Additionally in vitro results often differ from in vivo findings [24, 40]. Particularly when administered parentally, liposomes

will interact with various circulatory components and are then cleared by hepatocytes in vivo [40, 42]. 3.1.2. Liposome Charge Cationic liposomes are associated with efficient cellular delivery of drug cargoes and routinely Inhibitors,research,lifescience,medical applied for in vitro gene delivery [43]. Electrostatic interactions between positively charged liposomes and the negatively charged cell membranes and cell p53-mdm2 pathway surface proteoglycans [44] facilitate cell uptake. Unfortunately, cationic liposomes can cause cytotoxicity limiting their safety for clinical use [45]. In RAW264.7 macrophages cationic liposomes containing stearylamine (SA) have previously been shown to Inhibitors,research,lifescience,medical induce apoptosis through mitochondrial pathways generating reactive oxygen species (ROS), releasing cytochrome c, caspase-3 and -8 and more recently activating protein kinase C (PKC) δ possibly by cell surface proteoglycan interaction [38, 46–48]. Consequently interest for

drug delivery has turned to neutral and anionic liposomes. Negatively charged lipids such as phosphatidylserine (PS) and phosphatidylglycerol Inhibitors,research,lifescience,medical (PG) are preferentially recognised by macrophages [37]. Studies comparing phosphotidylcholine (PC; neutral) and PS-composed liposomes have established negative liposome formulations to have enhanced macrophage internalisation [49]. Additionally, studies by us to quantify this difference have found Inhibitors,research,lifescience,medical a 5.3-fold increase in the association of negatively charged 1,2-dioleoyl-sn-glycero-3-phospho-L-serine (DOPS):Cholesterol liposomes with a macrophage cell model, differentiated

THP-1 cells, compared to neutral 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC):Cholesterol liposomes (Figure 2) an effect which was also seen in vivo [50]. Negative charge can also be achieved by the incorporation of dicetylphosphate (DCP) [25, 40]. Vyas et al. showed a 3.4-fold increase in rifampicin lung retention in rats when rifampicin was encapsulated in negatively charged DCP, PC, and cholesterol-composed Inhibitors,research,lifescience,medical Microbiology and Molecular Biology Reviews liposomes and a 1.3-fold increase when encapsulated in the corresponding neutral liposomes compared to free drug after aerosol administration [25]. Figure 2 Uptake of neutral (DOPC:Chol 7:3) and anionic (DOPS:Chol 7:3) liposomes by differentiated THP-1 cells after 2 hours (n = 6 ± SEM) *P < .05; **P < .001. The composition of the inner membrane leaflet of eukaryotic cells [1] consists of PS and phosphatidylethanolamine (PE) with an outer layer of PC and sphingomyelin (SM) [51, 52]. In an apoptotic or necrotic event, PS will be exposed on the outer cell surface, and monocytic phagocytosis is induced. It is believed that PS targets scavenger receptors (SRs) on macrophages (Figure 1) but there may also be receptors specific for PS recognition.