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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]

Graphical abstract Abstract Magnetic resonance imaging (MRI) has been one of the most frequently-used diagnostic tools with high dimensional precision and positioning accuracy in clinical practices. To achieve contrast enhancement, utilization of high-efficient MR imaging contrast agents becomes a prime consideration and is indispensably reinforced the diagnosis precision, especially for the emerging precision medicine. Gadolinium (Gd)-based complexes has been widely used in current clinical MRI operations, however, numerous side effects were reported and highlighted in clinic. Those drawbacks render specific unmet needs to be clinically and technically improved with a new version of Gd-based compound. Here we report a newly-synthesized amphiphilic Gadodiamide-conjugated carboxymethyl-hexanoyl chitosan (termed as CHC-Gd) hybrid. The gadodiamide was selected is due to its smallest molecular size among other Gd-based complexes reported in literature, which assumed to give least influence on the resulting physicochemical properties such as colloidal stability, nanostructural evolution, and cytocompability, particularly self-assembly capability, of the resulting hybrid upon practical uses. Experimental outcomes showed a successful synthesis of the CHC-Gd hybrid using a one-pot synthesis protocol, where the gadodiamide complexes were covalently attached to the carboxyl groups along the CHC backbone. Self-assembly behavior can be observed to form a sphere-like nanoparticle of 100–200 nm in size as of amphiphilic native CHC macromolecule. Experimental outcomes indicated a largely improved cytocompatibility of the hybrid, compared with free Gd, suggesting the Gd+3 ions were well stabilized in the CHC nanostructure. Excellent contrastability in-vitro and in particular in vivo were measured, where for in-vivo test, a 10-40-folded reduction in dosage, compared with clinical Gd dose, was used and demonstrated a comparative-to-better imaging resolution and brightness. Therefore, from this preliminary investigation, a potential translation to clinical practice through the use of newly-synthesized amphiphilic CHC-Gd hybrid appears to be relatively promising. [ABSTRACT FROM AUTHOR]

Metallic nanoparticles have been utilized as analytical tools to detect a wide range of organic analytes. In most reports, gold (Au)-based nanosensors have been modified with ligands to introduce selectivity towards a specific target molecule. However, in a recent study a new concept was presented where bare Au-nanorods on self-assembled carboxymethyl-hexanoyl chitosan (CHC) nanocarriers achieved sensitive and selective detection of human serum albumin (HSA) after manipulation of the solution pH. Here this concept was further advanced through optimization of the ratio between Au-nanorods and CHC nanocarriers to create a nanotechnology-based sensor (termed CHC-AuNR nanoprobe) with an outstanding lower detection limit (LDL) for HSA. The CHC-AuNR nanoprobe was evaluated in simulated urine solution and a LDL as low as 1.5 pM was achieved at an estimated AuNR/CHC ratio of 2. Elemental mapping and protein adsorption kinetics over three orders of magnitude in HSA concentration confirmed accumulation of HSA on the nanorods and revealed the adsorption to be completed within 15 min for all investigated concentrations. The results suggest that the CHC-AuNR nanoprobe has potential to be utilized for cost-effective detection of analytes in complex liquids. [ABSTRACT FROM AUTHOR]

Lung cancer kills more humans than any other cancer and multidrug resistance (MDR) in cancer stem-like cells (CSC) is emerging as a reason for failed treatments. One concept that addresses this root cause of treatment failure is the utilization of nanoparticles to simultaneously deliver dual drugs to cancer cells with synergistic performance, easy to envision — hard to achieve. (1) It is challenging to simultaneously load drugs of highly different physicochemical properties into one nanoparticle, (2) release kinetics may differ between drugs and (3) general requirements for biomedical nanoparticles apply. Here self-assembled nanoparticles of amphiphilic carboxymethyl-hexanoyl chitosan (CHC) were shown to present nano-microenvironments enabling simultaneous loading of hydrophilic and hydrophobic drugs. This was expanded into a dual-drug nano-delivery system to treat lung CSC. CHC nanoparticles were loaded/chemically modified with the anticancer drug cisplatin and the MDR-suppressing Chinese herbal extract demethoxycurcumin, followed by biofunctionalization with CD133 antibody for enhanced uptake by lung CSC, all in a feasible one-pot preparation. The nanoparticles were characterized with regard to chemistry, size, zeta potential and drug loading/release. Biofunctionalized and non-functionalized nanoparticles were investigated for uptake by lung CSC. Subsequently the cytotoxicity of single and dual drugs, free in solution or in nanoparticles, was evaluated against lung CSC at different doses. From the dose response at different concentrations the degree of synergy was determined through Chou-Talalay’s Plot. The biofunctionalized nanoparticles promoted synergistic effects between the drugs and were highly effective against MDR lung CSC. The efficacy and feasible one-pot preparation suggests preclinical studies using relevant disease models to be justified. [ABSTRACT FROM AUTHOR]

Abstract: Chitosan is among the most abundant biopolymers on earth and has been either used or exhibited potential in a wide variety of industrial and biomedical applications. With the advancement of materials technologies, chitosan has been chemically modified to self-assemble into nanoarchitectures that are usable in advanced biomedical applications, such as drug nanocarriers, macroscopic injectables, tissue-engineering scaffolds, and nanoimaging agents. Colloidal amphiphilically modified chitosan (AMC) is a relatively recent material receiving increased attention with numerous publications addressing the medical advantages of specific systems. To date, many reviews have focused on the synthesis and biomedical properties of chitosan-based biomaterials, but a comprehensive study focusing on the colloidal properties of AMC in relation to biomedical performance appears to be lacking. This review provides a survey of the field, critically reviewing the colloidal properties and biomedical performance of AMC systems, such as nanoparticle drug delivery systems and macroscopic medical devices. Finally, the future development, market potential, and clinical implications of these promising colloidal-structured biomaterials are summarised. [Copyright &y& Elsevier]

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]

Abstract: Silane-modified amphiphilic chitosan was synthesized by anchoring a silane coupling agent, (3-aminopropyl)triethoxysilane, to a novel amphiphilic carboxymethyl-hexanoyl chitosan (CHC). The chemical structure of this new organic–inorganic hybrid molecule was characterized by FTIR and 13C-, 29Si-nuclear magnetic resonance, while the structural evolution was examined using scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), and dynamic light scattering (DLS). Experimental results indicated a self-assembly behaviour of molecules into nanoparticles with a stable polygonal geometry, consisting of ordered silane layers of 6nm in thickness. The self-assembly property was found to be influenced by chemical composition and concentration of silane incorporated, while the size can be varied by the amount of anchored silane. It was also demonstrated that such vesicle exhibited excellent cytocompatibility and cellular internalization capability in ARPE-19 cell line, and presented well-controlled encapsulation and release profiles for (S)-(+)-camptothecin. These unique properties render it as a potential drug delivery nanosystem. [Copyright &y& Elsevier]