Research ArticleMATERIALS SCIENCE

Neurotransmitter-derived lipidoids (NT-lipidoids) for enhanced brain delivery through intravenous injection

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Science Advances  24 Jul 2020:
Vol. 6, no. 30, eabb4429
DOI: 10.1126/sciadv.abb4429
  • Fig. 1 Design of NT-lipidoids for effective brain delivery.

    (A) Schematic illustration of formulating NT-lipidoid–doped LNPs for cargo delivery into the brain. (B) Synthesis route, lipid nomenclature, and chemical structure of NTs used for lipidoid synthesis. (C) Representative ex vivo fluorescence images of the dissected brain 1 hour after one-time intravenous injection of DiR-labeled NT-LNPs (1 mg/kg). DiR was doped into the NT-LNPs with a 10% weight ratio. The mice were perfused with saline before dissection.

  • Fig. 2 NT-LNPs delivering AmB into the mouse brain.

    (A) Chemical structure of PBA-Q76-O16B, NT1-O12B, and schematic illustration of the doped NT1-lipidoid AmB formulation. (B) Photographs of AmB formulations in NT1-O12B doped with different amounts of PBA-Q76O16B (weight ratio is used). The pure NT1-O12B/AmB encapsulates appeared as an opaque suspension, while the appearance of the encapsulates changed from translucent solutions to homogeneous transparent yellow solutions as the doping ratio of PBA-Q76-O16B lipidoid increased. Photo credit: Feihe Ma, Tufts University. (C) Hydrodynamic diameters and PDIs of different NT-LNP/AmB formulations determined by DLS measurements. (D) Representative fluorescence images of the dissected mouse brain 1 hour after one-time intravenous injection of DiR-loaded NT1-O12B/PBA-Q76-O16B LNPs (1 mg/kg). The weight ratio of DiR in LNPs is 10%. (E) AmB concentration in brain tissues 24 hours after intravenous injection of AmB (5 mg/kg) in various NT1-O12B/PBA-Q76-O16B LNP formulations measured using HPLC (n = 4 per group). The mice were perfused with saline before dissected. One-way analysis of variance (ANOVA), Sidak post hoc analysis, *P < 0.05, **P < 0.001, or ***P < 0.0001. Graphical data are represented as box and whisker plots with individual points overlaid, where error bars represent maximum and minimum values and the boxed line represents the median.

  • Fig. 3 NT-LNP facilitates the delivery of Tau-ASO into the mouse brain and for gene knockdown in both mRNA and protein levels.

    (A) Chemical structure of 306-O12B-3, NT1-O14B, and schematic illustration of the doped NT-lipidoid Tau-ASO formulation for brain delivery. (B) GFP silencing efficiency of HEK-GFP cells treated with or without ASO/NT-LNP complexes. The NT1-O14B LNPs alone showed no silencing efficacy, while doping NT1-lipidoid into 306-O12B-3 LNPs led to successful gene silencing in vitro. *P < 0.01 versus all other samples in the same group. (C) Tau-ASOs formulated with NT1-O14B doped with different ratios of 306-O12B-3, saline, or scrambled Tau-ASO-LNPs were intravenously injected into C57BL/6J mice (n = 6 per group) via the tail vein, and the brain was analyzed for total tau mRNA levels. Graphical data are represented as box and whisker plots with individual points overlaid, where error bars represent maximum and minimum values and the boxed line represents the median, *P < 0.05 or **P < 0.001. (D) Total tau protein levels of the NT1-O14B/306-O12B-3 = 3:7 group, comparing to that of saline or scrambled Tau-ASO, **P < 0.001. One-way ANOVA, Sidak post hoc analysis.

  • Fig. 4 In vivo delivery of Cre recombinase to the Ai14 mouse brain to induce gene recombination.

    (A) Schematic illustration of mixed LNP formulation using NT1-O14B and PBA-Q76-O16B for GFP-Cre protein delivery into the brain. (B) Fluorescence image of the brain slices of Ai14 mice treated with (−27)GFP-Cre in different LNP formulations. Ai14 mouse was intravenously injected with (−27)GFP-Cre complexed with NT1-O14B:PBA-Q76-O16B = 3:7, 10:0, or 0:10 LNPs. After 3 weeks, the group of NT1-O14B:PBA-Q76-O16B = 3:7 showed tdTomato expression indicative of Cre-mediated recombination in cerebral cortex, hippocampus, and cerebellum. Red, tdTomato. The white arrows in the hippocampus 3:7 subpanel indicate tdTomato+ cells. Blue, DAPI. Scale bars, 100 μm.

Supplementary Materials

  • Supplementary Materials

    Neurotransmitter-derived lipidoids (NT-lipidoids) for enhanced brain delivery through intravenous injection

    Feihe Ma, Liu Yang, Zhuorui Sun, Jinjin Chen, Xuehui Rui, Zachary Glass, Qiaobing Xu

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