Antibody-Targeted Stealth® Liposomes (2018)

I. Introduction 23311. 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 236Ill. Coupling Methods for Attaching Antibodies to S-Liposomes 236 
A. Noncovalent Biotin-Avidin Method 236 
B. Covalent Attachment of Ab to the Liposome Surface 2361. MPB-PE 238 
2. PDP-PE 238C. Covalent Attachment of Antibody to the Terminus of PEG 239 
1. PEG-HZ 239 
2. PDP-PEG 239D. N-glutaryl-PE Method 239IV. Target Recognition In Vitro 239V. Target Recognition In Vivo 240VI. Conclusions 242References 242Following 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 importantThe 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.