Matrix Metalloproteinase Gene Delivery for Liver Fibrosis

The resolution of advanced liver fibrosis has been recently recognized to be possible, if the causative stimuli are successfully removed. However, whether complete resolution from cirrhosis, the end stage of liver fibrosis, can be achieved is still questionable. Delivery of interstitial collagenases, such as matrix metalloproteinase (MMP)-1, in the liver could be an attractive strategy to treat advanced hepatic fibrosis from the view point that the imbalance between too few interstitial collagenases and too many of their inhibitors is the main obstacle to the resolution from fibrosis. Remodeling of hepatic extracellular matrix by delivered interstitial collagenases also facilitates the disappearance of activated hepatic stellate cells, the main matrix-producing cells in the liver, and promotes the proliferation of hepatocytes. This review will focus on the impact of the gene delivery of MMPs for the treatment of advanced liver fibrosis while discussing other current therapeutic strategies for liver fibrosis, and on the need for the development of a safe and effective delivery system of MMPs

Anti-Bimetallic Complexes of Divalent Lanthanides with Silylated Pentalene and Cyclooctatetraenyl Bridging Ligands as Molecular Models for Lanthanide-Based Polymers

The new pentalene antibimetallic compounds [MCp*(THF)](2)(mu,eta(5):eta(5)-C8H41,4-SiiPr3) were prepared for M = Eu (1), Yb (2) from the one-pot reaction of MI2(THF)(x) and KCp* and the subsequent addition of 2 equiv of C8H41,4-SiiPr3[K](2) in THF. The related series of COT1,4-SiiPr3-bridged triple-deckers [MCp*(THF)(x)](2)(mu,eta(8):eta(8)-COT1,4-SiiPr3) (M = Eu, x = 0 (3); M = Yb, x = 0 (4); M = Sm, x = 1 (5)) were synthesized similarly; additionally, the base-free derivative with M = Sm and x = 0 (6) could be prepared by reaction of [SmCp*(mu-I)(THF)(2)](2) with COT1,4-SiiPr3[K](2) in toluene with heating. The solid-state structures, as determined by X-ray diffraction, show antibimetallic arrangements in which the divalent lanthanide centers are held oil opposing sides of a planar bridging ligand. The pentalene ligand coordinates in an approximate eta(5):eta(5) mode, with the metal centers slipped toward the wingtip carbons, whereas the COT ligand is bound in an eta(8):eta(8) fashion with the metal centers aligned with the centroid of the bridging ligand. Electronic spectroscopy suggests the Eu and Yb pentalene complexes have a smaller f-d gap than their COT analogues, indicating a greater extent of through-ligand metal-metal interaction in the pentalene species. [EuCp*(THF)(x)](2)(mu-COT1,4-SiiPr3) displays a weak green-yellow emission in THF solution (lambda(max) 509 nm, Phi(em) < 0.1%) upon excitation in the UV, consistent with a 4f(6)5d(1) -> 4f(7) emission process, with a short lifetime indicative of Eu-Eu coupling through the bridging COT ligand. Cyclic voltammetry reveals that 1, 3, and 4 decompose rapidly upon oxidation, although the monocation 2(+) appears to be stable in THF solution. Through-ligand Yb-Yb coupling is suggested by the electrochemical data for 2, of magnitude similar to that observed for its transition-metal analogues. However, unfortunately, attempts to further quantify this conclusion by spectroscopic investigation of 2(+) were unsuccessful