PGSE-NMR and SANS studies of the interaction of model polymer therapeutics with mucin.

Occhipinti, Paola. 2011. PGSE-NMR and SANS studies of the interaction of model polymer therapeutics with mucin. PhD Thesis, Cardiff University.

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Abstract

The effective uptake/absorption of macromolecules through the body involves several processes: one of these is the transport of the molecule through the mucus layer. The mucus layer is a complex mixture of biological components. Among them, mucin is the molecule that mainly contributes to the gel properties of the layer. Therefore, an in-vitro mucin gel can mimic, to a first approximation, the in-vivo physico-chemical properties of the mucus. Therapeutic agents are often conjugated to polymers which behave as drug carriers to improve the tissue targeting specificity of the therapeutic molecule. Therefore, the understanding of the permeability of polymers through mucin solutions is fundamental in the construction of polymer-based drug delivery systems for therapeutics which can be adsorbed through the airways and the gastrointestinal tract. Furthermore, in the case of respiratory disorders such as cystic fibrosis (CF), the mucus can represent a real barrier for the therapeutics' access. The mobility through, and interactions with, mucin solutions of non-ionic/cationic/anionic polymers with different structures (from linear to dendritic) were studied by pulsed-gradient spin-echo nuclear magnetic resonance (PGSE-NMR) and small-angle neutron scattering (SANS). The interaction of non-ionic polymers were limited and related to the steric hindrance of the mucin networks. On the contrary, charged polymers such as polyamidoamines (PAMAM) dendrimers exhibited a pH-dependent interaction with the mucin molecules. At physiological pH, strong binding with mucin molecules was observed for positively charged polymers. PEGylation is a widely used modification of molecules, proteins and drug delivery systems by covalently attaching one or more polyethylene glycol (PEG) chains: in fact, PEG-modification can reduce the toxicity, increase the half-life of drug delivery systems by enhancing their body resistance and reducing the plasma clearance. PEGylation of positively charged PAMAM dendrimers reduced their adhesive interaction with the mucin molecules, improving greatly the diffusion of these polymers in mucin solutions. After being PEGylated, PEG-PAMAM conjugates can be positively considered as model drug carriers. Although mucin is the main component in mucus, a more complex and realistic mucus system was studied by SANS. Mucin solutions were enriched with extra components present in mucus, such as phospholipids and serum albumin. Hydrophobic lipid-mucin and protein-mucin interactions were observed. However, the adhesion of mucus components with mucin should be positively considered for the understanding of the mucus as a protective barrier and in the improvement of any treatment for the reinforcement of the mucosal barrier.

Item Type:	Thesis (PhD)
Status:	Unpublished
Schools:	Pharmacy
Subjects:	R Medicine > RM Therapeutics. Pharmacology
ISBN:	9781303197192
Date of First Compliant Deposit:	30 March 2016
Last Modified:	10 Oct 2017 15:24
URI:	https://orca.cardiff.ac.uk/id/eprint/54528

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