Polymer-based delivery
systems
To date, polymeric carriers have attracted major attention in siRNA
delivery system because of their high biocompatibility, low cytotoxicity
and their versatility for different modifications to accept desirable
properties (S. Aghamiri et al., 2019).
PLGA, which is an FDA-approved biodegradable polyester, has been used to
encapsulate siRNA for many years. PLGA poloxamer nanoparticles can be
applied to increase loading and transfection efficiency. Pan et
al . (Pan et al., 2015) demonstrated that targeting hypoxia-inducible
factor 2α (HIF-2α), known as endothelial PAS domain protein-1(EPAS1), by
siRNA encapsulated in PLGA poloxamer led to better intracellular uptake
and reduction of cell viability in pancreatic tumor cells in
vivo . EPAS1 was indicated to be upregulated in about 67 percent of
pancreatic cancer patients (J. Yang et al., 2016). In another study,
Guopei and his colleagues (Luo et al., 2009) used siRNA sequence of
methyl-CpG binding domain protein 1(MBD1) incorporated into PLGA
poloxamer carrier. MBD1 is a transcriptional regulator, which is
overexpressed in pancreatic cancer cell lines. They showed that PLGA
poloxamer as a non-viral gene vector for MBD1 siRNA can be effectively
transfected into BxPC-3 human pancreatic tumor cells and inhibit cell
growth and induce apoptosis (Fujita et al., 2003). As an enhancing
modification in this common siRNA delivery method, the surface of PLGA
is covered by cationic PEI to improve weak electrostatic interaction
between PLGA and siRNA.
A number of studies have used Cationic poly (lactic acid) (CPLA), a
non-toxic biodegradable polymer incorporated with siRNA to induce the
silencing of mutant K-ras gene in pancreatic cancer modelsin vivo . Guimiao et al . (Lin et al., 2013) designed a new
type of carrier with transforming the linear CPLAs into CLPA
nanocapsules. These nanocapsules are covalently cross-linked and display
several advantages over linear CLPAs such as stronger and steadier
scaffold structure. Also, the large surface can be more beneficial for
siRNA condensation. Negative charges of siRNA results in its attachment
to the surface of CLPA nanocapsules through electrostatic interactions.
This novel polymer formulation of CPLA for siRNA delivery was able to
transfect over 90% of PANC-1 cells and knockdown K-ras gene by
almost 50% in PDAC models in vivo .
Since 2011, there has been a rapid rise in the use of Star polymers as
delivery agents for various therapeutic purposes (Duong et al., 2014).
They can be cost-beneficially produced in large amounts and be modified
easily to increase their stability and targets particular cell types.
Teo et al . (Teo et al., 2016) delivered βIII-tubulin siRNA into
mice with orthotopic pancreatic MiaPaCa-2 by poly[oligo(ethylene
glycol) methyl ether methacrylate] (POEGMA) via intratumoral
administration to inhibit pancreatic tumor growth. The βIII-tubulin
siRNA/ POEGMA complexes rendered high transfection efficiency in
pancreatic cancer cells in vitro and in vivo . They also
demonstrated that in order to increase the ability of gene silencing and
overcome the problem of serum opsonization, cationic nanoparticles
PEGylation along with POEGMA (poly [oligo (ethylene glycol) methyl
ether methacrylate]) can be used to cover the positive charge.
The use of Poly Glutamic Acid-Based nanocarriers is a potentially
promising approach to overcome the existing limitations with the use of
RNAi such as low cellular uptake, degradation in the peripheral blood by
RNases, clearance by the kidneys and immunogenicity (Huang et al.,
2012). Although small RNAs are believed to stimulate cytokine secretion,
this type of amphiphilic polyglutamate amine (APA) delivery system does
not induce the secretion of TNF-α and IL-6. These nanocarriers show
minimal systemic side effects such as accumulation of small amounts in
the spleen and low level of immunotoxicity. These nanocarriers are
produced by attaching alkylamine and ethylenediamine parts to the
carboxylic groups (Han et al., 2018). c-MYC proto-oncogene encodes a
transcription factor, which plays a significant role in the regulation
of cell proliferation, growth, and apoptosis. MYC oncogene can be
targeted by both miR-34a and Polo-like kinases 1 (PLK1). To inhibit this
oncogene, a biocompatible APA polymeric nanocarrier has been designed to
transfer microRNA-mimic (to enhance miR-34a) and PLK1 siRNA into
PDAC-bearing mice through intravenous (IV) route. Results were promising
if high miR-34a and low PLK1 expression levels were present; hence, to
increase the therapeutic response and survival, restoration of miR-34a
together with down-regulation of PLK1 should occur (Gibori et al.,
2018).
These studies rationalize the need for continuous development of
polymeric based siRNA carriers to pancreatic tumors as well as other
solid tumors