Introduction: Glioblastoma multiforme (GBM) is the most aggressive form of brain cancer. Treatment effectiveness and drug delivery for GBM is limited due to the existence of the blood-brain barrier (BBB). SiRNA is a novel treatment modality with potential clinical success. SiRNA can be exploited to inhibit the expression of genes involved in cancer cell survival, migration and multiplication. However, siRNAs are negatively charged and hydrophilic which prohibits them from crossing the BBB. Therefore, they have to be conjugated to other molecules or delivered with nanoparticles, or they will be excreted by kidneys without reaching the brain. As a result, more effective strategies are needed to develop functional siRNAs and deliver them across the BBB to the tumor site.
Methods: In this review article, various nanoparticle-based siRNAs designed for GBM treatment (from 2018-2021) were studied. The keywords “glioblastoma”, “nanoparticles” “siRNA” and “GBM” were searched in PubMed, google scholar and Elsevier, while review articles were excluded. Ninety-five articles were found. Fifteen of them were relevant to our study topic.
Results: Several anti-GBM siRNAs were designed and successfully delivered to the brain through nanoparticles. In one study, a combination of several siRNAs targeting GBM genes (Robo1, EGFR, YAP1, survivin, NKCC1; responsible for GBM cell growth, proliferation, mutation and migration) were loaded into bioreducible poly beta-amino-ester (PBAE) nanoparticles and delivered to the tumor area. This method targeted and silenced multiple genes at once and decreased tumor cell proliferation and migration. Another study administered Aurora kinase B (AKB)-siRNA loaded into lactoferrin nanoparticles to mice, which showed a significant reduction of the tumor mass and invasiveness. Inhibiting DNA damage repair proteins (ATM and DNApk) in radiosensitized GBM cells with siRNA-loaded ECO nanoparticles has also shown to be an effective method in vitro and in vivo. Cationic liposomes are widely used nanocarriers because of their stability and high encapsulation capacity. Their surfaces can easily be modified and various agents such as aptamers or aptamers-like peptides (aptides) can be added in order to enhance siRNA delivery. In addition, due to siRNA being anionic, cationic nanocarriers are better at retaining the siRNA inside. In one study, cationic liposomes loaded with yes-associated protein (YAP)-siRNA demonstrated significant therapeutic effects when combined with gold nanorods. Gold nanorods are effective photothermic agents, which means they can adsorb light in near infrared (NIR) regions and convert it to heat in the tumor cells and kill them without damaging normal cells. Transferrin magnetic nanoparticles are also potential drug delivery candidates for GBM. They have to be administered along with the application of external magnetic fields around the tumor area in order to enhance the penetration of the siRNA across the BBB. Moreover, transferrin receptors are highly expressed on brain capillary endothelial cells, and using its ligand, transferrin in siRNA delivery can be an effective strategy to penetrate across the BBB. One study showed that multidrug resistance protein-1 (MRP1)-siRNA delivered with polyethyleneimine (PEI)-capped porous silicon nanoparticles, not only inhibited the growth of GBM, but also sensitized the tumor cells further to the effects of chemotherapy. Another study showed that the co-delivery of cisplatin and glutathione peroxidase-4 (GPX4)-siRNA with iron-oxide nanoparticles was highly effective since it led to both apoptosis caused by cisplatin, and ferroptosis caused by iron-oxide in tumor site. Recently, a study developed manganese-containing chitosan-matrix (mNP) nanoparticle that has been able to transfer siRNAs into brain intranasally in mice. The greatest advantages of this method are administration simplicity and non-invasiveness. Finally, PLGA nanoparticles were also used to encapsulate Golgi phosphoprotein 3 (GOLPH3)-siRNAs and deliver them to tumor area which resulted in inhibition of GBM cell growth. In this study GOLPH3 downregulation led to EGFR degradation, which significantly inhibited GBM cell growth.
Conclusion: Taken together, these results suggest that gene silencing by utilizing anti-GBM siRNAs and delivering them to the tumor site by nanoparticles appears to be an effective strategy for treating glioblastoma or inhibiting its progression.