Drug Targeting Organ-Specific Strategies

XXXIV Abbreviations and Acronyms

Drug Targeting Organ-Specific Strategies. Edited by G. Molema, D. K. F. Meijer Copyright © 2001 Wiley-VCH Verlag GmbH ISBNs: 3-527-29989-0 (Hardcover); 3-527-60006-X (Electronic)

1Drug Targeting: Basic Concepts and Novel Advances

Grietje Molema

1.1 Introduction

Since the early 1960s, many scientists have dedicated their research to the development of drug targeting strategies for the treatment of disease. In general, the aim of targeted therapies is to increase the efficacy and reduce the toxicity of drugs. The behaviour of the carrier molecules largely determines the pharmacokinetics and cellular distribution of the drug. Furthermore, selective delivery into the target tissue may allow a higher drug concentration at or in the target cells or even in specific compartments of the target cells. As a result, drug efficacy can be enhanced.

Whereas the majority of strategies studied so far have incorporated cytotoxic drugs for the treatment of cancer, it is believed that novel pharmacologically active substances will become more and more subject to study in the coming years. With the advent of molecular biological techniques, molecular mechanisms of disease become unravelled at an almost uncontrollable pace. As a result, new chemical entities (NCE) are generated that in principle can exert potent effects on disease processes but have a deficient distribution to the areas of disease. In addition, they can be highly toxic upon gaining access to healthy tissue. The chemical characteristics of NCEs may be such, that access to the site of action, in particular intracellular target enzyme systems, is minimal. By attaching an NCE to a carrier molecule, its whole body and cellular disposition can be considerably manipulated. Similarly, therapeutic macromolecules, gene transcription/translation modulating agents such as antisense oligonucleotides and genes themselves will progressively gain territory in the field of drug development. For these treatment modalities to become major successes, the delivery and/or targeting of these compounds will be an essential component [1].

The aim of this chapter is to introduce the basic principles of drug targeting as they have evolved over previous decades. The most important chemical features and biological behavioural characteristics of the carrier molecules exploited for drug targeting purposes will be addressed. Novel advances in the understanding of cellular routing of naturally-occurring entities such as viruses have in recent years been applied for cellular delivery purposes. Furthermore, a selection of drug targeting preparations that are either in the stage of clinical testing or have been approved for application in the clinic is discussed. As the basis of drug development lies in the understanding of the molecular basis of diseases, selective interference with regulatory processes in health and disease by drug targeting will become a powerful technology. Drug targeting can, in this respect, serve both as a therapeutic approach and as a research tool in unravelling the functions of these processes in normal physiology and under pathophysiological conditions.

1.2 Carriers used in Drug Targeting

Drug delivery and drug targeting research is blooming in a quantitative sense, as exemplified by the increase in research publications in international pharmaceutical and biomedical literature [1]. In the last three decades many strategies to deliver drugs in a controlled fashion have been developed. The aim of this section is to give a brief introduction on drug carriers employed in targeting strategies. For in-depth reviews on these subjects, the reader is referred to various (special) issues of journals such as Advanced Drug Delivery Reviews, the Journal of Controlled Release and the Journal of Drug Targeting.

The choice of carrier system to be used in drug targeting strategies depends on which target cells should be reached and what drug needs to be delivered. Carriers can be divided into particle type, soluble and cellular carriers. Particle type carriers include liposomes, lipid particles (low and high density lipoproteins, LDL and HDL respectively), microspheres and nanoparticles, and polymeric micelles. Soluble carriers consist of monoclonal antibodies and fragments thereof, modified plasma proteins, peptides, polysaccharides, and biodegradable carriers consisting of polymers of various chemical composition. For the site selective expression of genes, vectors such as liposomes, whole cells and viruses are widely exploited nowadays. With the advancement of chemical and recombinant DNA technology, combinations of strategies (e.g. antibody-targeted liposomes, or bispecific antibody-mediated cross linking of viral vectors and target cells) are now also under investigation.

1.2.1 Liposomes

Liposomes are small vesicles composed of unilamellar or multilamellar phospholipid bilayers surrounding one or several aqueous compartments. Charge, lipid composition and size (ranging from 20 to 10 000 nm) of liposomes can be varied and these variations strongly affect their behaviour in vivo. Many liposome formulations are rapidly taken up by macrophages. They are exploited either for macrophage-specific delivery of drugs or for passive drug targeting, allowing slow release of the drug over time from these cells into the general circulation. Cationic liposomes and lipoplexes have been extensively investigated for their application in non-viral vector mediated gene therapy.

The use of molecules such as polyethylene glycol (PEG) to prevent liposome recognition by phagocytic cells led to the development of so called ‘stealth’ liposomes with longer circulation times and increased distribution to peripheral tissues in the body [2]. Furthermore, a targeting device or homing ligand can be included at the external surface of the liposome in order to obtain target cell specificity as shown schematically in Figure 1.1. Although liposomes do not easily extravasate from the systemic circulation into the tissues, enhanced vascular permeability during an inflammatory response or pro-angiogenic conditions in tumours can favour local accumulation. Another approach is the design of target sensitive liposomes or fusogenic liposomes that become destabilized after binding and/or internalization to/into the target cells [2,3]. After two decades of development, the in vivo and pharmaceutical behaviour of liposomes is now better understood and forms the basis for further development of liposome-mediated drug targeting strategies for clinical application [4].

Figure 1.1. Schematic representation of four major liposome types. Conventional liposomes are either neutral or negatively charged. Stealth liposomes are sterically stabilized and carry a polymer coating to obtain a prolonged circulation time in the body. Immunoliposomes are antibody targeted liposomes and can consist of either conventional or sterically stabilized liposomes. Positive charge on cationic liposomes can be created in various ways. Reproduced from reference [112] with permission.

1.2.2 Monoclonal Antibodies and Fragments

The development of monoclonal antibodies by Köhler and Milstein in 1975 paved the way to antibody therapy for disease [5]. In the last 25 years, the number of pre-clinical and clinical studies with monoclonal antibodies and derivatives thereof have greatly increased. The majority of strategies based on antigen recognition by antibodies have been developed for cancer therapy. These strategies are mostly aimed at tumour associated antigens being present on normal cells but overexpressed by tumour cells [6]. More recently, antibodies against other molecules have been developed for clinical application. Examples are anti-TNFα antibodies for treatment of chronic inflammatory diseases and anti-VEGF (vascular endothelial growth factor) antibodies which inhibit new blood vessel formation or angiogenesis.

The advent of recombinant DNA technology led to the development of antibodies and fragments that are tailored for optimal behaviour in vivo [7,8]. Humanized and chimeric antibodies can be constructed to circumvent the human anti-mouse antibody response elicited by mouse antibody treatment of patients, which severely hampers the application of these powerful molecules. The treatment of rheumatoid arthritis patients with doses of as high as 10 mg kg–1 cA2 chimeric antibody specific for TNFα [9], emphasizes that at present the production and purification methods for these proteins have been optimized to such extent that clinical studies can be considerably intensified.