Sevda Salimifard1, Fariba Karoon Kiani2, Farzaneh Sadat Eshaghi3, Sepideh Izadi4, Kolsoom Shahdadnejad5, Ali Masjedi4, Morteza Heydari5, Armin Ahmadi6, Mohammad Hojjat-Farsangi7, Hadi Hassannia8, Hamed Mohammadi9, Samaneh Boroumand-Noughabi1, Mohammad Reza Keramati10, Farhad Jadidi-Niaragh11. 1. Cancer Molecular Pathology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Hematology and Blood Banking, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. 2. Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. 3. Department of Genetics, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran. 4. Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. 5. Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran. 6. Department of Chemical and Materials Engineering, The University of Alabama in Huntsville, AL 35899, USA. 7. Bioclinicum, Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden. 8. Immunogenetic Research Center, Mazandaran University of Medical Sciences, Sari, Iran. 9. Non-communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj. Iran. 10. Cancer Molecular Pathology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Hematology and Blood Banking, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. Electronic address: Keramatimr@mums.ac.ir. 11. Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran. Electronic address: jadidif@tbzmed.ac.ir.
Abstract
AIMS: Increased expression of inhibitor of apoptosis (IAP) genes has been associated with progressive cancer and chemoresistance. Accordingly, blockade of IAPs by BV6 has resulted in ameliorative outcomes. Interleukin (IL)-6 is another important mediator involved in the growth and survival of tumor cells. Therefore, we hypothesized that simultaneous inhibition of IAPs and IL-6 could be a new promising anti-tumor treatment strategy. MATERIALS AND METHODS: In this study, we generated and characterized hyaluronate-PEG-Chitosan-Lactate (H-PCL) nanoparticles (NPs) to simultaneously deliver IL6-specific siRNA and BV6 to 4T1 (breast cancer) and CT26 (colon cancer) cells, and investigate the anti-tumor properties of this combination therapy both in vitro and in vivo. KEY FINDINGS: H-PCL NPs exhibited good physicochemical properties leading to efficient transfection of cancer cells and suppression of target molecules. Moreover, combination therapy synergistically increased apoptosis, as well as decreased cell migration, proliferation, colony formation, and angiogenesis in both 4T1 and CT26 cell lines and suppressed cancer progression in tumor-bearing mice that was associated with enhanced survival time. SIGNIFICANCE: These findings imply the effectiveness of cancer combination therapy by using H-PCL NPs loaded with anti-IL-6 siRNA and BV6.
AIMS: Increased expression of inhibitor of apoptosis (IAP) genes has been associated with progressive cancer and chemoresistance. Accordingly, blockade of IAPs by BV6 has resulted in ameliorative outcomes. Interleukin (IL)-6 is another important mediator involved in the growth and survival of tumor cells. Therefore, we hypothesized that simultaneous inhibition of IAPs and IL-6 could be a new promising anti-tumor treatment strategy. MATERIALS AND METHODS: In this study, we generated and characterized hyaluronate-PEG-Chitosan-Lactate (H-PCL) nanoparticles (NPs) to simultaneously deliver IL6-specific siRNA and BV6 to 4T1 (breast cancer) and CT26 (colon cancer) cells, and investigate the anti-tumor properties of this combination therapy both in vitro and in vivo. KEY FINDINGS:H-PCL NPs exhibited good physicochemical properties leading to efficient transfection of cancer cells and suppression of target molecules. Moreover, combination therapy synergistically increased apoptosis, as well as decreased cell migration, proliferation, colony formation, and angiogenesis in both 4T1 and CT26 cell lines and suppressed cancer progression in tumor-bearing mice that was associated with enhanced survival time. SIGNIFICANCE: These findings imply the effectiveness of cancer combination therapy by using H-PCL NPs loaded with anti-IL-6 siRNA and BV6.