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Tumors may induce tolerogenesis through signaling dendritic cells to produce tolerogenic molecules, such as indoleamine 2, 3-dioxygenase 1 (IDO1). Tumor-associated immunosuppression is associated with higher mortality in patients. Small interfering RNA (siRNA) has been shown to silence specific target genes in the target cell. The siRNA associated with these genes could support a gene knockdown of these immunosuppressors and reduce mortality. Delivery of these therapeutic nucleic acids is difficult in vivo because siRNA is easily broken down inside the cell and the bloodstream through present nucleases. Use of liposome polymers has been reviewed extensively in literature. YSK12-C4, a lipid nanoparticle developed by Hokkaido University, is a lipid that has both fusogenic and cationic properties, making it ideal for dendritic cell uptake. However, limitations make it less effective in vivo as it may collect in areas other than the target human dendritic cells in the draining lymph node. To improve specific targeting in vivo, ligand-based targeting modifications (anti-DEC205, anti-CD11c, mannose+) and physical targeting (pKa modifications through YSK05 lipid addition) have been proposed to the YSK12-MEND system in order to better target dendritic cells in vivo. In order to estimate the theoretical efficacy of modified YSK12-MEND-siRNA, I investigated prior experiments, both in vivo and in vitro, to recognize the practicality of each modification. In murine hepatocytes, it was found that pKa improved specific uptake in vivo while anti-DEC205 and anti-CD11c peptides were found to be effective in dendritic cells in vivo in mice. Mannose+ lipid nanoparticles were ideal for targeting both dendritic cells and macrophages. These modifications will likely result in an improved uptake, more cell specificity, and transfection efficiency for human dendritic cells.
YSK12-C4, MEND, dendritic cells, mannose, pKa, DEC205, CD11c, specific tissue targeting
Lipids | Medical Pharmacology | Medicinal and Pharmaceutical Chemistry | Nucleic Acids, Nucleotides, and Nucleosides | Oncology | Pharmaceutics and Drug Design
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