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The high porosity and surface area of pSiNPs enables high concentrations of therapeutics to be delivered per weight of pSiNP [19, 20]

The high porosity and surface area of pSiNPs enables high concentrations of therapeutics to be delivered per weight of pSiNP [19, 20]. and delivery of siRNA are applied in vitro and in vivo. Result We established pSiNPs with polyethyleneimine (PEI) capping that enables high-capacity loading of siRNA (92?g of siRNA/mg PEI-pSiNPs), and optimised release profile (70% released between 24 and 48?h). These pSiNPs are biocompatible, and demonstrate cellular uptake and effective knockdown of MRP1 expression in GBM by 30%. Also, siRNA delivery was found to significantly reduce GBM proliferation as an associated effect. This effect is likely mediated by the attenuation of MRP1 transmembrane transport, followed by cell cycle arrest. MRP1 silencing in GBM tumour using MRP1-siRNA loaded pSiNPs was demonstrated in mice (82% reduction at the protein level 48 h post-injection), and it also produced antiproliferative effect in GBM by reducing the population of proliferative cells. These results indicate that in vitro observations are translatable in vivo. No histopathological signs of acute damage were observed in other MRP1-expressing organs despite collateral downregulations. Conclusions This study proposes the potential of efficient MRP1-siRNA delivery by using PEI-capped NCR3 pSiNPs in achieving a dual therapeutic role of directly attenuating the growth of GBM while sensitising Griseofulvin residual tumour cells to the effects of chemotherapy post-resection. Electronic supplementary material The online version of this article (10.1186/s12951-018-0365-y) contains supplementary material, which is available to authorized users. Keywords: Brain tumour, Gene delivery, Nanoparticles, Multidrug resistance-associated protein, siRNA, Cell proliferation Background Glioblastoma multiforme (GBM) is a deadly form of brain cancer with only a 5% survival rate at 5?years [1] and the age-standardised mortality rate of brain cancer in 2012 remains the same as in 1982 [2]. The mainstay of therapy is surgical resection. Factors that contribute Griseofulvin to the deadly nature of this cancer include the invasiveness of GBM cells, and therefore residual disease, at the resection margins; the selective permeability of the bloodCbrain barrier (BBB), and the inherent chemoresistance in the endothelial layer at the BBB and in the GBM cells [3, 4]. As the drug fails to penetrate and accumulate, it leads to poor chemotherapy effectiveness in both consolidation and treatment of unresectable tumours. Chemoresistance results from the expression of membrane-bound efflux transporters, such as the multidrug resistance protein (MRP) superfamily [5]. Multidrug resistance-associated protein 1 (MRP1), a MRP subtype, is a 190?kDa protein, through the hydrolysis of ATP, it actively removes substrates from cytoplasm [6]. Its overexpression in certain tumours removes drugs from cancer cells compromising treatment effectiveness [7]. Conventional drugs for GBM treatment, such as temozolomide (TMZ) and vincristine (VCR), are substrates of MRP1 which is overexpressed in brain tumours [8] and on the apical surface Griseofulvin of endothelial cells of the BBB [9]. These drugs are transported out of the tumour and out of the intracranial space, contributing significantly to the multidrug resistant phenotype of GBM. Inhibition of MRP1 is a strategy for chemosensitisation and this approach has been substantiated Griseofulvin in lung carcinoma in vitro and in vivo [10]. Small molecules are discovered to target and attenuate MRP1 function in various carcinomas over the last decade [11C13]. In comparison, small interfering RNA (siRNA) are more economical, versatile and effective in specific knockdown of protein [14], however its susceptibility to degradation and incapability in penetrating cell plasma membrane are the main obstacles for translation into clinical practice [15]. Nanoparticle delivery is a way to overcome those pharmacokinetic limitations, in which we demonstrated the use of bare porous silicon nanoparticles (pSiNPs) to deliver siRNA into cells [16]. In particular, pSiNPs were used as the delivery vehicle due to their high biocompatibility and degradability, and their degradation product, silicic acid, is non-toxic and is cleared rapidly [17, 18]. The high porosity and surface area of pSiNPs enables high concentrations of therapeutics to be delivered per weight of pSiNP [19, 20]. These pSiNPs have been employed in drug delivery applications such as delivery of enzymes [21], small molecules [22], and nucleotides [23]. The release of the drug can be easily tailored by controlling the degradation rate of pSiNPs and their surface chemistry [24, 25]. Thermal hydrocarbonisation (THC) treatment is a well-established modification to improve the hydrolytic stability of pSiNPs [26C28]. Owing to the polyanionic nature of siRNA, cationic surface treatments are believed to be more favourable to retain siRNA inside pSiNP [29]. MRP1 knockdown in GBM cells in vitro using various polymeric vectors as transfection method has suggested.