Overview of delivery of siRNA with nanocarriers for pancreatic cancer therapy

RNA interference (RNAi) mechanism in mammalian cells has brought new research areas for the treatment of numerous diseases. Small interfering RNA (siRNA) is a duplex RNA consisting of 21-23 nucleotides, which is responsible for RNAi-based gene silencing (Davis et al., 2010). When siRNA is produced by Dicer processing of long double-stranded RNAs or synthetic siRNAs are delivered into the cytoplasm. Subsequently, siRNA binds to the RNA-induced silencing complex (RISC). This complex is the platform on which the transformation of double strands to single-stranded by Argonaute-2 takes place and one strand mitigates a sequence-specific recognition of mRNA. The activated RISC recognizes the target transcript based on the sequence homology. Consequently, degradation starts from the 5′ end of antisense strand at the opposite of position 10 (B. Kim, Park, & Sailor, 2019).
In the past decade, the therapeutic potentials of siRNA have been proven in the treatment of genetic diseases, virus infections, and cancers (Sousa, Oliveira, Oliveira, & Sarmento, 2019). By designing the sequence of siRNA, any genes playing important role in the development of various diseases can be targeted in theory, including previously undruggable targets. Furthermore, various disorders such as viral infections, hereditary diseases, and tumors may benefit from its therapeutic potential.
In spite of the great potentials of siRNA to be developed as a drug, there are serious limitations that are hindering their practical applications. For instance, siRNAs do not simply cross over cytomembrane because of their low molecular weight (13 kDa) and anionic net charges. Moreover, siRNAs are susceptible to RNase digestion and rapid excretion through renal system. Furthermore, the accumulation of siRNAs in tumor cells is very low (Onoue, Yamada, & Chan, 2014). To address these challenges, siRNA chemical modifications and designing of innovative nanocarriers for delivery of siRNA have offered new opportunities for pancreatic cancer nano-siRNA drug development (Table 1). In this manner, siRNA-conjugated nanocarriers with a higher molecular weight can delay renal clearance and increase the accumulation of siRNAs in cancer cells (P. Zhang et al., 2018). Therefore, various nano-siRNA therapeutic agents have been designed and employed for clinical trials (Table 2). In this part, nanoparticle-based systems using lipid, rigid-particle, polymer, and specific ligands for the treatment of pancreatic cancer will be described in detail (Figure 1).
Figure 1. Instances of nanocarriers for pancreatic cancer therapy.