Three generations of thiolated cyclodextrins: A direct comparison of their mucus permeating and mucoadhesive properties

Haddadzadegan, Soheil; Knoll, Patrick; Wibel, Richard; Kali, Gergely; Bernkop-Schnürch, Andreas

doi:10.1016/j.actbio.2023.05.050

Cited by 7 publications

(24 citation statements)

References 47 publications

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“…18,25,38 Merely, PEG S-protected γ-CD-SH could reach, in the same experimental setup as described in this study, all mucus sections in a detectable amount due to mucus penetrating properties of PEG. 25 The advantageous property of S-protected β-CD-SS-MESNA lies in its ability to penetrate the firm mucus layer before it interacts with cysteines, which remain unaffected by the natural mucus turnover process. Contrarily, the poorly diffusing β-CD-SH reacts with the loose outer mucus layer, removed rapidly by this mucus clearance process, reducing this excipient's residence time.…”

Section: Acsmentioning

confidence: 64%

Enhanced Mucoadhesion of Thiolated β-Cyclodextrin by S-Protection with 2-Mercaptoethanesulfonic Acid

Kali,

Taha,

Campanella

et al. 2024

ACS Omega

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This study aimed at designing an S-protected thiolated β-cyclodextrin (β-CD) exhibiting enhanced mucoadhesive properties. The native β-CD was thiolated with phosphorus pentasulfide resulting in a thiolated β-CD (β-CD-SH) and subsequently Sprotected with 2-mercaptoethanesulfonate (MESNA) to form β-CD-SS-MESNA. The structure of the novel excipient was confirmed by 1 H NMR and Fourier-transform infrared spectroscopy. The sulfhydryl content of β-CD-SH, determined by Ellman's test, was 2281.00 ± 147 μmol/g, and it was decreased to 45.93 ± 19.40 μmol/g by Sprotection. Due to thiolation and S-protection, the viscosity of the mixture of mucus with β-CD-SH and β-CD-SS-MESNA increased 1.8 and 4.1-fold, compared to native β-CD, respectively. The unprotected β-CD-SH diffused to a lesser extent into the mucus than native β-CD, while S-protected β-CD-SS-MESNA showed the highest mucodiffusion among the applied CDs. A 1.5-and 3.0-fold higher cellular uptake of β-CD-SH and β-CD-SS-MESNA, compared to the native one, was established on Caco-2 cell line by flow cytometry, respectively, causing slightly decreased cell viability. On account of the enhanced mucoadhesion, this higher cellular uptake does not affect the application potential of β-CD-SS-MESNA as an oral drug delivery system since the carrier remains in the mucus and does not reach the underlying epithelial layer. According to these results, the S-protection of β-CD-SH with MESNA promotes improved mucodiffusion, strong mucoadhesion, and prolonged mucosal residence time.

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Section: Acsmentioning

confidence: 64%

Enhanced Mucoadhesion of Thiolated β-Cyclodextrin by S-Protection with 2-Mercaptoethanesulfonic Acid

Kali,

Taha,

Campanella

et al. 2024

ACS Omega

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“…Thiolated excipients are able to form disulfide bonds with cysteine-rich mucus glycoproteins, thereby causing an increase in viscosity. Strong interactions between nanocarrier and mucus should thus be mirrored by an apparent time-dependent increase in viscosity. , Results of the rheological studies are illustrated in Figure .…”

Section: Resultsmentioning

confidence: 99%

“…Interactions between thiolated and nonthiolated nanoemulsions with mucus were investigated by time-dependent rheological measurements with a cone–plate combination rheometer (HAAKE Mars Rheometer, Thermo Scientific, Vienna, Austria). , Therefore, 100 μL of nanoemulsions prepared in 50 mM HEPES buffer at pH 6.8 in a concentration of 0.2% (m/V) were mechanically mixed with 500 mg of mucus in a Petri dish. Samples were either directly transferred to the lower plate of the rheometer (0 h value) or after 2 or 4 h of additional incubation at 37 °C.…”

Section: Materials and Methodsmentioning

confidence: 99%

“…Mucoadhesive properties of the prepared thiolated and nonthiolated nanoemulsions were evaluated by a setup that was previously described in the literature with slight modifications. , Briefly, porcine intestinal mucosa, obtained from a local slaughterhouse, was cut into 3 cm × 2 cm segments and mounted onto a half-cut 50 mL Falcon tube. The tube was fixed with double-sided adhesive tape in an angle of 45° in an incubator providing 37 °C and 100% relative humidity.…”

Section: Materials and Methodsmentioning

confidence: 99%

“…While polymers of the first generation of thiomers contain free, unprotected thiol groups, the second generation of thiomers is characterized by S-protected thiol groups that are stable toward oxidation but can still form new disulfide bonds with endogenous thiols via thiol/disulfide exchange reactions . S-protected thiol groups can optionally exhibit high chemical reactivity, resulting in accelerated interaction with mucosal glycoproteins. − …”

Section: Introductionmentioning

confidence: 99%

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Power-Up for Mucoadhesiveness: Two Generations of Thiolated Surfactants for Enhanced Sticky Nanoemulsions

To,

Kali,

Haddadzadegan

et al. 2023

ACS Biomater. Sci. Eng.

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Nanoemulsions can be tuned toward enhanced gastro-intestinal retention time by incorporating thiolated surfactants into their surface. Tailoring the chemical reactivity of the thiol headgroup has major influence on mucoadhesive features of the nanoemulsion. Two generations of thiolated surfactants were synthetically derived from PEG-40-stearate featuring either a free thiol group or an S-protected thiol group. The surfactants were characterized regarding critical micelle concentration (CMC), hemolytic activity, and cytotoxicity. Subsequently, they were incorporated into nanoemulsions and the resulting nanoemulsions were characterized regarding particle size, polydispersity index (PDI), zeta potential, and time-dependent stability. Afterward, mucosal interactions as well as mucoadhesion on porcine intestinal mucosa were investigated. Successful synthesis of Cysteine-PEG-40-stearate (CYS-PEG-40-stearate) and MNA-Cysteine-PEG-40-stearate (MNA-CYS-PEG-40-stearate) was confirmed by 1 H NMR spectroscopy. Both chemical modifications led to slightly elevated CMC values while preserving low cytotoxicity and hemotoxicity. Incorporation into nanoemulsions had minor influence on overall physical particle characteristics, while interactions with mucus and mucoadhesiveness of the nanoemulsions were drastically improved resulting in the rank order PEG-40-stearate < CYS-PEG-40-stearate < MNA-CYS-PEG-40-stearate. Accordingly, thiolated surfactants, especially S-protected derivatives, are versatile tools to generate highly mucoadhesive nanoemulsions.

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Homologous Targeting and Adhesion Abilities of Cellular Microvesicles for Enhanced Intravesical Therapy of Bladder Cancer

Qi,

Wang,

et al. 2023

Advanced Therapeutics

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Bladder cancer is one of the most common clinical malignant tumors with a high recurrence rate after surgery. To improve the therapeutic effect, intravesical instillation of chemotherapeutic drugs is usually applied after surgery. However, due to the unique microenvironment in the bladder, the drug concentration is usually rapidly reduced with urinary excretion, leading to low accumulation in bladder cancer and poor therapeutic effect. Cellular microvesicles (MVs) have parental cell‐specific characteristics and hold homologous targeting and adhesion abilities to their parent cells, achieving efficient cell uptake in their parent cells. In this study, pirarubicin (THP), a clinically approved intravesical chemotherapeutic drug, is encapsulated into bladder cancer cell‐derived MVs to form THPMVs, which have high targeting and adhesion abilities to bladder cancer and facilitate intravesical therapy of bladder cancer. The results show THPMVs compared with free THP exhibited higher cellular uptake in MB49 bladder cancer cells and cause more significant apoptotic cells. After intravesical instillation into a bladder cancer mouse model, THPMVs can significantly accumulate in bladder cancer tissues, and cause an obvious reduction in bladder weights and volumes, exhibiting promising therapeutic effects. Homologous targeting and adhesion abilities of THPMVs greatly contribute to the intravesical therapy of bladder cancer.

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Three generations of thiolated cyclodextrins: A direct comparison of their mucus permeating and mucoadhesive properties

Cited by 7 publications

References 47 publications

Enhanced Mucoadhesion of Thiolated β-Cyclodextrin by S-Protection with 2-Mercaptoethanesulfonic Acid

Enhanced Mucoadhesion of Thiolated β-Cyclodextrin by S-Protection with 2-Mercaptoethanesulfonic Acid

Power-Up for Mucoadhesiveness: Two Generations of Thiolated Surfactants for Enhanced Sticky Nanoemulsions

Homologous Targeting and Adhesion Abilities of Cellular Microvesicles for Enhanced Intravesical Therapy of Bladder Cancer

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