Aurora Kinase B siRNA-loaded Lactoferrin Nanoparticles Potentiate the Efficacy of Temozolomide in Treating Glioblastoma

Abstract

Aim: To investigate the efficacy of lactoferrin nanoparticles (LfNPs) in delivering siRNA across the blood–brain barrier to treat glioblastoma multiforme (GBM) and with an additional objective of potentiation of conventional temozolomide (TMZ) chemotherapy. Methods: Aurora kinase B (AKB) siRNA-loaded nanoparticles (AKB–LfNPs) were prepared with milk protein, lactoferrin, by water in oil emulsion method. AKB–LfNPs were tested in cell lines and in GBM orthotopic mouse model with and without TMZ treatment. Results: AKB silencing, cytotoxicity and cell cycle arrest by these LfNPs were shown to be effective on GL261 cells. Tumor growth was significantly lower in AKB–LfNPs alone and in combination with TMZ treated mice and increased the survival by 2.5-times. Conclusion: Treatment of AKB–LfNPs to GBM mice improves life expectancy and has potential to combine with conventional chemotherapy.

Lactoferrin, a unique molecule with diverse therapeutical and nanotechnological applications

“…Moreover, entrapped siRNA within LF nanoparticles was found to be intact and highly resistant to RNaseA, whereas, free siRNA was completely degraded when it was exposed to similar conditions (incubation with RNaseA for 1 h at 37 °C). Additionally, incubation of siRNA-loaded LF nanoparticles with serum containing contains nucleases and proteases did not cause any significant change in their particle size over a period of about 10 h at 37 °C, which confirmed stability in serum [ 56 ]. Fabricated nanoplatform either alone or in combination with TMZ demonstrated inhibitory action on the viability of glioma (GL261) cells in vitro due to silencing of AKB gene and cell cycle arrest.…”

“…Afterwards, it will be slowly thawed in ice for about 4 h. Obtained nanoparticles will be collected by centrifugation, followed by washing with cold diethyl ether and finally it could be dispersed in appropriate medium ( Fig. 3 ) [ 56 ]. Although doxorubicin (DOX) is an efficient cytotoxic anticancer drug, but it is reported to be extensively toxic to heart and spleen, besides its limited oral absorption.…”

“…In an approach to sensitize the chemotherapeutical potential of temozolomide (TMZ), Aurora Kinase B (AKB) small interfering RNA-loaded LF nanoparticles were fabricated by water-in-oil emulsion method [ 56 ]. TMZ is the only approved drug for treatment of glioblastoma multiforme (GBM), which is a DNA methylating agent that can produce O6-methylguanine; a DNA adduct that can enhance cell cycle arrest and cell death.…”

“…Furthermore, when siRNA-loaded LF nanoparticles were intravenously injected into GBM orthotopic mouse model alone or in combination with TMZ, there was a pronounced inhibition of tumor growth and about 2.5 fold increase in the survival rate. These results suggested that siRNA-loaded LF nanoparticles could inhibit tumor growth or it could be combined with conventional chemotherapy to increase its efficacy with simultaneous decrease in the toxic side effects and resistance that may be acquired by many tumors upon repeated dosing [ 56 ].…”

“… [ 67 ] Aurora Kinase B (AKB) siRNA Intravenous + free temozolomide In vivo improved anti-tumor and 2.5 fold increase in survival rate in glioblastoma orthotopic mouse model. [ 56 ] Temozolomide Intravenous Better drug pharmacokinetic profile and brain accumulation with a notable decline in tumor volume and enhanced survival in glioma- bearing mice. [ 20 ] plasmid pGFPC1 (4.7 kb) encoding the green fluorescent protein gene – Enhanced gene delivery in cells expressing LF receptors.…”