Abstract
Nucleic acid and genetic medicines are increasingly being developed, owing to their potential to treat a variety of intractable diseases. A comprehensive understanding of the in vivo fate of these agents is vital for the rational design, discovery, and fast and straightforward development of the drugs. In case of intravascular administration of nucleic acids and genetic medicines, interaction with blood components, especially plasma proteins, is unavoidable. However, on the flip side, such interaction can be utilized wisely to manipulate the pharmacokinetics of the agents. In other words, plasma protein binding can help in suppressing the elimination of nucleic acids from the blood stream and deliver naked oligonucleotides and gene carriers into target cells. To control the distribution of these agents in the body, the ligand conjugation method is widely applied. It is also important to understand intracellular localization. In this context, endocytosis pathway, endosomal escape, and nuclear transport should be considered and discussed. Encapsulated nucleic acids and genes must be dissociated from the carriers to exert their activity. In this review, we summarize the in vivo fate of nucleic acid and gene medicines and provide guidelines for the rational design of drugs.
Highlights
Huang et al developed an efficient nonhydrodynamic in vivo transfection method using lipid calcium phosphate nanoparticles (LCP) [38], but the preparation procedure of LCP is complicated when compared with ethanol injection for lipid nanoparticles (LNP)
Approved Lumisiran (OXLUMO® ) and Inclisiran (Leqvio® ) are the first siRNAs that carry GalNAc ligands. Another recent example of ligand-conjugating antisense oligonucleotides (ASOs) was reported by Ämmälä et al, where an ASO conjugated to a peptide ligand that binds to the glucagon-like peptide-1 receptor (GLP1R) was developed to deliver ASOs to pancreatic insulin-secreting β-cells [129]
Some adaptor proteins, such as adaptor-related protein complex 2 subunit mu 1 (AP2M1) and annexin A2, are suggested to play key roles in sorting to direct phosphorothioate internucleotide linkage (PS)-ASOs to the productive routes, while vacuolar protein sorting-associated protein 28 homolog (VPS28) and tumor susceptibility gene 101 (TSG101), members of the endosomal sorting complex required for transport-I (ESCRT-I), are associated with the non-productive routes [155]
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. The development of antibodies targeting intracellular molecules is relatively difficult In such cases, nucleic acid therapy and gene therapy are promising options. Some chemically modified oligonucleotides with specific configurations, such as antisense and siRNA drugs, have managed to significantly overcome the biological barriers without any formulation agents, and have achieved remarkable success [5] Oher nucleic acids such as decoy oligonucleotides [6], microRNA (miRNA) [7], aptamers [8] and circular RNA [9,10] are available to target specific molecule(s). Pharmaceutics 2021, 13, 159 of providing the information necessary for the development of efficient and safe nucleic acid therapy and gene delivery strategies/systems.
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