PEG liposomes

Awasthi VD, Garcia D, Goins BA, et al. Circulation and biodistribution profiles of long-circulating PEG-liposomes of various sizes in rabbits. Int J Pharm 2003 253 121. 

Janssen A, et al. Peptide-targeted PEG-liposomes in anti-angiogenic therapy. Int J Pharm 2003 254 55. 

The HMPAO-glutathione method has been used in a number of preclinical animal studies (19). An example is shown in Figure 1, where the biodistribution of Tc-HMPAO-labeled PEG liposomes is compared to... 

The same liposomal preparation was used to investigate the effect of the administered dose on the biodistribution and pharmacokinetics (41). The effect of the lipid dose of Tc-HYNIC-PEG-liposomes was investigated in the low-dose range (0.02-1.0 pmol/kg), typically for noninvasive imaging applications. The biodistribution and pharmacokinetics of "Tc-HYNIC-PEG-liposomes at various dose levels were studied in rats and rabbits with a focal Escherichia coli infection. Moreover, the pharmacokinetics of Tc-HYNIC-PEG-liposomes at two lipid dose levels were studied in four patients. In rabbits, enhanced clearance was observed at a dose level of 0.02 pmol/kg. The circulatory half-life decreased from 10.4 to 3.5 hours (at 1.0 and 0.02 pmol/kg, respectively). At the lowest dose level, liposomes were mainly taken up by the liver and to a lesser extent by the spleen. Most importantly, the rapid clearance of low-dose PEG liposomes was also observed in humans when relatively low lipid doses were administered as is shown in Figure 4. This study showed that, at very low lipid doses, the biodistribution of PEG liposomes is dramatically altered. 

Dams ET, Oyen WJ, Boerman OC, et al. Tc-PEG liposomes for the scintigraphic detection of infection and inflammation clinical evaluation. J Nucl Med 2000 41 622. 

Laverman P, Van Bloois L, Boerman OC, Oyen WJ, Corstens FH, Storm G. Lyophilization of Tc-99m-HYNIC labeled PEG-liposomes. J Liposome Res 2000 10 117. 

Brouwers AH, De Jong DJ, Dams ET, et al. Tc-99m-PEG-liposomes for the evaluation of colitis in Crohn s disease. J Drug Target 2000 8 225. 

Szebeni J, Baranyi L, Savay S, et al. Role of complement activation in hypersensitivity reactions to doxil and hynic PEG liposomes experimental and clinical studies. J Liposome Res 2002 12 165. 

Free daunomycin and not PEG-conjugated hposomes containing daunomycin, disappear rapidly from the circulation. Plasma clearance of the hposome was reduced 66-fold by PEG-conjugation. Coupling 29 0X26 monoclonal antibodies per PEG-liposome partially reversed the effect of PEG-conjugation on plasma clearance. 

Plasma clearance (Cl), blood-brain barrier permeability surface area product (PS) and accumulation as % injected dose detected in brain tissue (%ID tissue) at 1 h after administration. Results show free [ H]-daunomycin (Daunomycin), [ H]-daunomycin encapsulated in conventional liposomes (Liposomes), sterically stabilized liposomes (PEG-liposomes), immunoliposomes (29 0X26, where 29 designates the number of 0X26 mAb conjugated per liposome) and control immunoliposomes where the 0X26 mAb was replaced by a non-specific isotype control antibody (IgG2a). Values are means SEM of n = 3 experiments. 

Mueller A, Bondurant B, O Brien DF (2000) Visible-light-stimulated destabilization of PEG-liposomes. Macromolecules 33 4799-4804... 

Immobilization of antibody on PEG-liposomes by (a) direct coupling to the liposome surface and (b) coupling to the terminal ends of the PEG chains... 

Intraperitoneal Administration The potential of PEGylated liposomes administered intraperitoneally has been evaluated for cancers located in the peritoneal cavity. For example, Syrigos et al. [238] studied the biodistribution of indium ( Relabeled PEGylated liposomes [Hydrogenated soya PC (HSPC)/ChoPPEG-DSPE] compared to free mIn via either i.p. or i.v. route to non-tumor bearing mice. The AUC of In-PEG liposomes was 74-fold higher than that of free indium. The relative ratio of the AUCs (RR-AUCs) for i.p. versus i.v. administration for peritoneum was 1.36 [423.6 vs. 311.3% individual dose (ID) g/h]. The blood AUC values for i.p. and... 

An increase in therapeutic efficacy and lower toxicity was reported with liposomes where the bradykinin analogue RMP-7 was chemically attached at the end of PEG molecules of PEGylated liposomes (approximate size 70nm) [384], RMP-7 exhibits high selectivity for the B2 receptor of the BBB endothelial cells, which shrunk and let the RMP-7-PEG liposomes to pass into the brain. Actually the mechanism used in that study was based on opening the tight junctions of the BBB. Liposome-incorporated nerve growth factor (NGF) concentration increased 10 times in comparison to free NGF, while they accumulated mainly in striatum, hippocampus, and cortex. 

A different type of immunoliposome was developed using antinuclear autoantibodies with nucleosome (NS)-restricted specificity [187], Anti-NS mAb 2C5 specifically recognizes human brain tumor cells. Evaluation of immunoliposomes 2C5-PEG-PC/Chol was carried out in nude mice bearing subcutaneous brain tumor (U-87 astrocytoma) and exhibited a threefold higher accumulation in the tumor in comparison to control (IgG-PEG liposomes). 

A phase III study was conducted to compare PEG-liposomal DXR (50 mg/m2 every 4 weeks) with paclitaxel (175 mg/m2 every 3 weeks) using 214 patients with relapse after first-line platinum-based chemotherapy [420], As previously, the response rates and PFS were not significantly different, but again the liposomal formulation was notably less toxic as fewer patients recorded with grade 4 adverse effects (17% compared to 71% for topotecan) and thus was more tolerable. 

A variety of new molecules either in combination with liposomal doxorubicin or not are in development at the moment [457]. For example, a phase III study will be conducted to test the efficacy and safety of pattupilone versus PEG-liposomal DXR in taxane/platinum refractory/resistant patients with recurrent epithelial ovarian, primary fallopian, or primary peritoneal cancer. A phase III randomized study of Telcyta with Doxil/Caelyx versus Doxil/Caelyx has been planned in patients with platinum-refractory or platinum-resistant ovarian cancer. A phase II study relevant to side effects and best dose of ixabepilone combined with liposomal DXR will be assessed in patients with advanced ovarian epithelial, peritoneal cavity, or fallopian tube cancer or metastatic breast cancer. 

Small pegylated liposomes have been shown to extravasate into tumors with leaky vasculature, and the prolonged circulation half-life has a positive effect on the extravasation. Passive tumor targeting of liposomes was visualized in a study of radio-labeled PEG-liposomes in patients with locally advanced cancers, and whole body gamma camera imaging was used to monitor biodistribution and tumor localization. Of 17 patients treated with In-DTPA (Diethylenetri-aminepentaacetic acid) labeled PEG-liposomes, tumor... 

PEG-liposomes DOX, paclitaxel, cisplatin Passive Clinical use, Phase Phase 1/11 ... 

PEG-liposomes DOX Folate Mice-bearing mouse Ml09 and human... 

PEG-liposomes DOX Anti-HER2 HER2 over expressed tumors in mice ... 

PEG-liposomes 2-Deoxy-5-fluorouridyly-Af- octadecyl-l-P-D- arabinofuranosylcytosine Anti-ED-P- fibronectin-scFv Mice bearing murine F9 teratocarcinoma " ... 

Ishida, O. Maruyama, K. Transferring conjugated PEG-liposomes as intracellular targeting carrier for tumor therapy. Nippon Rinsho 1998, 56 (3), 657-662. 

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