ABSTRACT
I. Introduction ............................................................................................................... 233
11. What Constitutes an "Ideal" Immunoliposome? ...................................................... 234 A. Rapid Simple Coupling Method ......................................................................... 234 B. High Coupling Efficiency of Ab to Liposome .................................................. 235 C. Optimum Ab Density at the Liposome Surface ................................................. 235 D. Appropriate Drug Loading and Release Characteristics .................................... 235 E. Retention of Long Circulation Half-Lives ......................................................... 235 F. Retention of Target Recognition In Vitro and In Vivo ...................................... 235 G. Ingredients Compatible with Use in Humans .................................................... 236 H. In Vivo Efficacy .................................................................................................. 236
Ill. Coupling Methods for Attaching Antibodies to S-Liposomes ................................. 236 A. Noncovalent Biotin-Avidin Method ................................................................... 236 B. Covalent Attachment of Ab to the Liposome Surface ...................................... 236
1. MPB-PE ......................................................................................................... 238 2. PDP-PE ........................................................................................................... 238
C. Covalent Attachment of Antibody to the Terminus of PEG ............................. 239 1. PEG-HZ .......................................................................................................... 239 2. PDP-PEG ........................................................................................................ 239
D. N-glutaryl-PE Method ......................................................................................... 239
IV. Target Recognition In Vitro ...................................................................................... 239
V. Target Recognition In Vivo ....................................................................................... 240
VI. Conclusions ............................................................................................................... 242
References ........................................................................................................................... 242
Following the first description of liposomes 30 years ago, 1 the use of liposomes as delivery systems to selectively deliver drugs to specific cells or tissues has received considerable attention. After the initial burst of enthusiasm for the use of liposomal drug carriers, it was realized that the mononuclear phagocyte system (MPS, also termed the reticuloendothelial system) presented a barrier that had to be overcome before liposomal drug therapy could be used effectively in the treatment of a wide range of diseases involving tissues other than the MPS.2 The pronounced tendency of "classical" liposome formulations (C-liposomes), particularly those containing phosphatidylserine, to target cells of the MPS, presents some important
The advent of new formulations of long circulating liposomes, first described by All en and Chonn,5 has renewed activity in the area of liposomal drug delivery systems, with several promising applications currently receiving preclinical testing in animal models,&- 12 and one formulation in clinical trials in humans. 13· 14 The first long circulating liposome formulations resulted from attempts to mimic some of the properties of the outer surface of red blood cells, and contained monosialoganglioside GMl as the hydrophilic, opsonin-repelling surface component thought to be responsible for their survival in the circulation.5•15 Gabizon and Papahadjopoulos demonstrated increased tumor uptake of these long circulating liposomes in experiments which, for the first time, demonstrated that site-specific delivery of liposomeentrapped drug to sites outside the MPS was a realistic possibility .16 Several reviews describing the dose-independent pharmacokinetics, the biodistribution and the mechanisms of action of these "first-generation" long circulating liposomes have been published. 17-20 Potential problems with the commercial acceptability of products containing GMl led to a search for safe, inexpensive substitutes with increased clinical acceptability. Second-generation formulations, containing lipid derivatives of polyethylene glycol (PEG), such as PEG-distearoyl phosphatidylethanolamine, have subsequently been described by us and others,21 - 25 and their properties have been explored.26-31 Long circulating liposomes have been termed Stealth® liposomes (Stealth® is a registered trademark of Liposome Technology, Inc.), because of their poor affinity for the cells of the MPS, i.e., their ability to avoid detection.32 These liposomes are also referred to as sterically stabilized liposomes (S-liposomes).25 •26 S-liposomal drug delivery systems are suitable for a number of therapeutic applications involving, primarily, sustained drug release, and selective delivery of drugs to specific target tissues such as cancers.
