Pharmacokinetics and biodistribution of recently-developed siRNA nanomedicines

Abstract

Small interfering RNA (siRNA) is a promising drug candidate, expected to have broad therapeutic potentials toward various diseases including viral infections and cancer. With recent advances in bioconjugate chemistry and carrier technology, several siRNA-based drugs have advanced to clinical trials. However, most cases address local applications or diseases in the filtering organs, reflecting remaining challenges in systemic delivery of siRNA. The difficulty in siRNA delivery is in large part due to poor circulation stability and unfavorable pharmacokinetics and biodistribution profiles of siRNA. This review describes the pharmacokinetics and biodistribution of siRNA nanomedicines, focusing on those reported in the past 5 years, and their pharmacological effects in selected disease models such as hepatocellular carcinoma, liver infections, and respiratory diseases. The examples discussed here will provide an insight into the current status of the art and unmet needs in siRNA delivery.

Lipophilic siRNA targets albumin in situ and promotes bioavailability, tumor penetration, and carrier-free gene silencing

“…The lower tumor:liver ratio observed with in vivo jetPEI and nanoparticle systems in the literature is consistent with reported challenges in achieving efficient nanoparticle delivery to tumor sites; in a comprehensive analysis of nanoparticle delivery to solid tumors, the median injected dose delivered to the tumor site was 0.7% (47). It is notable that even in recent, advanced, and promising nanoparticle systems, including those that use modifications for "stealth" or targeting mechanisms, the ratio of tumor:liver accumulation is consistently close to or below 1:1 (3,5,(57)(58)(59)(60)(61)(62). The marked improvement of siRNA-L 2 in relative tumor accumulation supports its translational promise.…”

Cholesterol-Containing Nuclease-Resistant siRNA Accumulates in Tumors in a Carrier-free Mode and Silences MDR1 Gene

“…The main problem to be solved in the transition of this effect from cell culture to the level of the organism is to ensure delivery of siRNA to the tumor in amounts sufficient to inhibit expression of the target gene. For siRNA delivery at the body level, different approaches are used: siRNA delivery in complexes with cationic lipids or cationic polymers, 29 use of different types of nanoparticle30, 31 and conjugation of siRNA with transport molecules such as cholesterol, 5 folate,32, 33 transferrin, 34 peptides,35, 36, 37 or aptamers 38, 39…”

Targeted Delivery of siRNA Lipoplexes to Cancer Cells Using Macrophage Transient Horizontal Gene Transfer

“…However, nanoparticles can have relatively poor tumor distribution, poor endosomal escape. The development of new particles alone may not always overcome the barrier to achieving efficient drug limitation involve nanoparticle delivery [6][7][8] or structural modification of the siRNA itself. [9] However, these limitations of siRNA pharmacokinetics do not impede their direct delivery to the eye, lung, and liver.…”

“…[9] However, these limitations of siRNA pharmacokinetics do not impede their direct delivery to the eye, lung, and liver. [7,10] One recent example is Patisiran (Alnylam), an RNAi therapeutic that targets a protein produced in the liver, has completed Phase 3 trials and is the first RNAi therapeutic to receive FDA approval. [11] Still, many cancerrelated RNAi therapies are limited by effective transport into solid tumors and endosomal escape once inside the cell.…”