Mike E. Lizarzaburu

Poly(cationic lipid)-mediated in vivo gene delivery to mouse liver

We have previously demonstrated that liposomes generated from poly(cationic lipid) (PCL) and cholesterol (Chol) have low cytotoxicity, are serum resistant, and display a transfection efficiency in vitro similar to commercially available cationic liposomes. Our in vivo experiments demonstrated that PCL–Chol liposomes bound much less avidly to serum proteins than did liposomes composed of 1,2-bis(dioleoyloxy)-3-(trimethylamonio)propane (DOTAP)–Chol or DOTAP–L-α dioleoyl phosphatidylethanolamine (DOPE). Injection of the lipoplexes (PCL–Chol+DNA) through the portal vein after partial hepatectomy (PH) led to much higher reporter gene expression (luciferase) in the liver than did naked DNA injection. Marked green fluorescent protein expression was visualized in almost all hepatocytes in the liver of mice receiving lipoplex injection, even in the absence of PH. Subcutaneous injection of thyroid hormone triiodothyromine (T3) significantly promoted hepatocyte regeneration and markedly enhanced PCL–Chol-mediated gene transfer in mouse liver when the lipoplex was administrated through either portal or tail vein. With T3 pretreatment, PCL–Chol exerted a better gene transfer efficacy in mouse liver than DOTAP–Chol or DOTAP–DOPE. Two injections of lipoplexes through an indwelling catheter in the portal vein extended the transgene expression at a high level when T3 injection was repeated. In conclusion, our findings demonstrate that the polymerized cationic liposomes are very stable in the blood and are effective agents for in vivo gene delivery, and that thyroid hormone administration offers a non-invasive approach to enhance liposome-mediated liver gene delivery.

Design and synthesis of protein superfamily-targeted chemical libraries for lead identification and optimization.

This review chronicles original literature dating back to 1992 outlining the applications of parallel synthesis and combinatorial chemistry to the synthesis of compound libraries focused towards specific superfamilies of molecular targets. Target families that have received significant literature coverage include kinases, proteases, nuclear hormone receptors and cell surface receptors, notably GPCRs.

Synthesis of aryl ethers from aminoalcohols using polymer-supported triphenylphosphine

Abstract Optimum conditions for the preparation of aryl–alkyl ethers from N-protected aminoalcohols using polymer-supported triphenylphosphine have been developed. In contrast to previous literature reports, it was discovered that the progress of this reaction is greatly improved when a tertiary amine base is employed, along with minor modifications being made to the order of reagent addition.

Convenient preparation of aryl ether derivatives using a sequence of functionalized polymers

A four-step synthesis to aryl ether derivatives, three of which utilize polymer-supported reagents, has been developed. Supported triphenylphosphine was successfully utilized in two distinct synthetic processes in the first step, whilst supported base and ionic and covalent scavengers were employed to complete the synthesis and purification of the target compounds.

A versatile synthesis of tetraester polyamine lipids for gene transfection

Abstract The preparation of polyamine lipids via Michael addition of diamines to tetraester bisacrylates is described. A new pentaerythritol protection strategy enabled the synthesis of a bis( p -methoxybenzyl)diether diol which was used to prepare the saturated and unsaturated diester cores.