Development of BMX siRNA Lipid Nanoparticles Using Novel Ionizable, and Cleavable Lipids Discovered through AI and Experimentation for Cancer Therapy
Faculty Mentor
Ahmed Abu Fayyad
Major/Area of Research
Pharmaceuticals
Description
INTRODUCTION: Prostate cancer is the most commonly diagnosed male malignancy across the world. It is also considered the fifth leading cause of cancer death in men. in 2020 there was 1,414,249 newly diagnosed cases and 375,000 deaths worldwide from prostate cancer (Leslie SW.2023). The Tec family nonreceptor tyrosine kinase BMX is activated downstream of PI3K and has been implicated in regulation of multiple pathways and in the development of cancers including prostate cancer (Chen S. 2018). The available science supports the role of BMX in advanced prostate cancer, head & neck cancer, aggressive brain cancer, and many other immunological diseases (Cenni, Gutmann et al. 2012). RNA interference plays an important role in regulating the gene expression level within the cells (Agrawal N. 2003). However, delivering small interfering RNA (siRNA is challenging due to many obstacles, such as extremely short half-life in vivo, rapid elimination via glomerular filtration, and inability to cross cell membranes (due to the hydrophilic nature and negative charge of siRNA molecules). In order to use siRNA as a treatment for prostate cancer, an effective delivery system is needed. This study demonstrates that BMX expression in prostate cancer is suppressed directly by siRNA using the delivery system.
METHODS: The delivery system used is composed of the negatively charged siRNA encapsulated into a multicomponent structure that contains (DOPE), 1,2-Dioleoyl-3-trimethylammonium propane (DOTAP), Cholesterol and Phosphatidylcholine. To further enhance the activity of the BMX siRNA lipid nanoparticle compositions two novel lipids; a cleavable PEGylated lipid, and an ionizable cationic lipid were synthesized and characterized by our team (Abu-Fayyad and Nazzal 2017) and then added to the formulation.
RESULTS: The designed and optimized novel BMX siRNA LNPs were physiochemically characterized and showed desired characteristics. Furthermore, AI-based tools were used to predict any potential interactions between the novel designed ionizable lipid and the BMX siRNA, with promising forecasted results being obtained. The optimized BMX siRNA LNPs showed a favored particle size and zeta potential values of 151 nm & 30 mV, respectively. The novel and optimized BMX siRNA LNPs showed acid-based release of the active therapeutic agent. In-vitro cell culture study against prostate cancer cell lines further supported the idea that these novel LNPs would be potent and more active compared to formulas of controls.
CONCLUSION: In summary, the current work showed a successful development and characterization of anticancer novel LNPs for targeting the novel and emerging target BMX as a second option of therapeutics development, after the initial reported work our group published recently on small molecule therapeutics development (Elsanhoury, Alasmari et al. 2023).
Development of BMX siRNA Lipid Nanoparticles Using Novel Ionizable, and Cleavable Lipids Discovered through AI and Experimentation for Cancer Therapy
INTRODUCTION: Prostate cancer is the most commonly diagnosed male malignancy across the world. It is also considered the fifth leading cause of cancer death in men. in 2020 there was 1,414,249 newly diagnosed cases and 375,000 deaths worldwide from prostate cancer (Leslie SW.2023). The Tec family nonreceptor tyrosine kinase BMX is activated downstream of PI3K and has been implicated in regulation of multiple pathways and in the development of cancers including prostate cancer (Chen S. 2018). The available science supports the role of BMX in advanced prostate cancer, head & neck cancer, aggressive brain cancer, and many other immunological diseases (Cenni, Gutmann et al. 2012). RNA interference plays an important role in regulating the gene expression level within the cells (Agrawal N. 2003). However, delivering small interfering RNA (siRNA is challenging due to many obstacles, such as extremely short half-life in vivo, rapid elimination via glomerular filtration, and inability to cross cell membranes (due to the hydrophilic nature and negative charge of siRNA molecules). In order to use siRNA as a treatment for prostate cancer, an effective delivery system is needed. This study demonstrates that BMX expression in prostate cancer is suppressed directly by siRNA using the delivery system.
METHODS: The delivery system used is composed of the negatively charged siRNA encapsulated into a multicomponent structure that contains (DOPE), 1,2-Dioleoyl-3-trimethylammonium propane (DOTAP), Cholesterol and Phosphatidylcholine. To further enhance the activity of the BMX siRNA lipid nanoparticle compositions two novel lipids; a cleavable PEGylated lipid, and an ionizable cationic lipid were synthesized and characterized by our team (Abu-Fayyad and Nazzal 2017) and then added to the formulation.
RESULTS: The designed and optimized novel BMX siRNA LNPs were physiochemically characterized and showed desired characteristics. Furthermore, AI-based tools were used to predict any potential interactions between the novel designed ionizable lipid and the BMX siRNA, with promising forecasted results being obtained. The optimized BMX siRNA LNPs showed a favored particle size and zeta potential values of 151 nm & 30 mV, respectively. The novel and optimized BMX siRNA LNPs showed acid-based release of the active therapeutic agent. In-vitro cell culture study against prostate cancer cell lines further supported the idea that these novel LNPs would be potent and more active compared to formulas of controls.
CONCLUSION: In summary, the current work showed a successful development and characterization of anticancer novel LNPs for targeting the novel and emerging target BMX as a second option of therapeutics development, after the initial reported work our group published recently on small molecule therapeutics development (Elsanhoury, Alasmari et al. 2023).