Development of Lipid Nanoparticles for Delivery of siRNA as Gene Therapy for Lung Cancer

Miksusanti Miksusanti (1), Rafiullah Amin (2), Amir Raza (3)
(1) Universiti Sriwijaya, Indonesia,
(2) Balkh University, Afghanistan,
(3) Badakhshan University, Afghanistan

Abstract

Lung cancer remains a significant health challenge with high mortality rates, necessitating innovative treatment approaches. Lipid nanoparticles (LNP) offer a promising platform for the delivery of small interfering RNA (siRNA) as gene therapy to target specific oncogenes in lung cancer cells. To develop and optimize LNPs for efficient siRNA delivery, improving gene silencing efficiency and therapeutic outcomes in lung cancer treatment. The study involved in vitro and in vivo experiments to characterize the LNPs, evaluate gene silencing efficiency, and assess therapeutic efficacy. LNPs were formulated with specific lipid compositions and tested on lung cancer cell lines and murine models. Optimized LNP formulations demonstrated high siRNA encapsulation efficiency (>85%), stable particle size (80-120 nm), and suitable zeta potential (-30 to -50 mV). In vitro studies showed over 70% gene silencing efficiency, while in vivo experiments indicated significant tumor growth inhibition and improved survival rates in murine models. Biodistribution studies confirmed targeted delivery to lung and tumor tissues with minimal off-target effects. The study highlights the potential of LNP-siRNA therapy as an effective and specific treatment for lung cancer. Further research and clinical trials are needed to validate these findings and optimize the delivery system for clinical use.


 

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References

Arduino, I., Liu, Z., Rahikkala, A., Figueiredo, P., Correia, A., Cutrignelli, A., Denora, N., & Santos, H. A. (2021). Preparation of cetyl palmitate-based PEGylated solid lipid nanoparticles by microfluidic technique. Acta Biomaterialia, 121, 566–578. https://doi.org/10.1016/j.actbio.2020.12.024

Borges, A., De Freitas, V., Mateus, N., Fernandes, I., & Oliveira, J. (2020). Solid Lipid Nanoparticles as Carriers of Natural Phenolic Compounds. Antioxidants, 9(10), 998. https://doi.org/10.3390/antiox9100998

Bost, J. P., Barriga, H., Holme, M. N., Gallud, A., Maugeri, M., Gupta, D., Lehto, T., Valadi, H., Esbjörner, E. K., Stevens, M. M., & El-Andaloussi, S. (2021). Delivery of Oligonucleotide Therapeutics: Chemical Modifications, Lipid Nanoparticles, and Extracellular Vesicles. ACS Nano, 15(9), 13993–14021. https://doi.org/10.1021/acsnano.1c05099

Böttger, R., Pauli, G., Chao, P.-H., Al Fayez, N., Hohenwarter, L., & Li, S.-D. (2020). Lipid-based nanoparticle technologies for liver targeting. Advanced Drug Delivery Reviews, 154–155, 79–101. https://doi.org/10.1016/j.addr.2020.06.017

Cheng, M. H. Y., Leung, J., Zhang, Y., Strong, C., Basha, G., Momeni, A., Chen, Y., Jan, E., Abdolahzadeh, A., Wang, X., Kulkarni, J. A., Witzigmann, D., & Cullis, P. R. (2023). Induction of Bleb Structures in Lipid Nanoparticle Formulations of mRNA Leads to Improved Transfection Potency. Advanced Materials, 35(31), 2303370. https://doi.org/10.1002/adma.202303370

Cornebise, M., Narayanan, E., Xia, Y., Acosta, E., Ci, L., Koch, H., Milton, J., Sabnis, S., Salerno, T., & Benenato, K. E. (2022). Discovery of a Novel Amino Lipid That Improves Lipid Nanoparticle Performance through Specific Interactions with mRNA. Advanced Functional Materials, 32(8), 2106727. https://doi.org/10.1002/adfm.202106727

Costa, C. P., Moreira, J. N., Sousa Lobo, J. M., & Silva, A. C. (2021). Intranasal delivery of nanostructured lipid carriers, solid lipid nanoparticles and nanoemulsions: A current overview of in vivo studies. Acta Pharmaceutica Sinica B, 11(4), 925–940. https://doi.org/10.1016/j.apsb.2021.02.012

Elia, U., Ramishetti, S., Rosenfeld, R., Dammes, N., Bar-Haim, E., Naidu, G. S., Makdasi, E., Yahalom-Ronen, Y., Tamir, H., Paran, N., Cohen, O., & Peer, D. (2021). Design of SARS-CoV-2 hFc-Conjugated Receptor-Binding Domain mRNA Vaccine Delivered via Lipid Nanoparticles. ACS Nano, 15(6), 9627–9637. https://doi.org/10.1021/acsnano.0c10180

Eygeris, Y., Gupta, M., Kim, J., & Sahay, G. (2022). Chemistry of Lipid Nanoparticles for RNA Delivery. Accounts of Chemical Research, 55(1), 2–12. https://doi.org/10.1021/acs.accounts.1c00544

Hald Albertsen, C., Kulkarni, J. A., Witzigmann, D., Lind, M., Petersson, K., & Simonsen, J. B. (2022). The role of lipid components in lipid nanoparticles for vaccines and gene therapy. Advanced Drug Delivery Reviews, 188, 114416. https://doi.org/10.1016/j.addr.2022.114416

Ju, Y., Lee, W. S., Pilkington, E. H., Kelly, H. G., Li, S., Selva, K. J., Wragg, K. M., Subbarao, K., Nguyen, T. H. O., Rowntree, L. C., Allen, L. F., Bond, K., Williamson, D. A., Truong, N. P., Plebanski, M., Kedzierska, K., Mahanty, S., Chung, A. W., Caruso, F., … Kent, S. J. (2022). Anti-PEG Antibodies Boosted in Humans by SARS-CoV-2 Lipid Nanoparticle mRNA Vaccine. ACS Nano, 16(8), 11769–11780. https://doi.org/10.1021/acsnano.2c04543

Kim, J., Jozic, A., Lin, Y., Eygeris, Y., Bloom, E., Tan, X., Acosta, C., MacDonald, K. D., Welsher, K. D., & Sahay, G. (2022). Engineering Lipid Nanoparticles for Enhanced Intracellular Delivery of mRNA through Inhalation. ACS Nano, 16(9), 14792–14806. https://doi.org/10.1021/acsnano.2c05647

Kimura, N., Maeki, M., Sato, Y., Ishida, A., Tani, H., Harashima, H., & Tokeshi, M. (2020). Development of a Microfluidic-Based Post-Treatment Process for Size-Controlled Lipid Nanoparticles and Application to siRNA Delivery. ACS Applied Materials & Interfaces, 12(30), 34011–34020. https://doi.org/10.1021/acsami.0c05489

Lee, S. M., Cheng, Q., Yu, X., Liu, S., Johnson, L. T., & Siegwart, D. J. (2021). A Systematic Study of Unsaturation in Lipid Nanoparticles Leads to Improved mRNA Transfection In Vivo. Angewandte Chemie International Edition, 60(11), 5848–5853. https://doi.org/10.1002/anie.202013927

Li, Q., Chan, C., Peterson, N., Hanna, R. N., Alfaro, A., Allen, K. L., Wu, H., Dall’Acqua, W. F., Borrok, M. J., & Santos, J. L. (2020). Engineering Caveolae-Targeted Lipid Nanoparticles To Deliver mRNA to the Lungs. ACS Chemical Biology, 15(4), 830–836. https://doi.org/10.1021/acschembio.0c00003

Liang, X., Chen, M., Bhattarai, P., Hameed, S., Tang, Y., & Dai, Z. (2021). Complementing Cancer Photodynamic Therapy with Ferroptosis through Iron Oxide Loaded Porphyrin-Grafted Lipid Nanoparticles. ACS Nano, 15(12), 20164–20180. https://doi.org/10.1021/acsnano.1c08108

Mehta, M., Bui, T. A., Yang, X., Aksoy, Y., Goldys, E. M., & Deng, W. (2023). Lipid-Based Nanoparticles for Drug/Gene Delivery: An Overview of the Production Techniques and Difficulties Encountered in Their Industrial Development. ACS Materials Au, 3(6), 600–619. https://doi.org/10.1021/acsmaterialsau.3c00032

Nakamura, T., & Harashima, H. (2020). Dawn of lipid nanoparticles in lymph node targeting: Potential in cancer immunotherapy. Advanced Drug Delivery Reviews, 167, 78–88. https://doi.org/10.1016/j.addr.2020.06.003

Nakamura, T., Sato, Y., Yamada, Y., Abd Elwakil, M. M., Kimura, S., Younis, M. A., & Harashima, H. (2022). Extrahepatic targeting of lipid nanoparticles in vivo with intracellular targeting for future nanomedicines. Advanced Drug Delivery Reviews, 188, 114417. https://doi.org/10.1016/j.addr.2022.114417

Nogueira, S. S., Schlegel, A., Maxeiner, K., Weber, B., Barz, M., Schroer, M. A., Blanchet, C. E., Svergun, D. I., Ramishetti, S., Peer, D., Langguth, P., Sahin, U., & Haas, H. (2020). Polysarcosine-Functionalized Lipid Nanoparticles for Therapeutic mRNA Delivery. ACS Applied Nano Materials, 3(11), 10634–10645. https://doi.org/10.1021/acsanm.0c01834

Noureddine, A., Maestas-Olguin, A., Saada, E. A., LaBauve, A. E., Agola, J. O., Baty, K. E., Howard, T., Sabo, J. K., Espinoza, C. R. S., Doudna, J. A., Schoeniger, J. S., Butler, K. S., Negrete, O. A., Brinker, C. J., & Serda, R. E. (2020). Engineering of monosized lipid-coated mesoporous silica nanoparticles for CRISPR delivery. Acta Biomaterialia, 114, 358–368. https://doi.org/10.1016/j.actbio.2020.07.027

Pattipeiluhu, R., Arias?Alpizar, G., Basha, G., Chan, K. Y. T., Bussmann, J., Sharp, T. H., Moradi, M., Sommerdijk, N., Harris, E. N., Cullis, P. R., Kros, A., Witzigmann, D., & Campbell, F. (2022). Anionic Lipid Nanoparticles Preferentially Deliver mRNA to the Hepatic Reticuloendothelial System. Advanced Materials, 34(16), 2201095. https://doi.org/10.1002/adma.202201095

Pilkington, E. H., Suys, E. J. A., Trevaskis, N. L., Wheatley, A. K., Zukancic, D., Algarni, A., Al-Wassiti, H., Davis, T. P., Pouton, C. W., Kent, S. J., & Truong, N. P. (2021). From influenza to COVID-19: Lipid nanoparticle mRNA vaccines at the frontiers of infectious diseases. Acta Biomaterialia, 131, 16–40. https://doi.org/10.1016/j.actbio.2021.06.023

Qiu, M., Li, Y., Bloomer, H., & Xu, Q. (2021). Developing Biodegradable Lipid Nanoparticles for Intracellular mRNA Delivery and Genome Editing. Accounts of Chemical Research, 54(21), 4001–4011. https://doi.org/10.1021/acs.accounts.1c00500

Samaridou, E., Heyes, J., & Lutwyche, P. (2020). Lipid nanoparticles for nucleic acid delivery: Current perspectives. Advanced Drug Delivery Reviews, 154–155, 37–63. https://doi.org/10.1016/j.addr.2020.06.002

Sebastiani, F., Yanez Arteta, M., Lerche, M., Porcar, L., Lang, C., Bragg, R. A., Elmore, C. S., Krishnamurthy, V. R., Russell, R. A., Darwish, T., Pichler, H., Waldie, S., Moulin, M., Haertlein, M., Forsyth, V. T., Lindfors, L., & Cárdenas, M. (2021). Apolipoprotein E Binding Drives Structural and Compositional Rearrangement of mRNA-Containing Lipid Nanoparticles. ACS Nano, 15(4), 6709–6722. https://doi.org/10.1021/acsnano.0c10064

Singh, A. K., Singh, S. S., Rathore, A. S., Singh, S. P., Mishra, G., Awasthi, R., Mishra, S. K., Gautam, V., & Singh, S. K. (2021). Lipid-Coated MCM-41 Mesoporous Silica Nanoparticles Loaded with Berberine Improved Inhibition of Acetylcholine Esterase and Amyloid Formation. ACS Biomaterials Science & Engineering, 7(8), 3737–3753. https://doi.org/10.1021/acsbiomaterials.1c00514

Sofias, A. M., Toner, Y. C., Meerwaldt, A. E., Van Leent, M. M. T., Soultanidis, G., Elschot, M., Gonai, H., Grendstad, K., Flobak, Å., Neckmann, U., Wolowczyk, C., Fisher, E. L., Reiner, T., Davies, C. D. L., Bjørkøy, G., Teunissen, A. J. P., Ochando, J., Pérez-Medina, C., Mulder, W. J. M., & Hak, S. (2020). Tumor Targeting by ?v ?3 -Integrin-Specific Lipid Nanoparticles Occurs via Phagocyte Hitchhiking. ACS Nano, 14(7), 7832–7846. https://doi.org/10.1021/acsnano.9b08693

Tenchov, R., Bird, R., Curtze, A. E., & Zhou, Q. (2021). Lipid Nanoparticles?From Liposomes to mRNA Vaccine Delivery, a Landscape of Research Diversity and Advancement. ACS Nano, 15(11), 16982–17015. https://doi.org/10.1021/acsnano.1c04996

Tenchov, R., Sasso, J. M., Wang, X., Liaw, W.-S., Chen, C.-A., & Zhou, Q. A. (2022). Exosomes?Nature’s Lipid Nanoparticles, a Rising Star in Drug Delivery and Diagnostics. ACS Nano, 16(11), 17802–17846. https://doi.org/10.1021/acsnano.2c08774

Wang, C., Zhang, Y., & Dong, Y. (2021). Lipid Nanoparticle–mRNA Formulations for Therapeutic Applications. Accounts of Chemical Research, 54(23), 4283–4293. https://doi.org/10.1021/acs.accounts.1c00550

Wang, W., Feng, S., Ye, Z., Gao, H., Lin, J., & Ouyang, D. (2022). Prediction of lipid nanoparticles for mRNA vaccines by the machine learning algorithm. Acta Pharmaceutica Sinica B, 12(6), 2950–2962. https://doi.org/10.1016/j.apsb.2021.11.021

Wang, W., Huang, Z., Li, Y., Wang, W., Shi, J., Fu, F., Huang, Y., Pan, X., & Wu, C. (2021a). Impact of particle size and pH on protein corona formation of solid lipid nanoparticles: A proof-of-concept study. Acta Pharmaceutica Sinica B, 11(4), 1030–1046. https://doi.org/10.1016/j.apsb.2020.10.023

Wang, W., Huang, Z., Li, Y., Wang, W., Shi, J., Fu, F., Huang, Y., Pan, X., & Wu, C. (2021b). Impact of particle size and pH on protein corona formation of solid lipid nanoparticles: A proof-of-concept study. Acta Pharmaceutica Sinica B, 11(4), 1030–1046. https://doi.org/10.1016/j.apsb.2020.10.023

Witzigmann, D., Kulkarni, J. A., Leung, J., Chen, S., Cullis, P. R., & Van Der Meel, R. (2020a). Lipid nanoparticle technology for therapeutic gene regulation in the liver. Advanced Drug Delivery Reviews, 159, 344–363. https://doi.org/10.1016/j.addr.2020.06.026

Witzigmann, D., Kulkarni, J. A., Leung, J., Chen, S., Cullis, P. R., & Van Der Meel, R. (2020b). Lipid nanoparticle technology for therapeutic gene regulation in the liver. Advanced Drug Delivery Reviews, 159, 344–363. https://doi.org/10.1016/j.addr.2020.06.026

Xu, Y., Fourniols, T., Labrak, Y., Préat, V., Beloqui, A., & Des Rieux, A. (2022). Surface Modification of Lipid-Based Nanoparticles. ACS Nano, 16(5), 7168–7196. https://doi.org/10.1021/acsnano.2c02347

Yaghmur, A., & Mu, H. (2021). Recent advances in drug delivery applications of cubosomes, hexosomes, and solid lipid nanoparticles. Acta Pharmaceutica Sinica B, 11(4), 871–885. https://doi.org/10.1016/j.apsb.2021.02.013

Yonezawa, S., Koide, H., & Asai, T. (2020). Recent advances in siRNA delivery mediated by lipid-based nanoparticles. Advanced Drug Delivery Reviews, 154–155, 64–78. https://doi.org/10.1016/j.addr.2020.07.022

Zhang, J., Shen, H., Xu, J., Liu, L., Tan, J., Li, M., Xu, N., Luo, S., Wang, J., Yang, F., Tang, J., Li, Q., Wang, Y., Yu, L., & Yan, Z. (2020). Liver-Targeted siRNA Lipid Nanoparticles Treat Hepatic Cirrhosis by Dual Antifibrotic and Anti-inflammatory Activities. ACS Nano, 14(5), 6305–6322. https://doi.org/10.1021/acsnano.0c02633

Zong, Y., Lin, Y., Wei, T., & Cheng, Q. (2023). Lipid Nanoparticle (LNP) Enables mRNA Delivery for Cancer Therapy. Advanced Materials, 35(51), 2303261. https://doi.org/10.1002/adma.202303261

Authors

Miksusanti Miksusanti
miksusanti@gmail.com (Primary Contact)
Rafiullah Amin
Amir Raza
Miksusanti, M., Amin, R., & Raza, A. (2024). Development of Lipid Nanoparticles for Delivery of siRNA as Gene Therapy for Lung Cancer. Journal of Biomedical and Techno Nanomaterials, 1(3), 117–128. https://doi.org/10.70177/jbtn.v1i3.1758

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