Engineering approaches in siRNA delivery

Abstract

siRNAs are very potent drug molecules, able to silence genes involved in pathologies development. siRNAs have virtually an unlimited therapeutic potential, particularly for the treatment of inflammatory diseases. However, their use in clinical practice is limited because of their unfavorable properties to interact and not to degrade in physiological environments. In particular they are large macromolecules, negatively charged, which undergo rapid degradation by plasmatic enzymes, are subject to fast renal clearance/hepatic sequestration, and can hardly cross cellular membranes. These aspects seriously impair siRNAs as therapeutics. As in all the other fields of science, siRNAs management can be advantaged by physical-mathematical descriptions (modeling) in order to clarify the involved phenomena from the preparative step of dosage systems to the description of drug-body interactions, which allows improving the design of delivery systems/processes/therapies. This review analyzes a few mathematical modeling approaches currently adopted to describe the siRNAs delivery, the main procedures in siRNAs vectors' production processes and siRNAs vectors' release from hydrogels, and the modeling of pharmacokinetics of siRNAs vectors. Furthermore, the use of physical models to study the siRNAs vectors' fate in blood stream and in the tissues is presented. The general view depicts a framework maybe not yet usable in therapeutics, but with promising possibilities for forthcoming applications.

Inhibition of CD83 Alleviates Systemic Inflammation in Herpes Simplex Virus Type 1-Induced Behçet’s Disease Model Mouse

“…Preventing cell surface expression of CD83 can significantly inhibit DC-mediated T cell activation [15]. siRNA is considered to be a potent drug molecule that can silence genes associated with pathogenesis, especially in the treatment of inflammatory diseases [48, 49]. The siRNA binds to the RNA-induced silencing complex (RISC); then the passenger siRNA chain departs and initiates the process of RNA interference process, causing mRNA fragmentation and degradation [50, 51].…”

Suppression of heat shock protein 70 by siRNA enhances the antitumor effects of cisplatin in cultured human osteosarcoma cells

“…Treatment with siRNA has a specific inhibitory effect; however, there are problems of in vivo stability and of delivery to locations (Inoue et al 2014;Barba et al 2017). Hsp70 inhibitors such as VER155008 may not obtain the expected inhibiting effects in some cases because of the influence of other chaperones and co-chaperones (Asling et al 2016).…”

Applications of Lipidic and Polymeric Nanoparticles for siRNA Delivery

“…The local transport of siRNA has less obstruction compared to systemic administration. The first of the unique features of the local administration is the need to an easy formulation that requires easier production and application and secondly provides application of lower doses that limit intracellular (time-concentration-dependent) immune responses [14].…”

“…In fact, due to collisions with RBCs, microparticles are pushed toward the artery wall where RBCs are virtually absent depending on the shape and size by a radial movement called the "waterfall effect." This event is also called margination, and they have stated that the extravasation cannot occur unless vectors are exposed to margination [14].…”