Combination Nanopreparations of a Novel Proapoptotic Drug – NCL-240, TRAIL and siRNA
| Autor: | Ganesh A. Thakur, Alexei Degterev, Aditi Jhaveri, Robert D. Riehle, Bhushan S. Pattni, Abhijit R. Kulkarni, Vladimir P. Torchilin |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Chemistry Pharmaceutical Survivin Pharmaceutical Science Antineoplastic Agents Apoptosis Micelle Cell Line Inhibitor of Apoptosis Proteins Polyethylene Glycols TNF-Related Apoptosis-Inducing Ligand Mice 03 medical and health sciences 0302 clinical medicine Cell Line Tumor Animals Humans Pharmacology (medical) Particle Size RNA Small Interfering Cytotoxicity Micelles Cell Proliferation Pharmacology Cell growth Chemistry Phosphatidylethanolamines Organic Chemistry Triazoles Molecular biology In vitro 030104 developmental biology Cell culture 030220 oncology & carcinogenesis Cancer cell MCF-7 Cells NIH 3T3 Cells Nanoparticles Molecular Medicine Chlorophenols Biotechnology |
| Zdroj: | Pharmaceutical Research. 33:1587-1601 |
| ISSN: | 1573-904X 0724-8741 |
| DOI: | 10.1007/s11095-016-1899-z |
| Popis: | To develop a multifunctional nanoparticle system carrying a combination of pro-apoptotic drug, NCL-240, TRAIL [tumor necrosis factor-α (TNF-α)-related apoptosis-inducing ligand] and anti-survivin siRNA and to test the combination preparation for anti-cancer effects in different cancer cells. Polyethylene glycol-phosphoethanolamine (PEG-PE) – based polymeric micelles were prepared carrying NCL-240. These micelles were used in combination with TRAIL-conjugated micelles and anti-survivin siRNA-S-S-PE containing micelles. All the micelles were characterized for size, zeta potential, and drug encapsulation efficiency. Different cancer cells were used to study the cytotoxicity potential of the individual as well as the combination formulations. Other cell based assays included cellular association studies of transferrin-targeted NCL-240 micelles and study of cellular survivin protein downregulation by anti-survivin siRNA-S-S-PE containing micelles. NCL-240 micelles and the combination NCL-240/TRAIL micelles significantly increased cytotoxicity in the resistant strains of SKOV-3, MCF-7 and A549 as compared to free drugs or single drug formulations. The NCL-240/TRAIL micelles were also more effective in NCI/ADR-RES cancer cell spheroids. Anti-survivin siRNA micelles alone displayed a dose-dependent reduction in survivin protein levels in A2780 cells. Treatment with NCL-240/TRAIL after pre-incubation with anti-survivin siRNA inhibited cancer cell proliferation. Additionally, a single multifunctional system composed of NCL-240/TRAIL/siRNA PM also had significant cytotoxic effects in vitro in multiple cell lines. These results demonstrate the efficacy of a combination of small-molecule PI3K inhibitors, TRAIL, and siRNA delivered by micellar preparations in multiple cancer cell lines. |
| Databáze: | OpenAIRE |
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