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.