In vitro cytotoxicity of novel pro-apoptotic agent DM-PIT-1 in PEG-PE-based micelles alone and in combination with TRAIL.

Abstract

The purpose of this study was to develope and characterize a micellar formulations of N-{[(2-hydroxy-5- nitrophenyl)amino]carbonothioyl}-3,5-dimethylbenzamide (DM-PIT-1)-a new small molecule non-lipid antagonist of phopshotidylinositol-3.4.5-triphopshate and inhibitor of the PI3-kinase pathway. Micelle-forming PEG(2000)-PE was used to solubilize DM-PIT-1. To improve the specificity of the micellar DM-PIT-1, cancer-targeting anti-nucleosomal mAb2C5 antibodies as well as Tumor necrosis factor- Related Apoptosis-Inducing Ligand (TRAIL) were attached to the surface of polymeric micelles. DM-PIT-1 was effectively incorporated (> 70%) into 14-16 nm micelles, which had a negative surface zeta potential of 4-5 mV. Micellar DM-PIT-1 demonstrated high in vitro cytotoxicity against various cancer cells. An improved potency of the dual-activity DM-PIT-1/TRAIL combination nanoparticles in inducing death of TRAIL-resistant cancer cells was shown. Efficacy of the TRAIL therapy was enhanced by combining it with the 2C5 antibody cancer-targeted micellar form of DM-PIT-1. In conclusion, DM-PIT-1 micellar preparations can be used for targeted combination therapy against TRAIL-resistant cancers.

• Authors: Igor Skidan, Benchun Miao, Ritesh V Thekkedath, Parita Dholakia, Alexei Degterev, Vladimir Torchilin
• Journal: Drug delivery (Drug Deliv) Vol. 16 Issue 1 Pg. 45-51 (Jan 2009) ISSN: 1521-0464 [Electronic] England
• PMID: 19555308 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antibodies, Monoclonal
• Antineoplastic Agents
• Benzamides
• Drug Carriers
• Micelles
• N-(((2-hydroxy-5-nitrophenyl)amino)carbonothioyl)-3,5-dimethylbenzamide
• Phosphatidylethanolamines
• Phosphatidylinositol Phosphates
• Phosphoinositide-3 Kinase Inhibitors
• TNF-Related Apoptosis-Inducing Ligand
• phosphatidylinositol 3,4,5-triphosphate
• dioleoyl-N-(monomethoxypolyethylene glycol succinyl)phosphatidylethanolamine
• Polyethylene Glycols

Topics

• Animals
• Antibodies, Monoclonal (administration & dosage, chemistry)
• Antineoplastic Agents (administration & dosage, chemistry, pharmacology)
• Apoptosis (drug effects)
• Benzamides (administration & dosage, chemistry, pharmacology)
• Cell Line, Tumor
• Drug Carriers (chemistry)
• Drug Delivery Systems
• Drug Resistance, Neoplasm
• Humans
• Mice
• Micelles
• Nanoparticles
• Neoplasms (drug therapy)
• Phosphatidylethanolamines (chemistry)
• Phosphatidylinositol Phosphates (antagonists & inhibitors)
• Phosphoinositide-3 Kinase Inhibitors
• Polyethylene Glycols (chemistry)
• Solubility
• TNF-Related Apoptosis-Inducing Ligand (administration & dosage, chemistry, metabolism)