Cationic and Ionizable Lipid Nanoparticles for Gene Therapy and Vaccine Applications


Cationic and Ionizable Lipid Nanoparticles for Gene Therapy and Vaccine Applications

Author: Nima Tamaddoni, PhD

13th August 2021

Cationic and Ionizable Lipid Nanoparticles for Gene Therapy and Vaccine Applications

Nima Tamaddoni, Ph.D.
T&T Scientific Corporation, Knoxville, TN 37918 USA

New generations of lipid nanocarriers, including solid lipid nanoparticles, cationic lipid-nucleic acid complexes, and nanostructured lipid carriers, are physically more stable and complex than previous nanoparticles used. Delivery time can be controlled with these lipid nanoparticles (Guevara et al., 2020). COVID-19 vaccines development in a brief period would not have been possible if we had not spent decades researching nanoparticles. Lipid nanoparticles are being used to treat cancer before and now are the main component of mRNA vaccines for COVID-19. Lipid nanoparticles keep the mRNA protected and help in their target delivery (Tenchoy et al., 2021).

Researchers use a novel amino-ionizable lipid to deliver Cas9mRNA and sgRNA for cancer treatment. Approximately 70% gene editing was observed in-vivo after using an intracerebral injection of CRISPR-LNPs to target PLK1. 50% inhibition in the growth of tumors was observed. In addition, an intraperitoneal injection containing EGFR-targeted sgPLK1 lipid nanoparticles resulted in 80% gene editing in vivo (Rosenblum et al., 2020). Onpattro was the first commercial RNA product. TKM-080301 is a new commercial product for the treatment of gastrointestinal neuroendocrine tumors. It contains siRNA enclosed in LNPs, which targets the PKL1 (Demeure et al., 2016).

FDA (Food and Drug Administration) approved Doxil® first, and it was proved clinically very effective. Now, 22 liposomal drug delivery products are approved, including the Abelcet®, Myocet®, AmBisome®, Depocyt®, Inflexal V®, and DaunoXome®. Two different liposomes are approved for anesthetic applications to encapsulate and deliver bupivacaine. Two approved liposomal formulations are available to deliver amphotericin B. Marqibo® to treat fungal infections (Shah et al., 2020; Thi et al., 2021).

A new delivery molecule, DLin-MC3-DMA, will be used in the near future for genetic drug delivery. The linker optimization process modifies it. It is ten folds more potent than DlinKC2-DMA, previously used for hepatic gene silencing (Thi et al., 2021). New classes of anticancer vaccines based on tumor neo-antigens are in development, based on mRNA lipid nanoparticle vaccines strategy. These LPN vaccines allow the collective release of multiple antigens at once from the same molecule (Guevara et al., 2020).

Some other approved liposomes include Epaxal, Mosquirix, Inflexal V, and Shingrix. These types are used to deliver virosomal influenza vaccines, glycoprotein E-based vaccines, and S antigen-based vaccines (Lu et al., 2021). Lipids have another essential property of working as adjuvants. Cationic lipids, dimethyl dioctadecyl ammonium bromide (DDA), allow antigen deposition at the target site and enhance internalization and antigen association (Thi et al., 2021).

In conclusion, many improvements in LNPs are being made to enhance stability and reduce drug leakage. Ionic attractions are used to make them more complex. One of the examples is DOP-DEDA, which is ionizable and considered suitable for the encapsulation of genes. Cholesterol is sometimes used for constricted packaging of the drug in LNPs. PEG is used to modify LNP surfaces, which enhances their stability. The LNPs with selective ligands are not entirely successful yet, which needs further research.

 

References:

  1. Demeure, M. J., Armaghany, T., Ejadi, S., Ramanathan, R. K., Elfiky, A., Strosberg, J. R., Smith, D. C., Whitsett, T., Liang, W. S., Sekar, S., Carpten, J. D., Fredlund, P., Niforos, D., Dye, A., Gahir, S., Semple, S. C., & Kowalski, M. M. (2016). A phase I/II study of TKM-080301, a PLK1-targeted RNAi in patients with adrenocortical cancer (ACC). Journal of Clinical Oncology, 34(15_suppl), 2547–2547. https://doi.org/10.1200/JCO.2016.34.15_suppl.2547
  2. Guevara, M. L., Persano, F., & Persano, S. (2020). Advances in lipid nanoparticles for mRNA-based cancer immunotherapy. Frontiers in Chemistry, 0. https://doi.org/10.3389/fchem.2020.589959Lu, W., Yao, J., Zhu, X., & Qi, Y. (2021). Nanomedicines: Redefining traditional medicine. Biomedicine & Pharmacotherapy, 134, 111103. https://doi.org/10.1016/j.biopha.2020.111103 
  3. Rosenblum, D., Gutkin, A., Kedmi, R., Ramishetti, S., Veiga, N., Jacobi, A. M., Schubert, M. S., Friedmann-Morvinski, D., Cohen, Z. R., Behlke, M. A., Lieberman, J., & Peer, D. (2020). CRISPR-Cas9 genome editing using targeted lipid nanoparticles for cancer therapy. Science Advances, 6(47), eabc9450. https://doi.org/10.1126/sciadv.abc9450 
  4. Shah, S., Dhawan, V., Holm, R., Nagarsenker, M. S., & Perrie, Y. (2020). Liposomes: Advancements and innovation in the manufacturing process. Advanced Drug Delivery Reviews, 154–155, 102–122. https://doi.org/10.1016/j.addr.2020.07.002 
  5. 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. https://doi.org/10.1021/acsnano.1c04996 
  6. Thi, T. T. H., Suys, E. J. A., Lee, J. S., Nguyen, D. H., Park, K. D., & Truong, N. P. (2021). Lipid-based nanoparticles in the clinic and clinical trials: From cancer nanomedicine to covid-19 vaccines. Vaccines, 9(4), 359. https://doi.org/10.3390/vaccines9040359

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