# PolySorbate-Based Drug Formulations for Brain-Targeted Drug Delivery and Anticancer Therapy
## 5 PS-Coated NPs for Efficient BBB Transport  
PS-coated NPs are known to efficiently deliver therapeutic molecules to the brain by crossing the BBB [113; 114; 115]. PS-coated NPs can interact strongly with the brain blood vessel endothelial cells. PS 80 enables the adsorption of apolipoproteins (e.g., apolipoprotein E (ApoE)) onto NPs [116], and the NPs interact with lipoprotein receptors on the luminal surface of the BBB, triggering the receptor-mediated transcytosis of the PS-coated NPs (Figure 7). Moreover, PS-coated particles reduce nonspecific uptake by the reticuloendothelial system [117]. In recent years, various PS-coated NPs have been developed to improve brain-specific delivery of drugs, such as tacrine [118], doxorubicin [119], hexapeptide dalargin [120], loperamide [121], and tubocurarine [122], by increasing LDL-mediated endocytosis [123]. [PERSON] et al. extensively investigated PS-coated nanoparticle systems for the brain-targeted delivery of drugs [113; 114; 115]. Transport of dalargin across the BBB was facilitated using PS 80-coated poly(butyl cyanoacrylate) (PBCA) NPs. Intravenous injection of PS 80-coated PBCA NPs encapsulating dalargin in mice showed an analgesic effect [113]. PBCA NPs encapsulating the anti-nociceptive peptide dalargin were coated with apolipoproteins for efficient brain targeting [115]; additionally, the NPs were coated with PS 80. The formulations were administered intravenously into mice, and the mean percentage of the maximum possible effect (MPE) was calculated. It was shown that PS 80 precoating achieved a significantly higher MPE than that in the control groups. PS 80-coated NPs adsorb apolipoproteins from the blood after injection, thus mimicking lipoprotein particles that can be efficiently internalized by the brain capillary endothelial cells via receptor-mediated endocytosis. Additionally, tail-flick test results using ApoE-deficient mice demonstrated that ApoE plays a critical role in the transport of NPs across the BBB. Figure 6: (**A**) Schematic illustration for the synthesis of polyethyleneimine-_graft_-PS (PEIP) copolymer. (**B**) Schematic representation for the fabrication of hydrogel NPs using PEIP and alginate (TEA: Triethylamine, DMSO: Dimethyl sulfoxide, CDI: Carbonyldiimidazole). Reproduced with permission from Reference [112]. Copyright 2016, Royal Society of Chemistry. These findings explain the mechanism of PS 80-coated drug carriers for brain-targeted delivery [115]. Recent progress in the use of PS-coated NPs for brain-targeted delivery is summarized in Table 1.  
Several studies have demonstrated that PS 80-coated NPs can improve drug accumulation in the brain [124; 125; 126; 127; 128; 129; 130; 131]. It has been reported that brain targeting of PS 80-coated NPs is closely associated with the interaction between PS 80 coating and brain microvessel endothelial cells [132]. Efficient penetration of the hexapeptide dalargin across the BBB was achieved using PS 80-coated PBCA NPs [124]. Intravenous administration of this formulation to mice exerted analgesic effects due to efficient phagocytic uptake by the brain blood vessel endothelial cells. This study demonstrated that PS-coated NPs facilitate the transport of large peptides that cannot penetrate the BBB in their native form. When dalargin bound to PS 80-coated NPs was intravenously administered to mice, a strong analgesic effect was observed; however, its administration with other surfactants, such as poloxamers 184, 188, 338, 407, poloxamine 908, cremophor EZ, cremophor RH 40, and Brij 35, showed negligible effects [125]. Rivastigmine-loaded PBCA NPs have been developed for the treatment of [PERSON]'s disease [126]. Animal model results showed that drug uptake in the brain increased four-fold for PBCA NPs coated with 1% PS 80 compared to free drugs. PS 80-bound poly(lactic-co-glycolic acid) (PLGA) NPs were prepared to increase the localization of acetylpuerarin (AP) in the brain of mice [133].