Liposomes have different morphologies based upon their composition and the formulation method. Furthermore, the morphology of complexes can contribute to their ability to deliver nucleic acids in vivo. Formulations frequently used for the delivery of nucleic acids are lamellar structures including small unilamellar vesicles (SUVs), multilamellar vesicles (MLVs), or the bilamellar invaginated vesicles (BIVs)
recently developed in our laboratory Figure 1. Several investigators have developed liposomal delivery systems using hexagonal structures; however, they have demonstrated efficiency primarily for the transfection of Inhibitors,research,lifescience,medical some cell types in culture and not for in vivo delivery. SUVs condense nucleic acids on the surface and form “spaghetti and meatballs” structures . DNA-liposome complexes made using SUVs produce little or no gene expression Inhibitors,research,lifescience,medical upon systemic delivery, although these complexes transfect numerous cell types efficiently in vitro [25, 26]. Furthermore, SUV liposome-DNA complexes cannot be targeted efficiently.
SUV liposome-DNA complexes also have a short half-life within Inhibitors,research,lifescience,medical the circulation, generally about 5 to 10 minutes. Polyethylene glycol (PEG) has been added to liposome formulations to extend their half-life [27–29]; however, PEGylation creates other problems that have not as yet been resolved. PEG seems to hinder delivery of cationic liposomes into cells due to its sterically hindering ionic interactions, and it interferes with optimal condensation of nucleic acids onto the cationic Inhibitors,research,lifescience,medical delivery vehicle. Furthermore, the resultant extremely
long half-life in the circulation, for example, up to several days, has caused problems for patients as illustrated Inhibitors,research,lifescience,medical by the increased SB431542 percentage of injected dose of the PEGylated liposomal formulation doxil that encapsulates the cytotoxic agent, doxorubicin, which accumulates in the skin, hands, and feet resulting in mucositis and hand and foot syndrome [30, 31] that cause extreme discomfort to the patient. Attempts to add ligands to doxil for delivery to specific cell surface receptors have not resulted in much cell-specific delivery, and an increased percentage of the injected targeted formulation still accumulates in Mannose-binding protein-associated serine protease the skin, hands, and feet. Addition of PEG into formulations developed in our laboratory also caused steric hindrance in the bilamellar-invaginated structures that hindered DNA encapsulation, and gene expression was substantially diminished. Recent efforts to use cleavable PEG are unimpressive and have not solved these problems [10, 12–17, 32]. The vast majority of the injected PEGylated complexes bypass the target cell, including those using cleavable PEG.