Enhanced Delivery of Neuroactive Drugs via Nasal Delivery with a Self-Healing Supramolecular Gel.

This paper reports the use of a self-assembling hydrogel as a delivery vehicle for the Parkinson's disease drug l-DOPA. Based on a two-component combination of an l-glutamine amide derivative and benzaldehyde, this gel has very soft rheological properties and self-healing characteristics. It is demonstrated that the gel can be formulated to encapsulate l-DOPA. These drug-loaded gels are characterized, and rapid release of the drug is obtained from the gel network. This drug-loaded hydrogel has appropriate rheological characteristics to be amenable for injection. This system is therefore tested as a vehicle for nasal delivery of neurologically-active drugs-a drug delivery strategy that can potentially avoid first pass liver metabolism and bypass the blood-brain barrier, hence enhancing brain uptake. In vitro tests indicate that the gel has biocompatibility with respect to nasal epithelial cells. Furthermore, animal studies demonstrate that the nasal delivery of a gel loaded with 3 H-labeled l-DOPA out-performed a simple intranasal l-DOPA solution. This is attributed to longer residence times of the gel in the nasal cavity resulting in increased blood and brain concentrations. It is demonstrated that the likely routes of brain penetration of intranasally-delivered l-DOPA gel involve the trigeminal and olfactory nerves connecting to other brain regions.

Self-assembled multivalent (SAMul) ligand systems with enhanced stability in the presence of human serum.

Self-assembled cationic micelles are an attractive platform for binding biologically-relevant polyanions such as heparin. This has potential applications in coagulation control, where a synthetic heparin rescue agent could be a useful replacement for protamine, which is in current clinical use. However, micelles can have low stability in human serum and unacceptable toxicity profiles. This paper reports the optimisation of self-assembled multivalent (SAMul) arrays of amphiphilic ligands to bind heparin in competitive conditions. Specifically, modification of the hydrophobic unit kinetically stabilises the self-assembled nanostructures, preventing loss of binding ability in the presence of human serum - cholesterol hydrophobic units significantly outperform systems with a simple aliphatic chain. It is demonstrated that serum albumin disrupts the binding thermodynamics of the latter system. Molecular simulation shows aliphatic lipids can more easily be removed from the self-assembled nanostructures than the cholesterol analogues. This agrees with the experimental observation that the cholesterol-based systems undergo slower disassembly and subsequent degradation via ester hydrolysis. Furthermore, by stabilising the SAMul nanostructures, toxicity towards human cells is decreased and biocompatibility enhanced, with markedly improved survival of human hepatoblastoma cells in an MTT assay.

Effect of buffer at nanoscale molecular recognition interfaces - electrostatic binding of biological polyanions.

We investigate the impact of an over-looked component on molecular recognition in water-buffer. The binding of a cationic dye to biological polyanion heparin is shown by isothermal calorimetry to depend on buffer (Tris-HCl > HEPES > PBS). The heparin binding of self-assembled multivalent (SAMul) cationic micelles is even more buffer dependent. Multivalent electrostatic molecular recognition is buffer dependent as a result of competitive interactions between the cationic binding interface and anions present in the buffer.

Morphological control of self-assembled multivalent (SAMul) heparin binding in highly competitive media.

Tuning molecular structures of self-assembling multivalent (SAMul) dendritic cationic lipopeptides controls the self-assembled morphology. In buffer, spherical micelles formed by higher generation systems bind polyanionic heparin better than worm-like micelles formed by lower generation systems. In human serum, the binding of spherical micelles to heparin is adversely affected, while worm-like micelles maintain their relative binding ability.

Efficient, non-toxic hybrid PPV-PAMAM dendrimer as a gene carrier for neuronal cells.

A novel hybrid dendrimer (TRANSGEDEN) that combines a conjugated rigid polyphenylenevinylene (PPV) core with flexible polyamidoamine (PAMAM) branches at the surface was synthesized and characterized. The potential of this material as a nonviral gene delivery system was also examined, and it was observed that dendriplexes formed by TRANSGEDEN and small interfering ribonucleic acids (siRNAs) can be incorporated into >90% of neuronal cells without any toxicity up to a dendrimer concentration of 3 µM. TRANSGEDEN was used to deliver a specific siRNA to rat cerebellar granular neurons (CGNs) to knock down the cofilin-1 protein. Cofilin-1 removal partially protects CGNs from N-methyl D-aspartate (NMDA)-mediated neuronal death.

A MALDI-TOF MS study of lanthanide(III)-cored poly(phenylenevinylene) dendrimers.

An extensive study by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) of some first-generation and second-generation lanthanide(III)-cored poly(phenylenevinylene) dendrimers is described. The complexes were obtained by self-assembly of suitably functionalized carboxylate dendrons around the lanthanide ion (La(3+), Er(3+)). Fourier transform infrared (FT-IR) spectroscopy gave reasonable evidence for the proposed structures. However, MS was used to ascertain unequivocally the complex formation. The most reliable results were found in the negative reflector mode, using 2-[(2E)-3-(4-tert-butylphenyl)-2-methylprop-2-enylidene]malononitrile (DCTB) as matrix. Well-defined and highly resolved base peaks corresponding to negative ions of [Gn(4)La](-) and [Gn(4)Er](-) were found in all cases, with an excellent match between the theoretical and observed isotope distributions. However, the 3:1 stoichiometry used in the synthesis guarantees an empirical formula Gn(3)Ln for the complexes.