Design and Properties of a Lipid-Based Carrier

The clment-ly available ddiverf systems h genetic drugs have ody Pimikd utility fsr systemic applications. Botk viral vectors and the non-viral “complex” gene deliveq systems formed with catlonic liposomes and plasmid dly by the retlculoendotheliai system resulting in highest “first-pass” orgaq such as the hmg liver and spleen. In an tiuwe response compromising tmnras&c~ion activity For successtii gene therapy for systemic diseases such as tumors, infl ation and infections a carrier system is required *hat is aau^a readily aecognized by macsophages of the r&culoendothel~aX s y s t e m . Wequired charastcristics for such a carrier are small size, neutral in charge and highly staS!e in serum with an extendec! sirr,uia~ion li&ime. XIis rev&V presents the concept and construction of a non-viral gene carrier system f0r systemic gene +&erapy. Tfie piasmid DNA is ewcapsn&d w&a a lipid bjRayer protecting “CBae IXUI fi$om efegradat’ion by nucieas!es. S‘hese IZ@&-ll& pa!rticlcs are on average 90 nrr in diameter and stabilized by an exchangeable ~o~ye~y~e~c glycoP coating. Extended circulation lifetimes can be achieved tit-h significant accumulation of&ace plasmid at a distal tumor sic& IX%Xeiow of Iuciferase activity in the CPkmor tissue tidicates that ‘ihe plasmid delivered was internalized a& transcribed. Approaches to increase Iraninfection activities are discussed. Lam’, Genetic drugs such as p!asmids containing therapeutic genes and antisense or ribozjime oligonucleotides have great potential for treatment of human diseases such as cancer, genetic disorders and infections. Recent advances in the understanding of medical diseases generally !ead to proposals for genetic interventions, particularly in oncology. The potential advantage of gene therapy over conventional therapy is the ability to regulate gene function in order to achieve specific activity, prolonged response and little toxicity. In oncology, for drugs to be effective, their access and efficacy at metastatic disease sites are necessary, since these are the primary determinant of survival in most cancers. Therefore, for gene therapy to be successful, systemic applications will 166 P. Scherrer et al. /Design and Properties of a Lipid-Based Carrier System generally be required. However, rapid breakdown and clearance from the blood compromise the effectiveness of these molecules for systemic treatment of disease. In addition, plasmids are large and highly charged molecules that cannot readily penetrate target cell membranes to reach their sites of action inside the cells. As a result, the development of an efficient delivery system that protects plasmid in the circulation and facilitates intracellular delivery into target cells is critical for the clinical success of gene therapy.