How the Delivery System of siRNA Drugs Affects Their PK Profile

Although several oligonucleotide drugs have been successfully approved, their target tissue delivery remains challenging. Due to their physicochemical characteristics, unmodified free oligonucleotide drugs are not only rapidly cleared by the body after dosing, but also pose a risk of off-target and toxic side effects. Therefore, nucleic acid-based drugs usually require chemical modifications and appropriate delivery systems to exert therapeutic effects. It is challenging for small interfering RNAs (siRNAs) drugs to reach the target sites by chemical modifications alone, and it is similar for the delivery of antisense oligonucleotides (ASOs). Therefore, an effective delivery system is key to successful oligonucleotide drug development.

The Significance of Delivery Systems for siRNA Drugs

In vivo delivery of siRNA drugs could be divided into three main phases: (1) reaching target tissues, (2) entering cells, and (3) lysosomal escape. The organism sets different biological barriers for siRNA drugs in each stage, but the delivery system could protect the siRNAs against all biological barriers to reach the cytoplasm and bind to target mRNA, thus exerting drug efficacy.

1. Lipid nanoparticle (LNP) delivery system: The success of lipid nanoparticle (LNP) delivery systems depends critically on using ionizable cationic lipids. These lipids exhibit different charging characteristics under different PH conditions, providing intelligent protection for siRNAs across biological barriers.¹

2. GalNAc delivery system: GalNAc-siRNA conjugates transport siRNA from the cell surface into the cell through specific binding of ASGPR followed by endocytosis. Consequently, the GalNAc-siRNA conjugates dissociate from ASGPR. ASGPR recycles back to the cell surface, while GalNAc-siRNA conjugates further dissociate, releasing free siRNAs that exert drug efficacy by silencing genes in the cytoplasm.^2,3

How the Delivery Systems Affect the PK Profile

The delivery system assists the siRNA drugs from the administration site in entering the target cell, and the siRNA exists mostly as a complex with the delivery system during the delivery process. Therefore, the delivery system influences siRNAs in vivo processes and distribution. Lipid nanoparticle (LNP) delivery systems primarily exhibit passive hepatic targeting. However, GalNac-siRNA conjugate delivery systems achieve active hepatic targeting through binding ligand GalNac to the ASGPR. Adjusting the structure, proportions or particle size of components or modifying oligonucleotide structures may result in significant changes in tissue distribution and gene-silencing efficacy of siRNA drugs.

In the development of delivery systems, quantifying the effects of changes in the delivery system on tissue distribution using PK studies combined with pharmacodynamic validation is key to unlocking the “smart” oligonucleotide delivery. This involves targeting different diseased tissues and treating multiple indications by adjusting the structure or proportion of delivery system components.^4,5

If you want to learn more details about the delivery system of oligonucleotide drugs and their effects on the PK profile, please read the article now.

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