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Abstract: Hydrogels composed of assembled colloids is a material class that is currently receiving much interest and shows great promise for use in biomedical applications. This emerging material class presents unique properties derived from the combination of nanosized domains in the form of colloidal particles with a continuous gel network and an interspersed liquid phase. Here we developed an amphiphilic chitosan-based, thermogelling, shear-reversible colloidal gel system for improved glaucoma treatment and addressed how preparation procedures and loading with the anti-glaucoma drug latanoprost and commonly used preservative benzalkonium chloride influenced the mechanical properties of and drug release from the colloidal gels. The results highlight that incorporated substances and preparation procedures have effects both on mechanical properties and drug release, but that the release of drug loaded in the colloidal carriers is mainly limited by transport out of the carriers, rather than by diffusion within the gel. The developed colloidal chitosan based gels hold outstanding biomedical potential, as confirmed by the ease of preparation and administration, low cytotoxicity in MTT assay, excellent biocompatibility and lowering of intraocular pressure for 40days in a rabbit glaucoma model. The findings clearly justify further investigations towards clinical use in the treatment of glaucoma. Furthermore, the use of this shear-reversible colloidal gel could easily be extended to localized treatment of a number of critical conditions, from chronic disorders to cancer, potentially resulting in a number of new therapeutics with improved clinical performance. [Copyright &y& Elsevier]

• The self-assembly of amphiphilic chitosan (CHC) in aqueous solution was disclosed in this study. • The DMC as a molecular probe was used to evaluate structural evolution and entrapping efficiency. • The associated DMC in the helical CHC drug nanocarriers gives an advantage for drug delivery. This investigation reports the nanostructural evolution and associated encapsulation and elution of a hydrophobic drug, demethoxycurcumin (DMC), as a molecular probe, with the carboxymethyl-hexanoyl chitosan (CHC), which has been a technically interesting amphiphilic chitosan-based polymer successfully developed in this lab for years. The self-assembly nature of the CHC in neutral aqueous solutions allowed efficient encapsulation of various drugs without deteriorating or changing drugs' activity. However, its self-assembly behavior associated with nanostructural stability or variation, in terms of residence time in aqueous solution has not been well characterized and how the CHC nanostructure may be altered upon entrapping a drug, followed releasing out of the nanostructure. In this study, the CHC/DMC assembled model was used to evaluate entrapping efficiency, CHC-DMC interaction, and nanostructural variation while the drug being encapsulated and released from the CHC nanoparticles. Experimental outcomes showed a fractal transition between nanoparticulate and short fiber-like network evolution of the CHC as time elapsed, with the presence or absence of the DMC probe. This entrapment of DMC is relatively efficient upon CHC assembly and the associated DMC arrangement inside the helical CHC macromolecule gave largely increasing space over the resulting CHC/DMC assembly. Its excellent colloidal and nanostructural stability over a reasonably long period of time in testing environment suggests that this CHC/DMC assembly not only provides a crucial advantage for drug delivery application but also considers as a nanostructural model for better understanding of the mechanism upon drug encapsulation and elution which may be applicable to alternative amphiphilic polysaccharide-based macromolecules. [ABSTRACT FROM AUTHOR]

Diabetes is a common global disease that causes immense suffering for individuals and huge costs for the health care system. To minimize complications such as organ degeneration, diabetic patients are required to undergo treatments to maintain the blood glucose level in the normal range, ideally mimicking normal insulin secretion. The normal physiological insulin secretion pattern in healthy individuals consists of a base (basal) level through the day and increased secretion after meals (bolus insulin). Thus effective treatments may combine long acting, low-level insulin therapy with boosts of short acting insulin and/or oral agents. To achieve long term management of basal insulin level, an injectable insulin-loaded gel composed of self-assembled nanoparticles from carboxymethyl-hexanoyl chitosan (CHC) and integrated lysozyme for controlled biodegradation and insulin release was developed. In vitro characterizations and evaluations confirmed that lysozyme was active on CHC and that the amount of lysozyme in a CHC hydrogel determined the degradation and insulin release rate. The degradation products were found to be highly cytocompatible using a cell assay. In vivo evaluation of the system in a diabetic mouse model revealed that the fasted blood glucose level could be maintained in the normal range for 10 days with a single injection of insulin-loaded CHC-lysozyme gel. The insulin-loaded CHC-lysozyme gels clearly show promise for use as a novel injectable long-acting insulin delivery system, with potential to manage the basal insulin level for many days with a single injection. [ABSTRACT FROM AUTHOR]

Abstract: Thermo-gelling injectable nanogels, with no burst release of loaded drug, were prepared by a simple route by combining self assembled nanocapsules of amphiphilically modified chitosan with glycerophosphate di-sodium salt and glycerol. The potential as a depot drug delivery system was demonstrated in vivo through the therapeutic effect of ethosuximide (ESM) loaded nanogels, suppressing spike wave discharges (SWDs) in Long Evan rat model. Simultaneously clearance of gels from the site of administration was monitored non-invasively using MRI. The gel structure was characterized using TEM and SEM, confirming the gels to be an assembly of nanocapsules and using two-photon microscopy to visualize the network structure. In vitro drug release studies using ESM revealed that the nanogels exhibited extended, mostly Fickian release. Finally, all investigated formulations displayed excellent cytotoxicity data determined by MTT assay using human retinal pigmented epithelium cells. All presented properties are highly desirable for injectable depot gels for drug delivery. [Copyright &y& Elsevier]