Lipid-based formulations of antisense oligonucleotides for systemic delivery applications

Abstract

Increasing the specificity of therapeutic drugs and improving their delivery to sites of disease are primary goals of today's pharmaceutical industry. One of the most exciting advances in recent years has been the development of antisense technologies, which are capable of modulating protein expression with exquisite specificity. Unfortunately, this class of drugs is particularly sensitive to nuclease degradation, is eliminated rapidly from the circulation after intravenous administration, and is severely limited in its ability to penetrate through cellular membranes unaided. Attempts to address these problems through medicinal chemistry have produced several key advances. However, chemical alterations to improve one property of the molecule often affect other properties, potentially in a negative manner. The past decade has seen extensive use of liposomes and lipid-based delivery systems to improve the pharmacological properties of a variety of drugs. The principal benefits afforded therapeutic agents by liposomal encapsulation are enhanced plasma-circulation lifetimes, increased delivery to sites of disease, and changes in tissue distribution, which can result in reduced toxic side effects. Liposomal preparations of doxorubicin (DOXIL) and daunorubicin (DaunoXome) have been approved for the treatment of HIV-associated Kaposi's sarcoma, whereas lipid-based formulations of amphotericin B (AmBisome, ABELCET, AMPHOTEC) are successful clinical products employed in the treatment of fungal infections. It is not surprising, therefore, that considerable interest has been on developing lipid-based delivery systems to overcome the problems associated with the systemic administration of DNA- and RNA-based therapeutics. The intent of this chapter is to introduce the reader to the various lipid-based formulations applied to polynucleic acid drugs, with emphasis on the generation and characterization of delivery vehicles for intravenous applications. The majority of examples apply to antisense oligodeoxynucleotides (ASODN) as they represent the most widely available class of DNA-based drugs.