Nishant S Gandhi1,2, Sudhakar Godeshala3, Dana-Lynn T Koomoa-Lange1, Bhavani Miryala3, Kaushal Rege3, Mahavir B Chougule4,5,6,7. 1. Department of Pharmaceutical Sciences, The Daniel K Inouye College of pharmacy, University of Hawaii at Hilo, Hilo, HI, 96720, USA. 2. Translational Bio-pharma Engineering Nanodelivery Research Laboratory, Department of Pharmaceutics and Drug Delivery, School of Pharmacy, Faser Hall, University of Mississippi, University, MS, 38677, USA. 3. Chemical Engineering, Arizona State University, Tempe, AZ, 85287-6106, USA. 4. Department of Pharmaceutical Sciences, The Daniel K Inouye College of pharmacy, University of Hawaii at Hilo, Hilo, HI, 96720, USA. chougule@olemiss.edu. 5. Translational Bio-pharma Engineering Nanodelivery Research Laboratory, Department of Pharmaceutics and Drug Delivery, School of Pharmacy, Faser Hall, University of Mississippi, University, MS, 38677, USA. chougule@olemiss.edu. 6. Pii Center for Pharmaceutical Technology, Research Institute of Pharmaceutical Sciences, University of Mississippi, University, MS, 38677, USA. chougule@olemiss.edu. 7. National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, University of Mississippi, University, MS, 38677, USA. chougule@olemiss.edu.
Abstract
PURPOSE: Lung cancer is one of the leading causes of deaths in the United States, but currently available therapies for lung cancer are associated with reduced efficacy and adverse side effects. Small interfering RNA (siRNA) can knock down the expression of specific genes and result in therapeutic efficacy in lung cancer. Recently, mTOR siRNA has been shown to induce apoptosis in NSCLC cell lines but its use is limited due to poor stability in biological conditions. METHODS: In this study, we modified an aminoglyocisde-derived cationic poly (amino-ether) by introducing a thiol group using Traut's reagent to generate a bio-reducible modified-poly (amino-ether) (mPAE). The mPAE polymer was used to encapsulate mTOR siRNA by nanoprecipitation method, resulting in the formation of stable and bio-reducible nanoparticles (NPs) which possessed an average diameter of 114 nm and a surface charge of approximately +27 mV. RESULTS: The mTOR siRNA showed increased release from the mTS-mPAE NPs in the presence of 10 mM glutathione (GSH). The polymeric mTS-mPAE-NPs were also capable of efficient gene knockdown (60 and 64%) in A549 and H460 lung cancer cells, respectively without significant cytotoxicity at 30 μg/ml concentrations. The NPs also showed time-dependent cellular uptake for up to 24 h as determined using flow cytometry. Delivery of the siRNA using these NPs also resulted in significant inhibition of A549 and H460 cell proliferation in vitro, respectively. CONCLUSIONS: The results demonstrate that the mPAE polymer based NPs show strong potential for siRNA delivery to lung cancer cells. It is anticipated that future modification can help improve the efficacy of nucleic acid delivery, leading to higher inhibition of lung cancer growth in vitro and in vivo.
PURPOSE: Lung cancer is one of the leading causes of deaths in the United States, but currently available therapies for lung cancer are associated with reduced efficacy and adverse side effects. Small interfering RNA (siRNA) can knock down the expression of specific genes and result in therapeutic efficacy in lung cancer. Recently, mTOR siRNA has been shown to induce apoptosis in NSCLC cell lines but its use is limited due to poor stability in biological conditions. METHODS: In this study, we modified an aminoglyocisde-derived cationic poly (amino-ether) by introducing a thiol group using Traut's reagent to generate a bio-reducible modified-poly (amino-ether) (mPAE). The mPAE polymer was used to encapsulate mTOR siRNA by nanoprecipitation method, resulting in the formation of stable and bio-reducible nanoparticles (NPs) which possessed an average diameter of 114 nm and a surface charge of approximately +27 mV. RESULTS: The mTOR siRNA showed increased release from the mTS-mPAE NPs in the presence of 10 mM glutathione (GSH). The polymeric mTS-mPAE-NPs were also capable of efficient gene knockdown (60 and 64%) in A549 and H460 lung cancer cells, respectively without significant cytotoxicity at 30 μg/ml concentrations. The NPs also showed time-dependent cellular uptake for up to 24 h as determined using flow cytometry. Delivery of the siRNA using these NPs also resulted in significant inhibition of A549 and H460 cell proliferation in vitro, respectively. CONCLUSIONS: The results demonstrate that the mPAE polymer based NPs show strong potential for siRNA delivery to lung cancer cells. It is anticipated that future modification can help improve the efficacy of nucleic acid delivery, leading to higher inhibition of lung cancer growth in vitro and in vivo.
Authors: Vishakha V Ambardekar; Huai-Yun Han; Michelle L Varney; Serguei V Vinogradov; Rakesh K Singh; Joseph A Vetro Journal: Biomaterials Date: 2010-11-02 Impact factor: 12.479
Authors: Sutapa Barua; Amit Joshi; Akhilesh Banerjee; Dana Matthews; Susan T Sharfstein; Steven M Cramer; Ravi S Kane; Kaushal Rege Journal: Mol Pharm Date: 2009 Jan-Feb Impact factor: 4.939