In vitro cytotoxicity of novel pro-apoptotic agent DM-PIT-1 in PEG-PE-based micelles alone and in combination with TRAIL.
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.
Skidan
Igor
I
Department of Pharmaceutical Sciences and Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA 02115, USA.
Miao
Benchun
B
Thekkedath
Ritesh V
RV
Dholakia
Parita
P
Degterev
Alexei
A
Torchilin
Vladimir
V
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000737:chemistry; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm; D006801:Humans; D051379:Mice; D008823:Micelles; D053758:Nanoparticles; D009369:Neoplasms / Q000188:drug therapy; D010714:Phosphatidylethanolamines / Q000737:chemistry; D018129:Phosphatidylinositol Phosphates / Q000037:antagonists & inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011092:Polyethylene Glycols / Q000737:chemistry; D012995:Solubility; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D001549:Benzamides; D004337:Drug Carriers; D008823:Micelles; C543892:N-(((2-hydroxy-5-nitrophenyl)amino)carbonothioyl)-3,5-dimethylbenzamide; D010714:Phosphatidylethanolamines; D018129:Phosphatidylinositol Phosphates; D000081082:Phosphoinositide-3 Kinase Inhibitors; D053221:TNF-Related Apoptosis-Inducing Ligand; C060974:phosphatidylinositol 3,4,5-triphosphate; C067972:dioleoyl-N-(monomethoxypolyethylene glycol succinyl)phosphatidylethanolamine; D011092:Polyethylene Glycols