Tri-partite complex for axonal transport drug delivery achieves pharmacological effect

Background

Targeted delivery of pharmaceutical agents into selected populations of CNS (Central Nervous System) neurons is an extremely compelling goal. Currently, systemic methods are generally used for delivery of pain medications, anti-virals for treatment of dermatomal infections, anti-spasmodics, and neuroprotectants. Systemic side effects or undesirable effects on parts of the CNS that are not involved in the pathology limit efficacy and limit clinical utility for many classes of pharmaceuticals. Axonal transport from the periphery offers a possible selective route, but there has been little progress towards design of agents that can accomplish targeted delivery via this intraneural route. To achieve this goal, we developed a tripartite molecular construction concept involving an axonal transport facilitator molecule, a polymer linker, and a large number of drug molecules conjugated to the linker, then sought to evaluate its neurobiology and pharmacological behavior.

Results

We developed chemical synthesis methodologies for assembling these tripartite complexes using a variety of axonal transport facilitators including nerve growth factor, wheat germ agglutinin, and synthetic facilitators derived from phage display work. Loading of up to 100 drug molecules per complex was achieved. Conjugation methods were used that allowed the drugs to be released in active form inside the cell body after transport. Intramuscular and intradermal injection proved effective for introducing pharmacologically effective doses into selected populations of CNS neurons. Pharmacological efficacy with gabapentin in a paw withdrawal latency model revealed a ten fold increase in half life and a 300 fold decrease in necessary dose relative to systemic administration for gabapentin when the drug was delivered by axonal transport using the tripartite vehicle.

Conclusion

Specific targeting of selected subpopulations of CNS neurons for drug delivery by axonal transport holds great promise. The data shown here provide a basic framework for the intraneural pharmacology of this tripartite complex. The pharmacologically efficacious drug delivery demonstrated here verify the fundamental feasibility of using axonal transport for targeted drug delivery.     

A laser-wire system for the international linear collider

A new laser-wire has been installed in the extraction line of the ATF at KEK. It aims at demonstrating that laser-wires can be used to measure micrometre scale beam size. In parallel, studies have been made to specify a laser suitable for the ILC laser-wires.      

Organomercury compounds : XIX. The preparation of pentafluorophenylmercurials by mercuration under basic conditions

Mercuration of pentafluorobenzene under basic conditions in aqueous tertbutanol by tetrabromomercurate(II) ions, phenylmercuric chloride, and p-tolylmercuric chloride yields bis(pentafluorophenyl)mercury, (pentafluorophenyl)-phenylmercury, and (pentafluorophenyl)-p-tolymercury respectively, in a single simple preparative step. Cleavage of bis(pentafluorophenyl)mercury with iodide or bromide ions in alcohols or aqueous alcohols gives pentafluorobenzene, tetrahalogenomercurate(II) ions, and base. Under alkaline conditions, tetrahalogenomercurate(II) ions are reduced to mercury by ethanol or methanol. Decomposition of (pentafluorophenyl)phenylmercury by iodide ions has also been studied.     

Organomercury compounds : XXVI. Thermal decomposition of mercuric 2,6-disubstituted benzoates

The main thermal decomposition path for mercuric 2,6-disubstituted benzoates, (RCO₂)₂Hg (R = 2,6-X₂C₆H₃; X = F, Cl, Br, or Me), can be varied considerably. In boiling dimethyl sulphoxide, decarboxylation occurs giving the corresponding diarylmercurial (X = F or Cl) or RHgO₂CR derivative (X = Me or Br). There is considerable competition from reaction of the mercuric salt with the solvent in the last three cases. With boiling pyridine as medium, the 2,6-difluorobenzoate yields a mixture of R₂Hg and RHgO₂CR derivatives, but the 2,6-dichlorobenzoate only gives (RCO₂)₂Hg(py)₂. Thermal decomposition of the mercuric benzoates under vacuum yields the carboxylic acids and complex mercuration products, mainly based on 3-mercurated 2,6-disubstituted benzoates, with partial additional mercuration and/or decarboxylation. Pyrolysis of mercuric 2,6-dichlorobenzoate at atmospheric pressure results in both mercuration and decarboxylation, giving m-dichlorobenzene as the main volatile product and a complex mercurial with 1,3-dimercurated-2,6-dichlorobenzene repeating units and 2,6-dichlorophenyl terminal groups.     

Organomercury Compounds: XV. The acceptor properties of diphenylmercury

Crystalline adducts, Ph₂Hg·2L (L = 1,10-phenanthroline, 2,9-dimethyl-1,10-phenanthroline, and 2,4,7,9-tetramethyl-1,10-phenanthroline), have been prepared by reaction of diphenylmercury and the appropriate ligands in hexane, but derivatives of the mercurial with a range of ligands having nitrogen, phosphorus, arsenic and oxygen donor atoms could not be prepared. No definite evidence for coordination of the phenanthroline ligands in the solid adducts could be obtained by infrared or ultraviolet spectroscopy. Molecular weights of the adducts in benzene or chloroform showed them to be completely dissociated in solution. Similar measurements for mixtures of the mercurial and a range of ligands in benzene showed no evidence for complex formation. Thus, any acceptor properties of diphenylmercury appear to be very weak.     

Synthesis and Structural Properties of Anhydrous Rare Earth Cinnamates, [RE(cinn)3]

Anhydrous rare earth tris(cinnamates) [RE(cinn)₃] (RE = La–Lu, Y and Sc and cinnH = trans‐cinnamic acid) were prepared by metathesis in water and by direct reaction of the metal with cinnamic acid in a 1,2,4,5‐tetramethylbenzene flux at ca. 200 °C. X‐ray crystal structure determinations and X‐ray powder data show that, in the solid state, the larger lanthanoids (La–Dy) form an isomorphous polymeric series consisting of homoleptic nine‐coordinate metal centres bonded to three chelating and bridging tridentate cinnamates. The late RE^III cinnamate (RE = Dy, Ho–Lu, Y) complexes also form linear one‐dimensional polymeric chains with all RE metal atoms being seven‐coordinate. The cinnamates are either bound tridentate bridging in a μ‐η²:η¹ fashion, or μ‐η¹:η¹ syn‐syn bidentate bridging. A structural break occurs at dysprosium which has been characterised in both crystallographic forms, and gives solely the late RE form when precipitated at 80 °C. Sc^III cinnamate was also isolated as an analytically pure precipitate which was, again, found to be anhydrous in nature. A structural change was identified by powder XRD between the late RE^III cinnamates and Sc^III cinnamate.