Acrylate-Tethering Drug Carrier: Covalently Linking Carrier to Biological Surface and Application in the Treatment of Helicobacter pylori Infection

Abstract

The development of carriers to sustain drugs at stomach surface is an attractive strategy to increase drug bioavailability locally and systematically. So far, the only reported carrier that can form a covalent bond with mucus, the thiolated carrier, relies on a reversible disulfide exchange reaction between thiols on the carrier and disulfide bridges on the mucus. Here we show the design and fabrication of a cellulose carrier with tethering acrylate groups (denoted here as clickable carrier) that, under a nontoxic condition, can efficiently react with thiols on biomaterials in situ through the thermodynamically driven and kinetically probable Michael thiol-ene click reaction. Here we show the attachments of the clickable carriers to a mucin protein, a surface of human laryngeal carcinoma cells, and a surface of a fresh porcine stomach. We also show that the required thiol moieties can be generated in situ by reducing existing cystine disulfide bridges with either the edible vitamin C or the relatively nontoxic tris(2-carboxyethyl) phosphine. Comparing to a control carrier, the clickable carrier can increase some drug concentrations in an ex vivo stomach tissue, and improve the Helicobacter pylori treatment in infected C57BL/6 mice.

Thiol Click Modification of Cyclic Disulfide Containing Biodegradable Polyurethane Urea Elastomers

“…While some limitations still exist in thiol-click chemistries, ,, as previously mentioned, the disulfide bond is relatively stable in oxidizing and physiologic pH conditions. Disulfide cleavage-based compounds have been employed for chemosensing, in the development of prodrugs, hydrogels, and nanocarriers, and in material fabrication. , Thiol-click reaction with disulfides for site-specific protein–polymer conjugation has been reported previously, for instance, the generation of free thiols by reducing the cystine disulfide bridge in a peptide (salmon calcitonin), or protein (mucin), for subsequent polymer attachment. However, the concept of disulfide-based click reaction with synthetic polymers containing cyclic disulfide bonds has not been reported to our knowledge.…”

Nanoparticles for oral delivery: Design, evaluation and state-of-the-art

“…Recently, polyethylene oxide-acrylate (PEO-Acr) substituted ethyl cellulose has been synthesized to develop nanoparticles that may modulate the mucus microstructure [169]. The investigators hypothesized that the acrylate-terminated ethyl cellulose would react via thiol-ene click reaction with the thiols generated from the treatment of mucin with biocompatible reducing agents.…”

“…The investigators hypothesized that the acrylate-terminated ethyl cellulose would react via thiol-ene click reaction with the thiols generated from the treatment of mucin with biocompatible reducing agents. The investigators demonstrated that the treatment of mucin with tris (2-carboxyethyl) phosphine hydrochloride (TCEP) or vitamin C could generate free thiols that subsequently react with the PEO-Acr terminated ethyl cellulose [169]. Furthermore, ex vivo studies on porcine stomach showed that PEO-Acr terminated fluorescent ethyl cellulose nanoparticles could bind to the mucosal surface in the presence of reducing agent TCEP, and the extent of binding was greater than that of non-modified fluorescent ethyl cellulose nanoparticles.…”

“…Finally, the in vivo efficacy of clarithromycin-loaded, PEO-Acr modified, ethyl cellulose nanoparticles co-administered with vitamin C was evaluated in H. pylori infected mice. Interestingly, these nanoparticles in combination with vitamin C showed greater eradication of H. pylori than non-modified clarithromycin-ethyl cellulose nanoparticles and clarithromycin suspension [169]. It would be interesting to further establish the ability of vitamin C to generate free thiols in vivo , and use fluorescence imaging to assess whether the reaction with the acrylate terminated nanocarriers increases gastric retention in vivo .…”