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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
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Antineoplastic Combined Chemotherapy Protocols / chemistry
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Antineoplastic Combined Chemotherapy Protocols / pharmacology
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use
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Apoptosis / drug effects
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Benzamides / administration & dosage*
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Benzamides / chemistry
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Benzamides / pharmacology
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Benzamides / therapeutic use
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Cell Line, Tumor
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Cell Survival / drug effects
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Chemistry, Pharmaceutical
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Chlorophenols / administration & dosage
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Chlorophenols / chemistry
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Chlorophenols / pharmacology
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Chlorophenols / therapeutic use
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Drug Carriers / chemistry*
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Female
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Humans
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In Situ Nick-End Labeling
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Mice
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Mice, Nude
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Micelles
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Nanoparticles / chemistry*
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Particle Size
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Phosphoinositide-3 Kinase Inhibitors
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Solubility
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Surface Properties
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TNF-Related Apoptosis-Inducing Ligand / administration & dosage*
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TNF-Related Apoptosis-Inducing Ligand / chemistry
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TNF-Related Apoptosis-Inducing Ligand / pharmacology
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TNF-Related Apoptosis-Inducing Ligand / therapeutic use
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Triazoles / administration & dosage
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Triazoles / chemistry
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Triazoles / pharmacology
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Triazoles / therapeutic use
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Xenograft Model Antitumor Assays
Substances
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Benzamides
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Chlorophenols
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Drug Carriers
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Micelles
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N-(((2-hydroxy-5-nitrophenyl)amino)carbonothioyl)-3,5-dimethylbenzamide
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NCL-240
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Phosphoinositide-3 Kinase Inhibitors
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TNF-Related Apoptosis-Inducing Ligand
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Triazoles