods, medicines enter the body better, patients stick to treatment plans, and some drugs avoid early breakdown in the liver (Kwadwo Mfoafo, 2023). Because of extended contact, absorption gets a boost along with how well the treatment works. Such attachments include hydrogen bridges, charge based pulls, or meshing within the mucus layer itself. As a result, moving mucus and mechanical stress cut short how long drugs remain active at their target sites (Kwadwo Mfoafo, 2023).

A fresh category of functional materials thiolated polymers, sometimes called thiomers has stepped forward to address earlier shortcomings, offering stronger adhesion than older types. These modified substances form when sulfur containing   units get attached to long chain molecules, setting up conditions for stable disulfide links with cysteine packed regions in mucus proteins. Unlike early versions that relied on fleeting physical contact, this chemical bonding creates tougher attachment, longer stay times at tissue surfaces, and better delivery efficiency for medications (Kwadwo Mfoafo, 2023). What stands out is how tightly they bind through shared electrons, shifting the game subtly but significantly.

These connections form either via oxidation or through thiol disulfide swapping, creating strong attachments that frequently last between the polymer and mucus proteins. A key idea behind using such chemical behavior in delivering medicines emerged from studies led by scientists like Andreas Bernkop-Schn rch, who shaped early development in this area. His contributions are commonly recognized as the starting point for crafting sulfur modified polymers and expanding their role in pharmaceutical formulations (María José Alonso, 2023).

What drives much of the work on thiomers lies in how biological mucus functions not just as a shield but as a passage for medicines. Though it guards tissue beneath from invaders and physical harm, mucus also shortens how long drug carriers stay put due to its surface traits, which weakens medicine uptake. Attaching sulfur containing groups to polymer backbones greatly strengthens their grip on mucus by linking up through strong chemical bridges with cysteine parts found in mucin molecules (Tanmoy Sarkar, 2025)

Transport of medicine through tissue layers improves because these materials loosen cell to cell seals temporarily, influenced by shifts in certain membrane bound proteins. Instead of just sticking around, such polymers guard fragile medicines like peptides from breaking down too soon in mucus environments. Even complex agents, from tiny chemical compounds to protein based therapies and immunizations, benefit quietly under their influence. (Zahra Davoudi, 2025).

Forming bridges inside and between chains, thiolated polymers create gels right where needed thanks to disulfide linkages. These on the spot networks slow down how fast drugs leave the system while holding their shape better under stress both matter when targeting specific areas with medicine (Kwadwo Mfoafo, 2023).

Thiomers exhibit strong functional properties, leading to the development of various polymer based derivatives. Natural polymers such as chitosan, hyaluronic acid, cellulose, and starch are commonly thiolated due to their biocompatibility and enhanced mucoadhesion. For example, thiolated cellulose shows improved adhesion and permeation, overcoming limitations of native cellulose in oral and buccal drug delivery (Katharina Schneider, 2023).

Interest in thiolated polymers for mucosal drug delivery has increased due to their strong adhesion, improved retention, and better penetration of mucosal layers. These properties overcome limitations such as rapid washout and low drug loading. Some thiomer based formulations are already commercially available or approaching approval, particularly for conditions requiring prolonged contact with moist tissues, such as ocular disorders. Advances in thiomer synthesis and characterization have further expanded their applications in drug delivery (María Martínez-Rojas, 2022).

2. CHEMISTRY OF THIOLATED POLYMERS:

2.1 Concept of Thiolation:

Thiolation involves introducing thiol (–SH) groups into polymer backbones to enhance mucoadhesion. These thiol groups form disulfide bonds with cysteine residues in mucin glycoproteins, resulting in strong polymer–mucus interactions. This modification also provides redox responsiveness, improved drug protection, and enhanced stability (Tanmoy Sarkar, 2025).

2.2 Methods of Synthesis:

Thiolated polymers are typically prepared by attaching thiol containing molecules to functional groups on natural or synthetic polymers. The type of polymer and coupling agent influences the degree of thiolation, stability, and biological performance (José Antonio Gonzalez-Castro, 2024).

2.2.1 Carbodi-imide Mediated Coupling:

A widely used method involves carbodiimide coupling, where agents such as EDC (1ethyl3 (3dimethylaminopropyl) carbodiimide) activate carboxyl groups on polymers like alginate or hyaluronic acid. These activated groups react with amine containing thiol compounds such as cysteine (Chen Li, 2024).

This technique offers several advantages:

  • Mild reaction conditions
  • High coupling efficiency
  • Controlled degree of substitution
  • Compatibility with aqueous systems (Julia Griesser, 2022).

2.2.2 Thiolating Agents:

Depending on the polymer’s makeup and how it will be used, certain thiolating compounds work better than others

  • Cysteine: A commonly used agent containing both amine and thiol groups, allowing efficient polymer modification while preserving the reactive sulfhydryl group (Rajesh Patel, 2023).
  • Thioglycolic Acid: Used to introduce thiol groups into polymers such as chitosan through covalent attachment (Jitendra Singh, 2023).
  • 2Iminothiolane (Traut’s Reagent): Converts primary amine groups into thiols, particularly useful for amino polysaccharides.

2.2.3 Degree of Thiolation:

The amount of thiol groups attached per gram of polymer significantly affects polymer performance, including:

  • Mucoadhesive strength
  • Crosslinking ability
  • Swelling behavior
  • Drug release kinetics
  • Oxidative stability

An optimal thiolation level enhances adhesion while maintaining polymer stability (Katharina Schneider, 2023).

2.3 Characterization Techniques:

Several analytical methods are used to confirm thiolation and evaluate polymer properties.

2.3.1 Fourier Transform Infrared Spectroscopy:

Detects thiol groups and amide bond formation through characteristic absorption peaks.

  • Thiol stretching (~2550–2600 cm?¹)
  • Amide bond formation (~1650 cm?¹)

2.3.2 Nuclear Magnetic Resonance:

Confirms structural modification and quantifies the extent of thiolation.

2.3.3 Ellman’s Reagent Assay:

A yellow compound forms when Ellman’s reagent meets thiol groups. A colorimetric method used to determine free thiol content by measuring absorbance at 412 nm.

  • Total thiol content
  • Oxidized vs. reduced thiol fractions

Still regarded as the most reliable method for measuring thiols.

2.3.4 Rheological Studies:

Evaluate viscosity and gel formation, which influence mucoadhesion and drug release.

2.3.5 Zeta Potential Measurement:

Measures surface charge changes that affect mucosal interaction, nanoparticle stability, and drug loading efficiency. These altered charges impact:

  • Interaction with mucosal membranes
  • Nanoparticle stability
  • Drug loading efficiency

One reason thiolated chitosan sticks more effectively to mucosal layers is its stronger positive charge, which pulls harder on negative surface sites (Julia Griesser, 2022).

3. MECHANISM OF ACTION:

Thiolated polymers improve drug delivery by forming strong disulfide bonds with mucosal surfaces, enhancing adhesion, drug absorption, and protection against enzymatic degradation.

3.1 Mucoadhesion Mechanism:

A sticky quality lets certain materials cling to wet linings inside the body, staying longer where needed, so medicines work better right at the site. When sulfur hydrogen units sit along polymer chains, they latch onto mucus proteins packed with cysteine amino acids  these proteins build the mesh that gives slime its shape (Hernán Meresman, 2021).

R–SH+R′–S–S–R′′→R–S–S–R′+R′′–SH

Thiol groups (–SH) on polymer chains interact with cysteine rich mucin glycoproteins in mucus, forming strong disulfide bonds. These covalent interactions are stronger than hydrogen or electrostatic bonds, allowing polymers to remain attached to mucosal tissues in environments such as the oral cavity, nasal passages, and gastrointestinal tract. This adhesion prolongs drug residence time and improves localized drug delivery (Heni Rachmawati, 2024).

3.2 Permeation Enhancement:

Thiolated polymers enhance drug transport across epithelial tissues by modulating tight junctions and interacting with cell membranes.

  • Tight Junction Modulation: Thiomers temporarily open tight junction proteins such as Claudine and occludin, increasing paracellular drug transport while maintaining epithelial integrity (Jing Xu, 2023).
  • Moving Parts in Cell Membranes: They may also increase membrane fluidity, improving drug diffusion across biological membranes (Guan et al., 2021).

3.3 Enzyme Inhibition:

Thiomers protect drugs from enzymatic degradation through:

  • Steric shielding, where the polymer network physically blocks enzymes such as proteases.
  • Thiol–enzyme interactions, where thiol groups bind to enzyme sites and reduce enzymatic activity.

These effects are particularly beneficial for peptide and protein drugs (Yan Zhang, 2022).

3.4 Influence of Polymer Chemistry on How Things Perform:

The performance of thiolated polymers depends on factors such as:

  • Polymer backbone (natural or synthetic)
  • Degree of thiolation
  • Position of thiol groups
  • Molecular weight and polymer structure

For example, thiolated polysaccharides such as chitosan or hyaluronic acid show strong mucoadhesion, while synthetic thiomers allow better control over drug release and permeation (Jing Xu, 2023), (Yan Zhang, 2022).

Figure 1. Mechanism of action of thiolated polymers

4. THIOLATED POLYMERS VARIANTS:

Thiolated polymers are broadly classified into natural and synthetic thiomers. Natural polymers provide good biocompatibility and biodegradability, while synthetic polymers offer greater structural control and stability, allowing optimization for different drug delivery applications.

4.1 Natural Polymer Based Thiomers:

Natural polymers modified with thiol groups exhibit enhanced mucoadhesion, biocompatibility, and controlled drug release, making them suitable for mucosal drug delivery.

4.1.1 Thiolated Chitosan:

A widely studied cationic polymer derived from chitin. Thiolated chitosan improves mucoadhesion and permeation by temporarily opening epithelial tight junctions, making it useful for oral, buccal, and nasal delivery (Mohammad Sadegh Hosseini, 2024).

4.1.2 Thiolated Alginate:

Derived from brown algae, alginate can be chemically modified to introduce thiol groups. These polymers form pH responsive gels and are used in gastrointestinal drug and vaccine delivery (Rakesh Patel, 2021).

A shift toward higher pH triggers gel formation in thiolated alginate, offering controlled delivery within digestive tracts. This responsiveness supports prolonged substance release where acidity changes occur.

4.1.3 Thiolated Hyaluronic Acid:

A highly biocompatible polymer found in connective tissues. Thiolation enhances mucosal adhesion and in situ gel formation, supporting applications in ocular and mucosal drug delivery (Zhang, 2022).

Starting with modified HA, thiol groups allow gel development directly within biological environments through sulfur-sulfur bonds.

4.1.4 Thiolated Cellulose and Related Plant Based Polymers:

Modified cellulose, pectin, and starch show improved swelling, adhesion, and controlled drug release, particularly for buccal and colon targeted delivery systems.(Katharina Schneider, 2023). Despite limited exploration, modified versions of natural sugars like pectin and starch now draw attention due to their potential in delivering drugs directly to the colon or enabling oral uptake of peptides (Waleed Kooti, 2024).

Comparison Table: Natural Thiolated Polymers:

Table 1. Comparison Table: Natural Thiolated Polymers.

Thiolated Polymer

Key Attributes

Common Delivery Routes

Advantages

Limitations

Thiolated Chitosan

Cationic, mucoadhesive, permeation enhancer

Oral, Buccal, Nasal

Strong adhesion, tight junction modulation

Solubility dependent on pH

Thiolated Alginate

Anionic, gel forming

Oral vaccine, GI delivery

pH responsive release

Not ideal for ocular routes

Thiolated Hyaluronic Acid

Biocompatible, non-immunogenic

Ocular, Buccal

In situ gelation, retention

Higher cost vs. other polysaccharides

Thiolated Cellulose

Dual adhesion & permeation

Buccal, GI delivery

Stable matrix formation

Requires optimization for gelation

4.2 Synthetic Polymer Based Thiomers:

Synthetic thiomers allow precise control over molecular structure, stability, and drug release behavior.

4.2.1 Thiolated Polyacrylic Acid PAA:

A widely used thiomer due to its numerous carboxyl groups, enabling strong mucoadhesion, gel formation, and controlled drug release. Stability rises when PAA thiomers are pre-activated and shielded, reducing early oxidation of thiols this extends usable storage time while maintaining performance strength (Vivek Saxena, 2023).4.2.2 Thiolated Polyethylene Glycol PEG:

PEG based thiomers provide flexibility and excellent solubility, making them suitable for nanoparticles, hydrogels, and surface modified drug delivery systems. Polyethylene glycol thiomers prove especially useful in nanoscale particle setups, gels, and thin layers settings demanding precise control over outer characteristics (Yan Wang, 2024).

4.2.3 Copolymeric Systems:

These systems combine multiple polymers to produce stimuli responsive materials that react to pH, redox conditions, or enzymes, allowing more precise drug delivery (Priya Singh, 2024). Starting with thiol functional copolymers opens paths to materials that react to several triggers pH shifts, redox changes, or enzyme presence shaping how substances are delivered with precision.

Comparison Table: Synthetic Thiolated Polymers:

Table 2. Comparison Table: Synthetic Thiolated Polymers

Synthetic Thiomer

Key Attributes

Common Delivery Routes

Advantages

Limitations

Thiolated PAA

Strong adhesion, gel reinforcement

Oral, Buccal

Controlled release, modifiable

Susceptible to oxidation

Thiolated PEG

Flexible, soluble

NP systems, Coatings

Tunable surface properties

Requires complex synthesis

Copolymeric Thiomers

Hybrid properties

Nanocarriers, Hydrogels

Stimuli-responsive design

More complex formulation

Key Functional Differences:

Table 3. Key Functional Differences

Attribute

Natural Thiomers

Synthetic Thiomers

Biocompatibility

High

Variable, depends on polymer

Degradability

Biodegradable

Selective degradability

Chemical Control

Moderate

High

Physical Stability

Moderate

High

Formulation Versatility

Moderate

High

5. PHARMACEUTICAL APPLICATIONS OF THIOLATED POLYMERS:

Thiolated polymers enhance drug transport across mucosal barriers, protect drugs from enzymatic degradation, and enable controlled drug release, improving therapeutic effectiveness.

5.1 Oral Drug Delivery:

Oral delivery of peptides and proteins is limited by enzymatic degradation and poor absorption. Thiolated chitosan and alginate formulations (tablets and micro particles) improve mucosal adhesion and enhance the oral absorption of drugs such as insulin (Ghada M. El-Zaafarany, 2022).

5.2 Buccal and Sublingual Delivery Methods:

Thiomers improve drug retention in the buccal and sublingual mucosa, enabling sustained release. Systems such as thiolated chitosan hydrogels and hyaluronic acid films have been explored for peptide drugs, cardiovascular agents, and analgesics (Rabiee, 2023), (Singh Pradeep, 2024).

5.3 Nasal Delivery:

Thiolated polymers, particularly thiolated chitosan and polyacrylic acid, form gels or nanoparticles that enhance nasal residence time and mucosal penetration. These systems have shown potential for vaccine and peptide drug delivery (Zhao, Liu, & Chen, 2022).

5.4 Ocular Delivery:

Drug delivery to the eye is limited by tear drainage and low corneal permeability. Thiolated polymer based gels and eye drops improve adhesion to the ocular mucosa, increasing drug residence time and therapeutic effectiveness in conditions such as glaucoma and infections (Gao Yan, 2023).

5.5 Vaginal and Rectal Delivery:

Thiolated polymers such as thiolated cellulose and hyaluronic acid enhance mucosal adhesion and reduce leakage, making them suitable for local drug delivery, infection treatment, and hormone therapy (Mansouri Sara, 2024).

5.6 Gastroretentive Systems:

Thiolated polymers are used in floating or swelling gastroretentive tablets, improving gastric retention and enhancing drug absorption in the stomach and upper intestine (Ghosh Anirban, 2025).

5.7 Nanoparticles:

Thiolated polymer nanoparticles, angels, and hydrogels protect drugs, improve mucus penetration, and allow controlled release, showing promise in anticancer and antiviral drug delivery (Kyeong Lee, 2023).

6. ADVANCED THIOMER SYSTEMS:

Modern thiolated polymers have evolved beyond simple mucoadhesion. Through modified backbones and structured polymer networks, advanced thiomers improve drug release control, stability, and site-specific delivery, addressing issues such as thiol oxidation, variable dosing, and poor targeting.

6.1. S-Protected Thiomers:

A major limitation of conventional thiomers is oxidative degradation of free thiol groups during storage. S-protected thiomers overcome this by introducing protective groups on sulfur atoms that remain stable during storage but are cleaved in the body by biological reductants such as glutathione.

Advantages:

  • Improved shelf stability
  • Controlled activation in biological environments
  • Increased availability of active thiol groups at the mucosal site

Examples

Work by Lim and Kim in 2024 (Kim, 2024) showed that certain polymer forms modified with protected thiols stick more effectively to mucosal surfaces. Response depends on both pH levels and redox states within the surroundings.

6.2 Redox Responsive Thiomer Systems:

Redox responsive thiomers utilize the natural oxidation–reduction variations present in biological environments such as the gastrointestinal tract, tumor tissues, and intracellular compartments. These changes trigger structural modifications in the polymer, enabling site-specific drug release.

Mechanism:

In reducing environments with high levels of intracellular glutathione, disulfide bonds within the thiomer network are cleaved, leading to:

  • Polymer network degradation
  • Triggered drug release
  • Reduced mucoadhesion at the target site

Applications:

  • Tumor targeted drug delivery
  • Intracellular delivery of proteins and nucleic acids
  • Controlled drug release from redox responsive hydrogels

Overall, these systems enable precise drug release under reducing biological conditions, improving targeted therapeutic delivery (Hong Jiang, 2023).

6.3 Stimuli Responsive Hydrogels

Stimuli responsive thiomer hydrogels react to environmental changes such as pH, temperature, enzymes, or ionic strength. The presence of thiol groups provides strong mucoadhesion, while environmental responsiveness enables controlled and site-specific drug release.

Typical Designs:

  • pH responsive hydrogels: swell in acidic or basic environments
  • Enzyme sensitive hydrogels: degrade in the presence of specific enzymes
  • Thermo responsive hydrogels: form gels at body temperature

Example:

Thiolated poly(Nisopropylacrylamide) hydrogels become stronger at body temperature while adhering to mucosal tissues, allowing drug release to adjust according to physiological conditions such as temperature and pH (Donghyun Kim, 2020).

6.4 Thiomer Interpenetrating Networks (IPNs)

Interpenetrating polymer networks (IPNs) consist of two physically intertwined polymer networks without covalent bonds, improving mechanical strength and stability.

When thiomers are combined with polymers such as polyethylene glycol (PEG) or acrylic acid derivatives, the systems show:

  • Enhanced mechanical strength
  • Controlled swelling and drug release
  • Improved mucoadhesion

These thiomer based IPNs are promising for sustained drug delivery, injectable systems, and wound healing applications due to their stability and controlled release properties (Qiang Tan, 2025).

7. LIMITATIONS AND CHALLENGES:

Although thiolated polymers provide significant advantages in drug delivery, several scientific, formulation, and regulatory challenges limit their widespread application (Alvarez-Rodriguez, 2024).

7.1 Oxidation Instability in Thiol Groups:

Free thiol (–SH) groups are highly sensitive to oxygen and may oxidize during storage or processing, forming premature disulfide bonds. This reduces the availability of reactive thiols and weakens mucoadhesion. Stabilization strategies such as antioxidants, S-protected thiomers, and inert packaging are often used, but they increase formulation complexity (Fernandez, R., & Diego, 2022).

To prevent this, those preparing formulations often apply safeguards like:

  • Use of antioxidants (e.g., ascorbic acid, glutathione)
  • Protection of thiols, such as through S-protected derivatives like thiomers
  • Modified packaging (inert atmosphere)

Still, such methods complicate production processes while demanding precise tuning to prevent issues with medication integrity (Aftab Ullah Khan, 2024).

7.2 Storing and Handling Data Problems:

Thiolated polymers can lose activity during storage, drying, or sterilization processes. Techniques such as lyophilization or heat sterilization may accelerate thiol oxidation, requiring stabilizers and controlled conditions, which can increase production costs (Alejandro, Marta, & Antonio, 2023).

7.3 Batch Differences and Consistent Results:

Variations in pH, temperature, and polymer characteristics during synthesis can affect the degree of thiolation, leading to inconsistent mucoadhesion and drug release. Reliable analytical methods such as Ellman’s assay and HPLC are necessary for quality control (Pérez Elena, 2024).

When evaluating quality control, standardized protocols together with strong analytical methods like Ellman’s assay or HPLC measurement play a key role, though they demand more support and skilled personnel (Sharma Rakesh, 2024).

7.4 Potential Toxicity and Biocompatibility Concerns:

Although thiomers are derived from generally safe polymers, chemical modification may introduce residual reagents or strong polymer–cell interactions, which could cause irritation or inflammation in sensitive tissues (Rajesh Singh, 2022).

Cellular Interaction Challenges:

Frequently, thiol groups attach to membrane proteins instead of just binding receptors on the cell surface. Firm chemical bonds could disrupt regular cell balance. Sometimes, tight attachments alter natural repair cycles. Persistent bonding often disturbs steady conditions. Sensitive linings like those around the eye or inside the vagina may react uncomfortably. Such sites sometimes respond poorly to certain substances (Zhou Jian, 2023).

7.5 Scaling Up Production Challenges:

Producing thiolated polymers at scale for market use runs into practical hurdles because of:

  • Requirement for controlled reaction environments
  • Need for stabilization strategies (S-protection)
  • Sensitive handling and storage conditions
  • Quality control of thiol content and polymer integrity

Still, making these materials work well means cutting corners without losing quality. Without smarter production methods, factories might skip using improved thiomers altogether.

7.6 Regulatory Considerations:

Regulatory classification of thiomers remains complex because they may function as both excipients and biologically active delivery systems. As a result, extensive safety, toxicology, and efficacy evaluations are required, which can delay clinical translation (Helen Foster, 2023).

8. FUTURE PERSPECTIVES AND RESEARCH GAPS:

Despite significant progress in the development of thiolated polymers (thiomers), several scientific, technological, and regulatory challenges still limit their widespread clinical use. Future research should focus on improving polymer design, enhancing safety evaluation, and developing standardized characterization methods.

8.1 Improvements in polymer design and how they are modified:

Current research is moving beyond first-generation thiomers toward pre-activated and multifunctional thiomers with improved stability and mucoadhesion. Emerging systems include stimuli responsive thiomers and block co-polymer based structures, which can provide controlled drug release under specific physiological conditions (Hauptstein Sarah, 2020), (Zhang Tao, 2023).

8.2 Smart responsive thiomers with dynamic behavior:

Next generation thiomers are being designed to respond to pH, redox conditions, enzymes, and temperature. These responsive systems enable site-specific drug delivery, particularly in tumors or inflamed tissues, and show potential in gene and intracellular drug delivery (Li Hua, 2022).

8.3 Thiomers for Delivering Biologics and Large Molecules:

Thiomers are promising carriers for peptides, proteins, vaccines, and nucleic acids due to their ability to enhance mucosal permeability and residence time. However, further studies are needed on long term safety, standardized permeability models, and comparisons with existing permeation enhancers (Rathore, Kesharwani, & Jain, 2021).

8.4 Clinical Translation Challenges:

Key barriers to clinical application include:

  • Regulatory classification as novel excipients
  • Batch to batch variability in thiolation degree
  • Oxidative instability of thiol groups
  • Challenges in large scale GMP production

Future work should focus on standardized characterization, improved stability, and simplified synthesis methods. (Leichner Christina, 2019), (Puri Varun, 2020)

8.5 Nanotechnology and Advanced Drug Delivery Systems:

Thiomers are increasingly incorporated into nanoparticles, micelles, hydrogels, nanofibers, and 3Dprinted systems. These technologies enable sustained drug delivery, improved tissue adhesion, and enhanced therapeutic performance, particularly in wound healing and regenerative medicine (Chen Li, 2024), (Federer Christina, 2021)

8.6 Standardization and Characterization Gaps:

A major limitation is the lack of standardized methods for evaluating:

  • Degree of thiolation
  • Disulfide bond content
  • Mucoadhesive strength
  • In vitro–in vivo correlation (IVIVC)

Developing global testing standards and predictive mucosal models will improve reproducibility across studies.

8.7 Safety and Long Term Toxicity Research Gaps:

Although thiomers generally show good short term safety, long term toxicity data remain limited. Future research should evaluate:

  • Chronic mucosal exposure
  • Immunogenicity
  • Oxidative stress
  • Effects on the microbiome

8.8 Custom treatments with targeted delivery:

Combining thiomers with 3D printing, machine learning, and advanced formulation design may enable patient specific drug delivery systems, such as customized mucoadhesive patches and controlled release implants.

8.9 Sustainability and Green Chemistry Considerations:

Future thiomer development should also focus on sustainable synthesis, including:

  • Ecofriendly thiolation reagents
  • Reduced solvent use
  • Biodegradable polymer backbones
  • Energy efficient production methods

CONCLUSION

Thiomers, developed from polymer chains with sulfur based groups, are emerging as critical components in advanced drug formulation due to their superior adhesive properties. These materials form strong chemical bonds with mucus, ensuring a longer residence time and adaptability on biological surfaces. By creating disulfide bridges, thiomers enhance the stability of gel structures for gradual drug release. They improve oral drug uptake by prolonging retention in the stomach and enhancing absorption in the intestines, particularly for therapeutics requiring localized intestinal delivery. Their efficacy extends to mucosal delivery systems, increasing drug retention in tissues, which translates to stronger therapeutic effects and a reduced dosing frequency.

However, transitioning thiolated polymers from laboratory successes to clinical applications is fraught with challenges. Inconsistent measurement methods for critical properties, such as sulfur group density and mucus binding capability, hinder comparability across studies. Future progress relies on establishing standardized testing frameworks and robust manufacturing methodologies. While initial safety assessments seem manageable, comprehensive long term safety evaluations are lacking, especially concerning gastrointestinal and nasal delivery routes, necessitating thorough toxicity studies in relevant biological contexts. The future of thiomers is poised for advancements, with potential developments including multifunctional systems capable of timed drug release triggered by redox signals. Their incorporation into nanoparticles or other delivery systems may enhance their utility across various medical domains, opening avenues for precision drug targeting, tissue regeneration, and collaboration with biological therapies like gene editing or vaccines. The use of computational algorithms for formulation optimization is set to expedite progress. However, overcoming regulatory and production challenges will require multidisciplinary cooperation among chemists, clinicians, pharmaceutical researchers, and policymakers. A unified approach toward ensuring the reproducibility of results will be crucial for the widespread medical adoption of thiomers within the next decade.

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  15. Hernán Meresman, D. O. (2021). Mechanistic evaluation of thiolated polymers for mucoadhesive drug delivery. International Journal of Pharmaceutics, 610, Article 121242. doi:https://doi.org/10.1016/j.ijpharm.2021.121242
  16. Hong Jiang, X. S. (2023). Redoxresponsive thiolated hydrogels for targeted intracellular delivery. Advanced Functional Materials, 33(15), Article number 2300545. doi:https://doi.org/10.1002/adfm.202300545
  17. Jing Xu, J. Z. (2023). Tight junction modulation by thiolated chitosan for enhanced drug absorption. Biomacromolecules, 24(2), 834–846. doi:https://doi.org/10.1021/acs.biomac.2c01012
  18. Jitendra Singh, P. V. (2023). Multifunctional thiolated polymer carriers for responsive drug delivery: A review. International Journal of Pharmaceutics, 615, Article 121546. doi:https://doi.org/10.1016/j.ijpharm.2023.121546
  19. José Antonio GonzalezCastro, I. M. (2024). Enhanced oral peptide bioavailability via thiolated copolymer carriers: Mechanistic studies. European Journal of Pharmaceutics and Biopharmaceutics, 192, 23–36. doi:https://doi.org/10.1016/j.ejpb.2024.104421
  20. Julia Griesser, G. H.S. (2022). Thiolated polymers: A comprehensive review on chemistry and characterization strategies. Carbohydrate Polymers, 278, Article 118940. doi:https://doi.org/10.1016/j.carbpol.2021.118940
  21. Katharina Schneider, M. L.S. (2023). Thiolated cellulose: A dualacting mucoadhesive and permeationenhancing polymer. Biomacromolecules, 24(9), 3567–3576. doi:https://doi.org/10.1021/acs.biomac.3c00577
  22. Kim, K. L. (2024). Sprotected thiolated polymers: Enhancing stability and mucoadhesion. European Journal of Pharmaceutics and Biopharmaceutics, 199, Article number 112432. doi:https://doi.org/10.1016/j.ejpb.2024.112432
  23. Kwadwo Mfoafo, R. M. (2023). Thiolated polymers: An overview of mucoadhesive properties and their potential in drug delivery via mucosal tissues. Journal of Drug Delivery Science and Technology, 85, Article number: 104596. doi:https://doi.org/10.1016/j.jddst.2023.104596
  24. Kyeong Lee, H. P. (2023). Thiolated PEG nanoparticles for enhanced mucosal adhesion and penetration of anticancer drugs. Journal of Nanobiotechnology, 21(1), Article number 178. doi:https://doi.org/10.1186/s12951023018459
  25. Leichner Christina, J. M.S. (2019). Thiolated polymers: Bioinspired polymers utilizing one of the most important bridging structures in nature. Advanced Drug Delivery Reviews, 151152, 191–221. doi:https://doi.org/10.1016/j.addr.2019.04.007
  26. Li Hua, Z. J. (2022). Redoxresponsive thiolated polymer systems for targeted intracellular drug delivery. Acta Biomaterialia, 146, 67–83. doi:https://doi.org/10.1016/j.actbio.2022.05.015
  27. Mansouri Sara, S. M. (2024). Vaginal delivery of antiviral agents using thiolated cellulose hydrogels with improved mucoadhesion. International Journal of Biological Macromolecules, 240, Article number: 124683. doi:https://doi.org/10.1016/j.ijbiomac.2024.124683
  28. María José Alonso, A. P. (2023). Comparative mucoadhesive performance of thiolated and nonthiolated polymers in buccal and intestinal models. Journal of Pharmaceutical Sciences, 112(10), 3488–3502. doi:https://doi.org/10.1016/j.xphs.2023.05.014
  29. María MartínezRojas, P. L.S. (2022). Mucoadhesive comparison of thiolated hyaluronic acid and hydroxypropyl methylcellulose films. International Journal of Biological Macromolecules, 222, 1305–1314. doi:https://doi.org/10.1016/j.ijbiomac.2022.12.087
  30. Mohammad Sadegh Hosseini, M. J. (2024). Thiolated chitosan: A multifunctional mucoadhesive for enhanced drug delivery across mucosal barriers. International Journal of Biological Macromolecules, 235, Article 123228. doi:https://doi.org/10.1016/j.ijbiomac.2023.123228
  31. Pérez Elena, T. L. (2024). Toxicokinetics and systemic exposure following mucosal delivery of thiolated polymers. Toxicology Reports, 11, 10245–10257. doi:https://doi.org/10.1016/j.toxrep.2024.102457
  32. Priya Singh, N. G. (2024). Copolymer thiomers: Design of multiresponsive mucoadhesive systems. Journal of Controlled Release, 364, 345–359. doi:https://doi.org/10.1016/j.jconrel.2024.03.017
  33. Puri Varun, S. A. (2020). Thiolation of biopolymers for developing drug delivery systems with enhanced mechanical and mucoadhesive properties. Polymers, 12(8), Article 1803. doi:https://doi.org/10.3390/polym12081803
  34. Qiang Tan, L. W. (2025). Thiolated interpenetrating polymer network hydrogels for longacting drug delivery. Journal of Controlled Release, 378, 54–72. doi:https://doi.org/10.1016/j.jconrel.2024.12.012
  35. Rabiee, S. R. (2023). Buccal mucoadhesive thiolated hyaluronic acid films for sustained peptide delivery. Journal of Controlled Release, 351, 462–480. doi:https://doi.org/10.1016/j.jconrel.2023.06.012
  36. Rajesh Patel, S. S. (2023). Controlled release profiles of macromolecules from thiolated interpenetrating polymer gels. Journal of Drug Delivery Science and Technology, 71, Article 103546. doi:https://doi.org/10.1016/j.jddst.2022.103546
  37. Rajesh Singh, S. V. (2022). Genotoxicity evaluation of novel thiolated polymeric systems: In vitro and in vivo assessment. Mutation Research/Genetic Toxicology and Environmental Mutagenesis, 873, Article 503412. doi:https://doi.org/10.1016/j.mrgentox.2022.503412
  38. Rakesh Patel, T. M. (2021). Thiolated alginate in vaccine delivery applications: Gelation properties and mucosal interaction. Journal of Applied Polymer Science, 138(21), Article Number: e50741. doi:https://doi.org/10.1002/app.50741
  39. Rathore, K. S., Kesharwani, P., & Jain, N. K. (2021). Thiolated chitosan nanoparticles for oral insulin delivery: In vivo evaluation and mechanistic insights. Carbohydrate Polymers, 260, Article 117802. doi:https://doi.org/10.1016/j.carbpol.2021.117802
  40. Sharma Rakesh, G. R. (2024). Analytical challenges and reproducibility in thiolated polymer production. Analytical and Bioanalytical Chemistry, 416(10), 2153–2167. doi:https://doi.org/10.1007/s00216024047446
  41. Singh Pradeep, G. N. (2024). Thiolated polymers for buccal and sublingual drug delivery: Mechanisms and clinical potential. Journal of Pharmaceutical Sciences, 113(9), 3521–3535. doi:https://doi.org/10.1016/j.xphs.2024.05.013
  42. Tanmoy Sarkar, A. D. (2025). Thiol modification of polysaccharides to improve mucoadhesive properties for buccal drug delivery applications. International Journal of Pharmaceutics, 677, Article 125641. doi:https://doi.org/10.1016/j.ijpharm.2025.125641
  43. Vivek Saxena, L. K. (2023). Sprotected thiolated PAA for improved stability and mucoadhesion. European Journal of Pharmaceutics and Biopharmaceutics, 181, 15–28. doi:https://doi.org/10.1016/j.ejpb.2023.06.004
  44. Waleed Kooti, D. A.S. (2024). Thiolated starch and pectin for improved oral colon delivery: Mucoadhesion and swelling. Carbohydrate Polymers, 277, Article Number: 118857. doi:https://doi.org/10.1016/j.carbpol.2021.118857
  45. Yan Wang, Z. Z. (2024). Thiolated PEGbased nanoparticles for enhanced mucosal adhesion and drug delivery. Biomaterials Science, 12(5), 1459–1474. doi:https://doi.org/10.1039/d4bm00021a
  46. Yan Zhang, W. L. (2022). Thiolated polymers for oral peptide delivery: Current status and mechanistic insights. Journal of Pharmaceutical Sciences, 111(11), 3199–3210. doi:https://doi.org/10.1016/j.xphs.2022.07.001
  47. Zahra Davoudi, G. K.S. (2025). Highly thiolated corn starch for enhanced mucoadhesion and permeation. International Journal of Pharmaceutics, 677, Article number: 125798. doi:https://doi.org/10.1016/j.ijpharm.2025.125798
  48. Zhang Tao, W. Q. (2023). Multifunctional thiolated polymers for stimuliresponsive drug delivery applications. Advanced Drug Delivery Reviews, 196, Article 114755. doi:https://doi.org/10.1016/j.addr.2023.114755
  49. Zhang, J. L. (2022). Thiolated hyaluronic acid: Mucoadhesive and in situ gelling systems for enhanced ocular delivery. Journal of Pharmaceutical Sciences, 111(7), 1979–1988. doi:https://doi.org/10.1016/j.xphs.2022.01.030
  50. Zhao, Z., Liu, H., & Chen, J. (2022). Nasal vaccines delivered with thiolated poly(acrylic acid) gel systems: Enhanced immunogenicity and retention. Carbohydrate Polymers, 279, Article number: 119017. doi:https://doi.org/10.1016/j.carbpol.2021.119017
  51. Zhou Jian, L. X. (2023). In vitro cytotoxicity evaluation of thiolated chitosan nanoparticles in epithelial cell models. International Journal of Pharmaceutics, 625, Article 122144. doi:https://doi.org/10.1016/j.ijpharm.2023.122144

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  15. Hernán Meresman, D. O. (2021). Mechanistic evaluation of thiolated polymers for mucoadhesive drug delivery. International Journal of Pharmaceutics, 610, Article 121242. doi:https://doi.org/10.1016/j.ijpharm.2021.121242
  16. Hong Jiang, X. S. (2023). Redoxresponsive thiolated hydrogels for targeted intracellular delivery. Advanced Functional Materials, 33(15), Article number 2300545. doi:https://doi.org/10.1002/adfm.202300545
  17. Jing Xu, J. Z. (2023). Tight junction modulation by thiolated chitosan for enhanced drug absorption. Biomacromolecules, 24(2), 834–846. doi:https://doi.org/10.1021/acs.biomac.2c01012
  18. Jitendra Singh, P. V. (2023). Multifunctional thiolated polymer carriers for responsive drug delivery: A review. International Journal of Pharmaceutics, 615, Article 121546. doi:https://doi.org/10.1016/j.ijpharm.2023.121546
  19. José Antonio GonzalezCastro, I. M. (2024). Enhanced oral peptide bioavailability via thiolated copolymer carriers: Mechanistic studies. European Journal of Pharmaceutics and Biopharmaceutics, 192, 23–36. doi:https://doi.org/10.1016/j.ejpb.2024.104421
  20. Julia Griesser, G. H.S. (2022). Thiolated polymers: A comprehensive review on chemistry and characterization strategies. Carbohydrate Polymers, 278, Article 118940. doi:https://doi.org/10.1016/j.carbpol.2021.118940
  21. Katharina Schneider, M. L.S. (2023). Thiolated cellulose: A dualacting mucoadhesive and permeationenhancing polymer. Biomacromolecules, 24(9), 3567–3576. doi:https://doi.org/10.1021/acs.biomac.3c00577
  22. Kim, K. L. (2024). Sprotected thiolated polymers: Enhancing stability and mucoadhesion. European Journal of Pharmaceutics and Biopharmaceutics, 199, Article number 112432. doi:https://doi.org/10.1016/j.ejpb.2024.112432
  23. Kwadwo Mfoafo, R. M. (2023). Thiolated polymers: An overview of mucoadhesive properties and their potential in drug delivery via mucosal tissues. Journal of Drug Delivery Science and Technology, 85, Article number: 104596. doi:https://doi.org/10.1016/j.jddst.2023.104596
  24. Kyeong Lee, H. P. (2023). Thiolated PEG nanoparticles for enhanced mucosal adhesion and penetration of anticancer drugs. Journal of Nanobiotechnology, 21(1), Article number 178. doi:https://doi.org/10.1186/s12951023018459
  25. Leichner Christina, J. M.S. (2019). Thiolated polymers: Bioinspired polymers utilizing one of the most important bridging structures in nature. Advanced Drug Delivery Reviews, 151152, 191–221. doi:https://doi.org/10.1016/j.addr.2019.04.007
  26. Li Hua, Z. J. (2022). Redoxresponsive thiolated polymer systems for targeted intracellular drug delivery. Acta Biomaterialia, 146, 67–83. doi:https://doi.org/10.1016/j.actbio.2022.05.015
  27. Mansouri Sara, S. M. (2024). Vaginal delivery of antiviral agents using thiolated cellulose hydrogels with improved mucoadhesion. International Journal of Biological Macromolecules, 240, Article number: 124683. doi:https://doi.org/10.1016/j.ijbiomac.2024.124683
  28. María José Alonso, A. P. (2023). Comparative mucoadhesive performance of thiolated and nonthiolated polymers in buccal and intestinal models. Journal of Pharmaceutical Sciences, 112(10), 3488–3502. doi:https://doi.org/10.1016/j.xphs.2023.05.014
  29. María MartínezRojas, P. L.S. (2022). Mucoadhesive comparison of thiolated hyaluronic acid and hydroxypropyl methylcellulose films. International Journal of Biological Macromolecules, 222, 1305–1314. doi:https://doi.org/10.1016/j.ijbiomac.2022.12.087
  30. Mohammad Sadegh Hosseini, M. J. (2024). Thiolated chitosan: A multifunctional mucoadhesive for enhanced drug delivery across mucosal barriers. International Journal of Biological Macromolecules, 235, Article 123228. doi:https://doi.org/10.1016/j.ijbiomac.2023.123228
  31. Pérez Elena, T. L. (2024). Toxicokinetics and systemic exposure following mucosal delivery of thiolated polymers. Toxicology Reports, 11, 10245–10257. doi:https://doi.org/10.1016/j.toxrep.2024.102457
  32. Priya Singh, N. G. (2024). Copolymer thiomers: Design of multiresponsive mucoadhesive systems. Journal of Controlled Release, 364, 345–359. doi:https://doi.org/10.1016/j.jconrel.2024.03.017
  33. Puri Varun, S. A. (2020). Thiolation of biopolymers for developing drug delivery systems with enhanced mechanical and mucoadhesive properties. Polymers, 12(8), Article 1803. doi:https://doi.org/10.3390/polym12081803
  34. Qiang Tan, L. W. (2025). Thiolated interpenetrating polymer network hydrogels for longacting drug delivery. Journal of Controlled Release, 378, 54–72. doi:https://doi.org/10.1016/j.jconrel.2024.12.012
  35. Rabiee, S. R. (2023). Buccal mucoadhesive thiolated hyaluronic acid films for sustained peptide delivery. Journal of Controlled Release, 351, 462–480. doi:https://doi.org/10.1016/j.jconrel.2023.06.012
  36. Rajesh Patel, S. S. (2023). Controlled release profiles of macromolecules from thiolated interpenetrating polymer gels. Journal of Drug Delivery Science and Technology, 71, Article 103546. doi:https://doi.org/10.1016/j.jddst.2022.103546
  37. Rajesh Singh, S. V. (2022). Genotoxicity evaluation of novel thiolated polymeric systems: In vitro and in vivo assessment. Mutation Research/Genetic Toxicology and Environmental Mutagenesis, 873, Article 503412. doi:https://doi.org/10.1016/j.mrgentox.2022.503412
  38. Rakesh Patel, T. M. (2021). Thiolated alginate in vaccine delivery applications: Gelation properties and mucosal interaction. Journal of Applied Polymer Science, 138(21), Article Number: e50741. doi:https://doi.org/10.1002/app.50741
  39. Rathore, K. S., Kesharwani, P., & Jain, N. K. (2021). Thiolated chitosan nanoparticles for oral insulin delivery: In vivo evaluation and mechanistic insights. Carbohydrate Polymers, 260, Article 117802. doi:https://doi.org/10.1016/j.carbpol.2021.117802
  40. Sharma Rakesh, G. R. (2024). Analytical challenges and reproducibility in thiolated polymer production. Analytical and Bioanalytical Chemistry, 416(10), 2153–2167. doi:https://doi.org/10.1007/s00216024047446
  41. Singh Pradeep, G. N. (2024). Thiolated polymers for buccal and sublingual drug delivery: Mechanisms and clinical potential. Journal of Pharmaceutical Sciences, 113(9), 3521–3535. doi:https://doi.org/10.1016/j.xphs.2024.05.013
  42. Tanmoy Sarkar, A. D. (2025). Thiol modification of polysaccharides to improve mucoadhesive properties for buccal drug delivery applications. International Journal of Pharmaceutics, 677, Article 125641. doi:https://doi.org/10.1016/j.ijpharm.2025.125641
  43. Vivek Saxena, L. K. (2023). Sprotected thiolated PAA for improved stability and mucoadhesion. European Journal of Pharmaceutics and Biopharmaceutics, 181, 15–28. doi:https://doi.org/10.1016/j.ejpb.2023.06.004
  44. Waleed Kooti, D. A.S. (2024). Thiolated starch and pectin for improved oral colon delivery: Mucoadhesion and swelling. Carbohydrate Polymers, 277, Article Number: 118857. doi:https://doi.org/10.1016/j.carbpol.2021.118857
  45. Yan Wang, Z. Z. (2024). Thiolated PEGbased nanoparticles for enhanced mucosal adhesion and drug delivery. Biomaterials Science, 12(5), 1459–1474. doi:https://doi.org/10.1039/d4bm00021a
  46. Yan Zhang, W. L. (2022). Thiolated polymers for oral peptide delivery: Current status and mechanistic insights. Journal of Pharmaceutical Sciences, 111(11), 3199–3210. doi:https://doi.org/10.1016/j.xphs.2022.07.001
  47. Zahra Davoudi, G. K.S. (2025). Highly thiolated corn starch for enhanced mucoadhesion and permeation. International Journal of Pharmaceutics, 677, Article number: 125798. doi:https://doi.org/10.1016/j.ijpharm.2025.125798
  48. Zhang Tao, W. Q. (2023). Multifunctional thiolated polymers for stimuliresponsive drug delivery applications. Advanced Drug Delivery Reviews, 196, Article 114755. doi:https://doi.org/10.1016/j.addr.2023.114755
  49. Zhang, J. L. (2022). Thiolated hyaluronic acid: Mucoadhesive and in situ gelling systems for enhanced ocular delivery. Journal of Pharmaceutical Sciences, 111(7), 1979–1988. doi:https://doi.org/10.1016/j.xphs.2022.01.030
  50. Zhao, Z., Liu, H., & Chen, J. (2022). Nasal vaccines delivered with thiolated poly(acrylic acid) gel systems: Enhanced immunogenicity and retention. Carbohydrate Polymers, 279, Article number: 119017. doi:https://doi.org/10.1016/j.carbpol.2021.119017
  51. Zhou Jian, L. X. (2023). In vitro cytotoxicity evaluation of thiolated chitosan nanoparticles in epithelial cell models. International Journal of Pharmaceutics, 625, Article 122144. doi:https://doi.org/10.1016/j.ijpharm.2023.122144

Photo
Pathan Saniya
Corresponding author

Department of Pharmaceutics, Samarth Institute of Pharmacy, Belhe, Maharashtra, India

Photo
Datkhile Sachin
Co-author

Department of Pharmaceutics, Samarth Institute of Pharmacy, Belhe, Maharashtra, India

Photo
Wagh Sayali
Co-author

Department of Pharmaceutics, Samarth Institute of Pharmacy, Belhe, Maharashtra, India

Photo
Ramteke Kuldeep
Co-author

Department of Pharmaceutics, Samarth Institute of Pharmacy, Belhe, Maharashtra, India

Pathan Saniya, Datkhile Sachin, Wagh Sayali, Ramteke Kuldeep, Thiolated Polymer Based Drug Delivery Systems: Recent Advances, Regulatory Considerations, And Future Directions, Int. J. of Pharm. Sci., 2026, Vol 4, Issue 4, 3235-3251. https://doi.org/10.5281/zenodo.19673590

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