Drug Delivery to Macrophages for the Therapy of Cancer and Infectious Diseases zy RICHARD KIRSH, PETER J. BUGELSKI, AND GEORGE POSTE zyxw Smith KIine and French Laboratories Philadelphia, Pennsylvania 191 01 INTRODUCTION The role of cells of the mononuclear phagocyte system (MPS), which includes the Kupffer cells in the liver; alveolar, splenic, lymph node, and bone marrow macro- phages; tissue histiocytes; and circulating blood monocytes, in host defense against neoplastic and infectious disease has attracted increasing attention over the past ten year^.'^.^* This interest stems from three principal aspects of the functional behavior of mononuclear phagocytes. First, when activated,” mononuclear phagocytes display significant cytotoxicity towards neoplastic cells and invading microorganisms while leaving “normal” host cells completely unharmed. Second, mononuclear phagocytes will infiltrate sites of infection and neoplastic lesions thus circumventing the need to target therapeutic agents to such sites. Third, agents that activate the tumoricidal and microbiocidal properties of mononuclear phagocytes augment host defense against tumors and infectious disease. Collectively, these observations, coupled with the disappointing results obtained in both clinical and experimental trials with immuno- logically specific therapeutic modalities mediated by T- and B-lymphocytes, have led to renewed interest in the functions of macrophages in host defense and renewed interest in the therapeutic value of augmenting the immunologically non-specific tumoricidal and microbiocidal properties of mononuclear phagocytes in the therapy of cancer and infectious diseases. The ability to selectively target drugs to specific cells within the body has been one of the most coveted goals in experimental and clinical therapeutics. To this end, a wide variety of macromolecular, particulate, and cellular matrices have been proposed for use as drug carrier systems. These include antibodies, dextrans, plasma proteins, polynucleotides, red blood cells, polymorphonuclear leukocytes, gelatin or albumin microspheres, synthetic polymeric nanoparticles, multiphase microemulsions, and liposomes. Many of these systems have failed to fulfill their initial promise but interest in targetable drug delivery systems remains Current information on the application of liposomes to drug delivery in zyx vivo, with particular emphasis on their use for the selective delivery of antibiotics and biological response modifiers (BRM) to mononuclear phagocytes will be reviewed. Although liposomes have received considerable attention in experimental therapeutics, surpris- ingly little emphasis has been given to evaluation of the issues of toxicity and pharmaceutical formulation required for successful commercialization of these car- ‘The term “activated macrophage” will refer to macrophages that display tumoricidal and/or microbiocidal activity. zyxwvut 141