title: Micellar formulations of pro-apoptotic DM-PIT-1 analogs and TRAIL in vitro and in vivo.
abstract: We have developed and characterized micellar formulations of analogs to the recently developed inhibitor of the phosphatidylinositol-3-kinase (PI3K) pathway (N-[(2-hydroxy-5-nitrophenyl)amino]carbonothioyl-3,5-dimethylbenzamide (DM-PIT-1)) for their physicochemical, loading and cytotoxic properties. The first generation inhibitor DM-PIT-1 is a non-lipid, small molecule inhibitor of phosphatidylinositol-3,4,5-triphosphate/Pleckstrin homology (PIP3/PH) binding capable of inhibiting the growth of tumor cells both in vitro and in vivo. A second generation of improved and druggable analogs has been developed. All compounds were successfully loaded (>70%) in PEG2000-PE micelles of 16-20 nm in size with several analogs demonstrating favorable cytotoxic activity against A2780 ovarian carcinoma. These compounds were also successfully incorporated into polyethylene glycol-phosphatidylethanolamine (PEG-PE) micelles combined with surface-bound tumor necrosis factor related apoptosis inducing ligand (TRAIL). The resulting multifunctional combination micelles were able to significantly enhance cytotoxic activity in the TRAIL-resistant A2780 cell line. Additionally, analogs NCL-176 and NCL-240 were effective in inhibiting tumor growth in an in vivo subcutaneous tumor model of A2780. These results indicate the utility of delivering TRAIL and PI3K pathway inhibitors in a combined micellar preparation.
authors.affiliation: Department of Pharmaceutical Sciences, Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA 02115, USA.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Riehle
authors.forename: Sinziana
authors.initials: S
authors.lastname: Cornea
authors.forename: Alexei
authors.initials: A
authors.lastname: Degterev
authors.forename: Vladimir
authors.initials: V
authors.lastname: Torchilin
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D002733:Chlorophenols / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D004337:Drug Carriers / Q000737:chemistry*; D005260:Female; D006801:Humans; D020287:In Situ Nick-End Labeling; D051379:Mice; D008819:Mice, Nude; D008823:Micelles; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012995:Solubility; D013499:Surface Properties; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D014230:Triazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D001549:Benzamides; D002733:Chlorophenols; D004337:Drug Carriers; D008823:Micelles; C543892:N-(((2-hydroxy-5-nitrophenyl)amino)carbonothioyl)-3,5-dimethylbenzamide; C000611383:NCL-240; D000081082:Phosphoinositide-3 Kinase Inhibitors; D053221:TNF-Related Apoptosis-Inducing Ligand; D014230:Triazoles