Liposome formulation of a novel hydrophobic aryl-imidazole compound for anti-cancer therapy.
OBJECTIVE
A cholesterol-free liposome formulation formed from mixtures of egg phosphatidylcholine (ePC) and poly (ethylene glycol) conjugated distearoylphosphatidylethanolamine (DSPE-PEG 2000) was optimized and evaluated for delivery of a novel anti-cancer agent ML220 (2-(5-bromo-1H-indol-3-yl)-1H-phenanthro [9,10-d] imidazole).


CONCLUSIONS
ML220 is highly lipophilic with a water solubility of 0.14 mug/ml and calculated log P of 5.69. The ML220-loaded liposomes had a unimodal size-distribution and a mean diameter of 89 nm. The drug to lipid ratio in the formulation was 1:3.5 (mol:mol) and the drug loading efficiency was 83% providing a more than 50,000-fold increase in the water solubility of ML220. The formulation was demonstrated to be stable in vitro at 37 degrees C for over 2 weeks with a delayed drug release profile. Evaluation of the subacute toxicity of the liposome formulated drug in C3H mice revealed no overt signs of toxicity. Also, a biexponential drug plasma concentration pattern was found upon evaluation of the pharmacokinetics in Balb/C mice. The in vivo evaluation of the anti-cancer activity in a human colon HT29 carcinoma model revealed a significant delay in tumor growth.


CONCLUSIONS
Overall, the ePC/DSPE-PEG liposomes were demonstrated to be a suitable delivery system for ML220. These studies also highlight the potential of cholesterol-free liposomes as a formulation strategy for highly lipophilic drugs.
Liu
Jubo
J
Department of Pharmaceutical Sciences, University of Toronto, ON, Canada.
Lee
Helen
H
Huesca
Mario
M
Young
Aiping
A
Allen
Christine
C
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004339:Drug Compounding; D004354:Drug Screening Assays, Antitumor; D004355:Drug Stability; D005260:Female; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007093:Imidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D008081:Liposomes; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D010316:Particle Size; D010616:Phenanthrenes / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D010713:Phosphatidylcholines / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D012995:Solubility; D014018:Tissue Distribution
C512108:2-(5-bromo-1H-indol-3-yl)-1H-phenanthro(9,10-d)imidazole; D000970:Antineoplastic Agents; D007093:Imidazoles; D008081:Liposomes; D010616:Phenanthrenes; D010713:Phosphatidylcholines; D011092:Polyethylene Glycols; C010942:1,2-distearoyllecithin