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