Combination Nanopreparations of a Novel Proapoptotic Drug – NCL-240, TRAIL and siRNA

• Published in: Pharmaceutical research 2016-07, Vol.33 (7), p.1587-1601
• Main Authors: Riehle, Robert, Pattni, Bhushan, Jhaveri, Aditi, Kulkarni, Abhijit, Thakur, Ganesh, Degterev, Alexei, Torchilin, Vladimir
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Biochemistry; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Cancer; Cell Line; Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry, Pharmaceutical - methods; Chlorophenols - chemistry; Chlorophenols - pharmacology; Drug delivery systems; Drugs; Humans; Inhibitor of Apoptosis Proteins - metabolism; MCF-7 Cells; Medical Law; Mice; Micelles; Nanoparticles; Nanoparticles - administration & dosage; Nanoparticles - chemistry; NIH 3T3 Cells; Particle Size; Pharmacology/Toxicology; Pharmacy; Phosphatidylethanolamines - chemistry; Polyethylene Glycols - chemistry; Research Paper; RNA, Small Interfering - chemistry; RNA, Small Interfering - pharmacology; TNF-Related Apoptosis-Inducing Ligand - chemistry; TNF-Related Apoptosis-Inducing Ligand - pharmacology; Triazoles - chemistry; Triazoles - pharmacology; Tumor necrosis factor
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1007/s11095-016-1899-z

Purpose 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. Methods 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. Results 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. Conclusion 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.