Jong-Mok Kim

Phototriggering of liposomal drug delivery systems

Over the past several years, photodynamic therapy (PDT) has been approved for the treatment of various cancers. Additional applications of photochemical processes for triggering site-specific drug delivery are in early stages of development at this time. This review focuses on the literature appearing between January 1996-June 2001 that describe new and ongoing studies of phototriggering mechanisms that may ultimately find utility in drug delivery applications.

Biomedical Applications of Cyclodextrin Based Polyrotaxanes

Due to their controllable size, low cytotoxicity, and unique architecture, cyclodextrin‐based polyrotaxanes and pseudopolyrotaxanes have been developed to encompass a broad range of diverse medical applications from erodable hydrogels to drug and gene delivery. This review summarizes the synthesis, characterization, dynamics, applications, and potential utility of cyclodextrin based polyrotaxanes and pseudopolyrotaxanes for medical applications. Specifically, this article reviews the literature appearing on this topic between 1999 and November 2006.

Interactions between pH-sensitive liposomes and model membranes

The structure and dynamics of two different pH-sensitive liposome systems were investigated by means of cryo-transmission electron microscopy and different photophysical techniques. Both systems consisted of dioleoylphosphatidylethanolamine (DOPE) and contained either oleic acid (OA) or a novel acid-labile polyethylene glycol-conjugated lipid (DHCho-MPEG5000) as stabiliser. Proton induced leakage, lipid mixing and structural changes were studied in the absence and presence of EPC liposomes, as well as in the presence of liposomes designed to model the endosome membrane. Neither DHCho-MPEG5000- nor OA-stabilised liposomes showed any tendency for fusion with pure EPC liposomes or endosome-like liposomes composed of EPC/DOPE/SM/Cho (40/20/6/34 mol.%). Our investigations showed, however, that incorporation of lipids from the pH-sensitive liposomes into the endosome membrane may lead to increased permeability and formation of non-lamellar structures. Taken together the results suggest that the observed ability of DOPE-containing liposomes to mediate cytoplasmic delivery of hydrophilic molecules cannot be explained by a mechanism based on a direct, and non-leaky, fusion between the liposome and endosome membranes. A mechanism involving destabilisation of the endosome membrane due to incorporation of DOPE, seems more plausible.

Synthesis and Self-Assembly of Glycal-Based Bolaforms

Glycal-based bolaforms serve as synthetically flexible components of molecular self-assembly. The compounds are prepared in good yield by a Ferrier reaction between triacetylglucal or -galactal or diacetylxylal and a long chain alpha,omega-diol, followed by deacetylation under Zemplen conditions. The reactions are stereoselective and preferentially afford the alpha-diastereomer. The bolaforms undergo self-assembly in water or water/dioxane solution to give a variety of nanostructures. In solution, bolaforms with C8 or C10 chains between glucal headgroups form nanoscale vesicles. In contrast, bolaforms with C12 chains exhibit lower solubility and a dynamic self-assembly, forming several different nanoscale structures. However, the solid-state structures of C12 bolaform isomers adopt shapes very similar to those of bolaforms possessing more extensive hydrogen-bonding networks, indicating that multiple hydrogen bonds in solution are important to formation of stable, discrete nanostructures but that only a few key intermolecular interactions between bolaform headgroups are necessary to determine the structure in the solid state. The diversity and differentiation of the functional groups present in glycal-based bolaforms suggest that they could be useful probes of the various noncovalent forces controlling the structure of new nanomaterials.

Acid- and Oxidatively-Labile Vinyl Ether Surfactants: Synthesis and Drug Delivery Applications

Liposomes have now evolved into a commercially-important drug delivery vehicle by overcoming a host of problems that were initially encountered with first generation liposomes. In spite of these impressive advances, the great potential of liposomes as drug delivery vehicles will not be fully realized until more effective targeting and membrane fusion mechanisms have been incorporated into their formulations. Our laboratory has developed several plasmenyl-type lipids for use in acid- or photooxidatively-triggerable liposomes. This review summarizes our progress toward the design, synthesis, and triggered release of encapsulated agents upon acid-catalyzed hydrolysis or photosensitized oxidation of plasmenyl-type lipid systems. Application of these materials in cascade triggering and intracellular drug delivery schemes is also described.

Synthesis and Self-assembly Properties of Acylated Cyclodextrins and Nitrilotriacetic Acid (NTA)-modified Inclusion Ligands for Interfacial Protein Crystallization

Three different β-cyclodextrins, peracylated on the primary hydroxymethyl rim of the cyclodextrin (6-C n )7β-CD, and nine different nitrilotriacetic acid-modified inclusion ligands (R-NTA) have been prepared and their self-assembly properties characterized. These modular amphiphiles have been developed to promote two-dimensional crystallization of proteins at the lipid-water interface. Pressure-area isotherm data suggest that the occupancy of the host sites within the (6-C n )7β-CD monolayers vary as a function of the known host-guest binding constant for the unmodified β-CD host and R guest substituents. Negative-stain TEM experiments show that vesicles are formed upon mild sonication of (6-C10)7β-CD and (6-C16)7β-CD in 10 mM Tris, pH 7.4 buffer. These results indicate that (6-C n )7β-CD forms stable lyotropic phases that may be useful for templating the interfacial crystallization of histidine-tagged proteins or other molecules capable of interacting with the R-NTA guest ligands.

Oriented insertion of phi29 N-hexahistidine-tagged gp10 connector protein assemblies into C20BAS bolalipid membrane vesicles.

Ni(2+):NTA-PEG600-grafted glass surfaces are capable of immobilizing N-his6 gp10 connector protein assemblies from the phi29 DNA packaging motor and mediating their transplantation into bolalipid vesicles whose membrane thickness is compatible with the hydrophobic domain of the gp10 assemblies.