Robert Riehle1, Bhushan Pattni1, Aditi Jhaveri1, Abhijit Kulkarni1, Ganesh Thakur1, Alexei Degterev2, Vladimir Torchilin3,4. 1. Center for Pharmaceutical Biotechnology and Nanomedicine, Department of Pharmaceutical Sciences, Northeastern University, 140 The Fenway, Room 236, 360 Huntington Avenue, Boston, Massachusetts, 02115, USA. 2. Department of Biochemistry, Tufts University School of Medicine, Boston, Massachusetts, USA. 3. Center for Pharmaceutical Biotechnology and Nanomedicine, Department of Pharmaceutical Sciences, Northeastern University, 140 The Fenway, Room 236, 360 Huntington Avenue, Boston, Massachusetts, 02115, USA. v.torchilin@neu.edu. 4. Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, 21589, Saudi Arabia. v.torchilin@neu.edu.
Abstract
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.
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.
Authors: Rudi Bao; Denise C Connolly; Maureen Murphy; Jeffrey Green; Jillian K Weinstein; Debra A Pisarcik; Thomas C Hamilton Journal: J Natl Cancer Inst Date: 2002-04-03 Impact factor: 13.506
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Authors: Rupa R Sawant; Aditi M Jhaveri; Alexander Koshkaryev; Lin Zhu; Farooq Qureshi; Vladimir P Torchilin Journal: Mol Pharm Date: 2013-12-19 Impact factor: 4.939
Authors: Bhushan S Pattni; Srikar G Nagelli; Bhawani Aryasomayajula; Pranali P Deshpande; Abhijit Kulkarni; William C Hartner; Ganesh Thakur; Alexei Degterev; Vladimir P Torchilin Journal: Pharm Res Date: 2016-06-28 Impact factor: 4.200
Authors: Bhushan S Pattni; Aditi Jhaveri; Ivy Dutta; James D Baleja; Alexei Degterev; Vladimir Torchilin Journal: Int J Pharm Date: 2017-08-24 Impact factor: 5.875