Micellar formulations of pro-apoptotic DM-PIT-1 analogs and TRAIL in vitro and in vivo

• Published in: Drug delivery Vol. 20; no. 2; pp. 78 - 85
• Main Authors: Riehle, Robert D., Cornea, Sinziana, Degterev, Alexei, Torchilin, Vladimir
• Format: Journal Article
• Language: English
• Published: England Informa Healthcare USA, Inc 01.02.2013; Taylor & Francis
• Subjects: Animals; antagonists; Anticancer; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - chemistry; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Apoptosis - drug effects; Benzamides - administration & dosage; Benzamides - chemistry; Benzamides - pharmacology; Benzamides - therapeutic use; Cell Line, Tumor; Cell Survival - drug effects; Chemistry, Pharmaceutical; Chlorophenols - administration & dosage; Chlorophenols - chemistry; Chlorophenols - pharmacology; Chlorophenols - therapeutic use; Drug Carriers - chemistry; Female; Humans; In Situ Nick-End Labeling; Mice; Mice, Nude; Micelles; multifunctional drug delivery; Nanoparticles - chemistry; Particle Size; PEG-PE micelles; Phosphatidylinositol 3-Kinase - antagonists & inhibitors; PIP; Solubility; Surface Properties; TNF-Related Apoptosis-Inducing Ligand - administration & dosage; TNF-Related Apoptosis-Inducing Ligand - chemistry; TNF-Related Apoptosis-Inducing Ligand - pharmacology; TNF-Related Apoptosis-Inducing Ligand - therapeutic use; TRAIL; Triazoles - administration & dosage; Triazoles - chemistry; Triazoles - pharmacology; Triazoles - therapeutic use; Xenograft Model Antitumor Assays
• ISSN: 1071-7544; 1521-0464
• DOI: 10.3109/10717544.2013.766780

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.