Less Reactive Thiol Ligands: Key towards Highly Mucoadhesive Drug Delivery Systems

Abstract

As less reactive s-protected thiomers can likely interpenetrate the mucus gel layer to a higher extent before getting immobilized via disulfide bond formation with mucins, it was the aim of this study to develop a novel type of s-protected thiomer based on the less reactive substructure cysteine-N-acetyl cysteine (Cys-NAC) in order to obtain improved mucoadhesive properties. For this purpose, two types of s-protected thiomers, polyacrylic acid-cysteine-mercaptonicotinic acid (PAA-Cys-MNA) and polyacrylic acid-cysteine-N-acetyl cysteine (PAA-Cys-NAC), were synthesized and characterized by Fourier-transform infrared spectroscopy (FT-IR) and the quantification of attached disulfide ligands. The viscosity of both products was measured in the presence of NAC and mucus. Both thiomers were also evaluated regarding swelling behavior, tensile studies and retention time on the porcine intestinal mucosa. The FT-IR spectra confirmed the successful attachment of Cys-MNA and Cys-NAC ligands to PAA. The number of attached sulfhydryl groups was in the range of 660–683 µmol/g. The viscosity of both s-protected thiomers increased due to the addition of increasing amounts of NAC. The viscosity of the mucus increased in the presence of 1% PAA-Cys-MNA and PAA-Cys-NAC 5.6- and 10.9-fold, respectively, in comparison to only 1% PAA. Both s-protected thiomers showed higher water uptake than unmodified PAA. The maximum detachment force (MDF) and the total work of adhesion (TWA) increased in the case of PAA-Cys-MNA up to 1.4- and 1.6-fold and up to 2.4- and 2.8-fold in the case of PAA-Cys-NAC. The retention of PAA, PAA-Cys-MNA, and PAA-Cys-NAC on porcine intestinal mucosa was 25%, 49%, and 76% within 3 h, respectively. The results of this study provide evidence that less reactive s-protected thiomers exhibit higher mucoadhesive properties than highly reactive s-protected thiomers.

In Vitro Investigation of Thiolated Chitosan Derivatives as Mucoadhesive Coating Materials for Solid Lipid Nanoparticles

“…While mucoadhesive nanoparticles suffer from drawbacks where mucus permeating nanoparticles offer benefits and vice versa, S-protected thiolated polymers were able to provide both strong adhesion and efficient mucus diffusion by two different mechanisms. As shown in recent studies, , decreased reactivity of l -cysteine as S-protecting ligand resulted in a higher diffusivity and deeper mucus diffusion while still showing stronger interaction than nonthiolated SLN. CS-Cys-MNA, on the other hand, served as a matrix from which SLN could diffuse into the mucus layer.…”

“…In recent studies, a disulfide bond-bearing ligand was bound to a polymer backbone , to yield less-reactive S-protected thiolated polymers, whereas a thiol/disulfide-exchange reaction was used in this study. The latter was not applied for less-reactive S-protected thiolated polymers, yet it is common for 6-MNA-S-protection. , FT-IR spectra are in line with previously synthesized S-protected thiolated CS derivatives modified with N -acetylcysteine .…”

“…As a result of their comparatively lower reactivity, they enable diffusion into the mucus layer before forming disulfide bonds. 19 , 20 Thus, S-protection with l -cysteine allows thiolated polymers to reach deeper into the mucus and surpass the loose outer mucus layer that undergoes rapid turnover.…”

“…To increase stability toward oxidation and to improve the reactivity of thiol moieties, 6-MNA was proposed as a highly reactive S-protecting ligand. , Recently, researchers introduced less-reactive S-protecting ligands such as l -cysteine and N -acetylcysteine. As a result of their comparatively lower reactivity, they enable diffusion into the mucus layer before forming disulfide bonds. , Thus, S-protection with l -cysteine allows thiolated polymers to reach deeper into the mucus and surpass the loose outer mucus layer that undergoes rapid turnover.…”

Thiolated Nanoparticles for Biomedical Applications: Mimicking the Workhorses of Our Body

“…On mucus gel layers without a pH‐gradient, however, less reactive thiols seem to be advantageous in order to avoid an extensive binding to outer mucus regions. [ 137 ] Thiolated NPs can be additionally decorated with mucolytic enzymes in order to improve their mucus permeation behavior. [ 16 ] Alternatively, thiolated polymers can be used as coating material for nanocarriers such as liposomes to generate high mucoadhesive properties.…”