Small interfering rna (sirna) is an important rnai tool that can be used to treat cancer. the sirna could target several genes involved in the growth, proliferation and apoptosis of cancer cells. in this review, we discussed the safe and effective sirna delivery by nanoparticles in target cells.
there are several biological barriers presented to sirna delivery into tumor tissue. sirnas have very short in vivo half-lives. also, its high concentration causes the activation of immune responses and cytokines production in vivo. the plasma membrane is an important barrier for sirna uptake. despite their small size, the negative charge of sirna molecules prevents them from crossing cell membranes. the electrostatic interactions between the negative charge of sirna and cell membrane, reduce its cellular uptake. nanoparticles are used for delivery of the sirna to the target cells. the important advantages of using nanoparticles as a carrier system, include: 1- they protect the sirna from plasmatic nucleases and immune responses (the increased sirna half-life in the blood 2-they are inert and hence non-immunogenic and 3- some can stimulate the production of interferon and natural killer (nk) cells, resulting in activation of antitumor immune enhancing the efficiency of the therapy altogether .
Recent studies showed that natural or synthetic lipids (e.g., liposomes), cationic polymers (e.g, chitosan) could be able to deliver sirna molecules for gene silencing. for example, yang et al. developed the liposomes protamine chondroitin sulfate (chs) nanoparticles (lpc-np) for anti- egfr sirna delivery in mcf7 breast cancer cells. the lpc-np was modified by peg and t7 peptide. t7, a transferrin-like peptide, is a targeting ligand for transferrin receptor-overexpressed mcf7 breast cancer cells. then the t7 peptide modified lpc-np (t7-lpc/siegfr) were used for anti- egfr sirna delivery in mcf7 breast cancer cells. the epidermal growth factor receptor (egfr) is overexpressed in many cancers and which plays an essential role in the survival of cancer cells. in another study, the pegylated chitosan nanoparticles (peg-cs) were used for sirna delivery into 4t1 cells (the breast cancer cell lines). the poly ethylene glycol (peg) improves solubility and stability of the chitosan nanoparticles in the physical environment, thus the cellular uptake of peg- chitosan /sirna in tumor cells was significantly increased compared to naked sirna (sun et al, 2016). aln-vsp02, the first dual-targeted sirna drug, was developed by the alnylam pharmaceuticals (cambridge, ma, usa). aln-vsp is a lipid nanoparticle formulation containing two sirnas for kinesin spindle protein (ksp) and vascular endothelial growth factor (vegf) (xu and wang, 2015).
The liposomal nanoparticles have been used for sirna delivery into cells. yang et al found that t7-lpc/siegfr is an effective application in transferring the sirna into cells. peg could decrease aggregation of lpc-np in serum, and t7 peptide could enhance the cellular uptake and the gene silencing effect of sirna. chitosan as sirna delivery carrier has many advantages such as it is nontoxic, nonimmunogenic and biodegradable. sun et al. reported that peg- chitosan nanoparticle is a safe and efficient vector for sirna delivery into 4t1 cells, and sirna loaded in the nanoparticles can inhibit cell proliferation and metastases by gene silencing. aln-vsp02 phase 1 trial for the treatment of advanced solid tumors with liver involvement was initiated in april 2009. the research results showed that the ksp/vegf sirnas bind to both ksp and vegf messenger rnas (mrnas), preventing translation of ksp and vegf proteins. silencing of vegf and ksp plays an important role in inhibiting cell growth and inducing apoptosis of cancer cells.
Delivery of sirna to the cancer cell is the most challenging step. the results of this review suggested that nanoparticles could be an effective and safe delivery system for sirna-based cancer therapy. more nanoparticle-based sirna therapeutics is expected to become available in the near future.