乳铁蛋白修饰纳米粒包载的α-倒捻子素对AD模型动物脑内特征性病理改变的影响
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摘要
目的:采用乳铁蛋白修饰的PEG-PLA纳米粒为递药工具包载α-M,探讨其对快速老化SAMP8小鼠AD相关脑内病理特征的改善作用。方法:用乳化/溶剂蒸发法制备载α-M的PEG-PLA纳米粒NP(α-M),将巯基化的乳铁蛋白连接于纳米粒表面,得到Lf-NP(α-M)。7月龄SAMP8系小鼠尾静脉给予注射生理盐水、Lf-NP(α-M)或空白纳米粒溶液,每日一次,连续两周。正常老化小鼠SAMR为模型对照组,通过对脑组织进行免疫组化分析,观察Lf-NP(α-M)对SAMP8小鼠脑内炎症、Aβ沉积等AD特征性病理变化的影响。结果:0.5、2 mg/kgα-M对SAMP8小鼠脑内小胶质细胞激活、星形胶质细胞增生以及Aβ沉积均无显著影响;0.5mg/kg Lf-NP(α-M)可抑制小胶质细胞的激活(P<0.001),2 mg/m L Lf-NP(α-M)显著抑制星形胶质细胞增生以及Aβ沉积(P<0.05)。结论:乳铁蛋白修饰的包载α-M的可降解纳米粒脑靶向递药系统成功有效,显著提高α-M的成药性并改善AD模型小鼠脑内特征性病理改变。
Objective: Lactoferrin was covalently conjugated to the α-M-loaded nanoparticles to receive Lf-NP(α-M), the dis-ease modification effects of Lf-NP(α-M) in AD model mice was studied. Methods: α-M was loaded by poly(ethylene glycol)-poly(l-lactide)nanoparticles using emulsion/solvent evaporation method, and lactoferrin was covalently conjugated to it to form Lf-NP(α-M). We adopt the normal aging mice SAMR as negative control to SAMP8 mice. Saline and blank nanoparticles or Lf-NP(α-M) were injected to SAMP8 mice once a day for two weeks through the tail vein. The Aβ deposition and neuroinflammatory responses in animal brain were assessed after that, to evaluated its disease modification effects in AD. Results: α-M alone at 0.5 and 2 mg/kg could not significantly inhibit the activation of microglia, the proliferation of astrocyte and the deposition of Aβ in the brain of SAMP8 mice. Lf-NP(α-M) could significantly attenuate the activation of the microglia 0.5 mg/kg(P<0.001), and the inhibiting effects of the proliferation of astrocyte and the deposition of Aβ were significant at 2 mg/kg. Conclusions: Lf-NP(α-M) was a successful biodegradable and brain targeting drug delivering system, it could elevate the druggability of α-M, Lf-NP(α-M) could significantly improve the characterized pathological changes of AD in the brain of SAMP8 mice.
Objective: Lactoferrin was covalently conjugated to the α-M-loaded nanoparticles to receive Lf-NP(α-M), the dis-ease modification effects of Lf-NP(α-M) in AD model mice was studied. Methods: α-M was loaded by poly(ethylene glycol)-poly(l-lactide)nanoparticles using emulsion/solvent evaporation method, and lactoferrin was covalently conjugated to it to form Lf-NP(α-M). We adopt the normal aging mice SAMR as negative control to SAMP8 mice. Saline and blank nanoparticles or Lf-NP(α-M) were injected to SAMP8 mice once a day for two weeks through the tail vein. The Aβ deposition and neuroinflammatory responses in animal brain were assessed after that, to evaluated its disease modification effects in AD. Results: α-M alone at 0.5 and 2 mg/kg could not significantly inhibit the activation of microglia, the proliferation of astrocyte and the deposition of Aβ in the brain of SAMP8 mice. Lf-NP(α-M) could significantly attenuate the activation of the microglia 0.5 mg/kg(P<0.001), and the inhibiting effects of the proliferation of astrocyte and the deposition of Aβ were significant at 2 mg/kg. Conclusions: Lf-NP(α-M) was a successful biodegradable and brain targeting drug delivering system, it could elevate the druggability of α-M, Lf-NP(α-M) could significantly improve the characterized pathological changes of AD in the brain of SAMP8 mice.
引文
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[27]Huang JL,Jing X,Tian X,et al.Neuroprotective Properties of Panax notoginseng Saponins via Preventing Oxidative Stress Injury in SAMP8 Mice[J].Evid Based Complement Alternat Med,2017,2017:8713561
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[2]Hu J,Lin T,Xu J,et al.Polyphenols isolated from leaves of Vitis thunbergii var.taiwaniana regulate APP related pathway[J].Bioorg Med Chem Lett,2016,26(2):505-511
[3]Tomobe K,Fujii H,Sun B,et al.Modulation of infection-induced inflammation and locomotive deficit and longevity in senescence-accelerated mice-prone(SAMP8)model by the oligomerized polyphenol Oligonol[J].Biomed Pharmacother,2007,61(7):427-434
[4]Spagnuolo C,Napolitano M,Tedesco I,et al.Neuroprotective Role of Natural Polyphenols[J].Curr Top Med Chem,2016,16(17):1943-1950
[5]Gasca CA,Castillo WO,Takahashi CS,et al.Assessment of anticholinesterase activity and cytotoxicity of cagaita(Eugenia dysenterica)leaves[J].Food Chem Toxicol,2017,24
[6]Xicota L,Rodriguez-Morato J,Dierssen M,et al.Potential Role of(-)-Epigallocatechin-3-Gallate(EGCG)in the Secondary Prevention of Alzheimer Disease[J].Curr Drug Targets,2017,18(2):174-195
[7]Hayden EY,Yamin G,Beroukhim S,et al.Inhibiting amyloidβ-protein assembly:Size-activity relationships among grape seed-derived polyphenols[J].J Neurochem,2015,135(2):416-430
[8]Guo H,Dong YQ,Ye BP.Cranberry extract supplementation exerts preventive effects through alleviating Aβtoxicity in Caenorhabditis elegans model of Alzheimer's disease[J].Chin J Nat Med,2016,14(6):427-433
[9]Libro R,Giacoppo S,Soundara Rajan T,et al.Natural Phytochemicals in the Treatment and Prevention of Dementia:An Overview[J].Molecules,2016,21(4):518
[10]Korshavn KJ,Jang M,Kwak YJ,et al.Reactivity of Metal-Free and Metal-Associated Amyloid-βwith Glycosylated Polyphenols and Their Esterified Derivatives[J].Sci Rep,2015,5:17842
[11]Wang Y,Xia Z,Xu JR,et al.Α-mangostin,a polyphenolic xanthone derivative from mangosteen,attenuatesβ-amyloid oligomers-induced neurotoxicity by inhibiting amyloid aggregation[J].Neuropharmacology,2012,62(2):871-881
[12]Li L,Brunner I,Han AR,et al.Pharmacokinetics ofα-mangostin in rats after intravenous and oral application[J].Mol Nutr Food Res,2011,55 Suppl 1:S67-74
[13]Aisha AF,Ismail Z,Abu-Salah KM,et al.Solid dispersions ofα-mangostin improve its aqueous solubility through self-assembly of nanomicelles[J].J Pharm Sci,2012,101(2):815-825
[14]Kopp M,Kollenda S,Epple M.Nanoparticle-Protein Interactions:Therapeutic Approaches and Supramolecular Chemistry[J].Acc Chem Res,2017,8
[15]Wang L,Hu C,Shao L.The antimicrobial activity of nanoparticles:present situation and prospects for the future[J].Int J Nanomedicine,2017,12:1227-1249
[16]Gref R,Lück M,Quellec P,et al.'Stealth'corona-core nanoparticles surface modified by polyethylene glycol(PEG):influences of the corona(PEG chain length and surface density)and of the core composition on phagocytic uptake and plasma protein adsorption[J].Colloids Surf B Biointerfaces,2000,18:301-313
[17]Lee JH,Choi JW.Application of Plasmonic Gold Nanoparticle for Drug Delivery System[J].Curr Drug Targets,2017,Apr 27
[18]Brown M S,Goldstein J L.A receptor-mediated pathway for cholesterol homeostasis[J].Science,1986,232(4746):34-47
[19]Zhang Y,Zhang QZ,Zha LS,et al.Preparation,characterization and application of pyrene-loaded methoxy poly(ethylene gly col)-poly(lactic acid)copolymer nanoparticles[J].Colloid Polym Sci,2004,282:1323-1328
[20]Tobio M,Gref R,Sanchez A,et al.Stealth PLA-PEG nanoparticles as protein carriers for nasal administration[J].Pharm Res,1998,15(2):270-275
[21]Huwyler J,Wu D,Pardridge WM.Brain drug delivery of small molecules using immunoliposomes[J].Proc Natl Acad Sci,1996,93(24):14164-14169
[22]De Haan A,Tomee JF,Huchshorn JP,et al.Limmunoadjuvant system for stimulation of mucosal and systemic antibody responses against inactivated measles virus administered intranasally to mice[J].Vaccine,1995,13(14):1320-1324
[23]Narasimhan S,Maheshwaran S,Abu-Yousef IA,et al.Anti-Bacterial and Anti-Fungal Activity of Xanthones Obtained via Semi-Synthetic Modification ofα-Mangostin from Garcinia mangostana[J].Molecules,2017,22(2)
[24]Aukkanimart R,Boonmars T,Sriraj P,et al.In Vitro and In Vivo Inhibitory Effects ofα-Mangostin on Cholangiocarcinoma Cells and Allografts[J].Asian Pac J Cancer Prev,2017,18(3):707-713
[25]Wang MH,Zhang KJ,Gu QL,et al.Pharmacology of mangostins and their derivatives:A comprehensive review[J].Chin J Nat Med,2017,15(2):81-93
[26]Zhang KJ,Gu QL,Yang K,et al.Anticarcinogenic Effects ofα-Mangostin:A Review[J].Planta Med,2017,83(3-04):188-202
[27]Huang JL,Jing X,Tian X,et al.Neuroprotective Properties of Panax notoginseng Saponins via Preventing Oxidative Stress Injury in SAMP8 Mice[J].Evid Based Complement Alternat Med,2017,2017:8713561
[28]Zhang ZX,Zhao RP,Wang DS,et al.Fuzhisan Ameliorates the Memory Deficits in Aged SAMP8 Mice via Decreasing AβProduction and Tau Hyperphosphorylation of the Hippocampus[J].Neurochem Res,2016,41(11):3074-3082