Inorganic theranostic nanoparticles for Tuberculous Meningitis
用于治疗结核性脑膜炎的无机治疗诊断纳米颗粒
基本信息
- 批准号:2767186
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:英国
- 项目类别:Studentship
- 财政年份:2020
- 资助国家:英国
- 起止时间:2020 至 无数据
- 项目状态:未结题
- 来源:
- 关键词:
项目摘要
Tuberculous meningitis (TBM) is the most severe form of tuberculosis infection with very high mortality and accountsfor 2-5% of all tuberculosis (TB) cases among children and HIV-positive adults, causing permanent neurologicalconsequences and disability. There is an urgent clinical need to develop vehicles to deliver antimicrobials/antiinflammatoriesdirectly inside the brain to treat and diagnose early stage TBM.The PhD research project will focus on 4 tasks: (1) synthesis of theranostics nanoparticles (NPs) with controlled size(<100 nm) for optimal BBB crossing. (2) Decoration of NPs with pH responsive polymer which allows NPs to be absorbedand pass into the blood stream. (3) NPs physicochemical characterisation. (4) In vitro testing of NPs transcytosisformulation.Task 1: Synthesis of NPs. The PhD student will design and develop spherical (MSNs) and flower (MSNFs) shapemesoporous silica NPs with controlled size (<100 nm) containing first line antibiotics for optimal BBB crossing. The silicanetwork will be obtained by a modified Stöber method. Different concentrations of therapeutic ions (Ce, and Fe - forMRI imaging) will be incorporated into MSNs using a post grafting method.Task 2: Decoration of NPs with pH responsive polymer. A double polymeric shell will be synthesised in order toenable the oral administration of the new therapeutic NPs. MSNs/MSNFs will be decorated with pH responsive polymer(Eudragit E100) which is soluble and swells at gastric pH (up to 5), allowing NPs to be absorbed and pass into the bloodstream. Moreover, a permeable pH independent polymer (Eudragit RL 100) will be used to decorate MSNs and MSNFs.Eudragit RL 100 avoids drug release in the stomach and in the gut. COOH-MSNs and COOH-MSNFs will befunctionalised, using carbodiimide as coupling reagents, with the L-Dopa molecule that is shown to strongly improvetheir BBB crossing.Task 3: MSNs and MSNFs physicochemical characterisation. Ion release kinetics of the MSNs/MSNFs@CeO2-Fe3O4 in different biological media will be performed by ICP-MS. The NPs will be characterised using a range oftechniques including TEM-EDX, NMR, DLS, SAXS/WAXS and BET and HPLC. The magnetic properties of the NPs willbe studied by using a SQUID magnetometer. XPS and EELS will be used to measure the oxidation state of the ceria indifferent media.Task 4: In vitro testing of MSNs/MSNFs@CeO2-Fe3O4 transcytosis formulations.The most promising MSNs/MSNFs@CeO2-Fe3O4 systems will be selected for testing in vitro. Cell lines and primaryastrocytes, microglia, and neurons will be cultured with selected MSNs/MSNFs@CeO2-Fe3O4. The toxicity of the newsystem to healthy neuronal (astrocyte, microglia, neurons) and infected THP-1 microglial cells will be tested by usingMTT and LDH assays. ROS production will also be measured and correlated to the oxidation state of the nanoceria.Inflammation will be assayed by measuring cytokine release. The antibacterial properties of the NPs system will bemeasured using a colony forming assay.To investigate the ability of the MSNs/MSNFs@CeO2-Fe3O4 to cross the BBB and, if necessary, adjust the nano-drugformulation, a convergence of multi-disciplinary in vitro studies, using monocultures and specialised, unique co-culturemodels, of TBM, microglia and brain endothelial cell monolayers being developed at the Crick by Prof. Robert Wilkinsontranswell model of the TBM infected BBB will be used. In both the barrier and diseased cells, a range of cell andmolecular biological processes will be monitored, including nanocarrier drug efficacy, bioreactivity, particle uptake,transformation, particle degradation/products of degradation, translocation, and function and BBBpermeability/disruption.
结核性脑膜炎(TBM)是最严重的结核病感染形式,死亡率非常高,占儿童和HIV阳性成人中所有结核病(TB)病例的2-5%,造成永久性神经学后果和残疾。临床上迫切需要开发直接在脑内递送抗菌剂/抗炎剂的载体,以治疗和诊断早期TBM。博士研究项目将集中在4个任务上:(1)合成具有可控尺寸(<100 nm)的治疗诊断纳米颗粒(NP),以实现最佳的BBB穿越。(2)用pH响应性聚合物修饰NP,使NP被吸附并进入血流。(3)NP的物理化学表征。(4)NPs转胞吞作用的体外测试。任务1:NPs的合成。该博士生将设计和开发球形(MSNs)和花形(MSNFs)中孔二氧化硅纳米颗粒,其尺寸可控(<100 nm),含有一线抗生素,用于最佳的BBB交叉。将通过改进的Stöber方法获得硅树脂。不同浓度的治疗离子(用于MRI成像的Ce和Fe -)将使用后接枝方法并入MSNs.Task 2:用pH响应聚合物修饰NPs。将合成双聚合物壳,以便能够口服新的治疗性纳米颗粒。MSN/MSNF将用pH响应性聚合物(Eudragit E100)修饰,该聚合物是可溶的并且在胃pH(高达5)下溶胀,允许NP被吸收并进入血流。此外,可渗透的pH非依赖性聚合物(Eudragit RL 100)将用于修饰MSN和MSNFs Judragit RL 100避免了药物在胃和肠道中的释放。COOH-MSNs和COOH-MSNFs将被功能化,使用碳二亚胺作为偶联试剂,与L-Dopa分子,这被证明是强烈改善他们的BBB cross.Task 3:MSNs和MSNFs的物理化学表征。将通过ICP-MS进行MSNs/MSNFs@CeO2-Fe 3 O 4在不同生物介质中的离子释放动力学。将使用一系列技术表征NP,包括TEM-EDX,NMR,DLS,SAXS/WAXS和BET以及HPLC。纳米粒子的磁性将通过使用SQUID磁强计进行研究。XPS和EELS将用于测量氧化铈的氧化态。任务4:MSNs/MSNFs@CeO2-Fe 3 O 4转胞吞制剂的体外测试将选择最有前途的MSNs/MSNFs@CeO2-Fe 3 O 4系统进行体外测试。细胞系和原代星形胶质细胞、小胶质细胞和神经元将与选定的MSN/MSNFs@CeO2-Fe 3 O 4一起培养。新系统对健康神经元(星形胶质细胞、小胶质细胞、神经元)和感染的THP-1小胶质细胞的毒性将通过使用MTT和LDH测定来测试。ROS的产生也将被测量并与纳米铈氧化态相关联。炎症将通过测量细胞因子的释放来分析。为了研究MSNs/MSNFs@CeO2-Fe 3 O 4穿过BBB的能力,并在必要时调整纳米药物配方,多学科体外研究的融合,使用TBM的单培养物和专门的独特的共培养物,将使用由Robert Wilkinsontranswell教授在Crick开发的小胶质细胞和脑内皮细胞单层的TBM感染的BBB模型。在屏障和病变细胞中,将监测一系列细胞和分子生物学过程,包括纳米载体药物功效、生物活性、颗粒摄取、转化、颗粒降解/降解产物、易位和功能以及BBB渗透性/破坏。
项目成果
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其他文献
吉治仁志 他: "トランスジェニックマウスによるTIMP-1の線維化促進機序"最新医学. 55. 1781-1787 (2000)
Hitoshi Yoshiji 等:“转基因小鼠中 TIMP-1 的促纤维化机制”现代医学 55. 1781-1787 (2000)。
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LiDAR Implementations for Autonomous Vehicle Applications
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2021 - 期刊:
- 影响因子:0
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吉治仁志 他: "イラスト医学&サイエンスシリーズ血管の分子医学"羊土社(渋谷正史編). 125 (2000)
Hitoshi Yoshiji 等人:“血管医学与科学系列分子医学图解”Yodosha(涉谷正志编辑)125(2000)。
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Effect of manidipine hydrochloride,a calcium antagonist,on isoproterenol-induced left ventricular hypertrophy: "Yoshiyama,M.,Takeuchi,K.,Kim,S.,Hanatani,A.,Omura,T.,Toda,I.,Akioka,K.,Teragaki,M.,Iwao,H.and Yoshikawa,J." Jpn Circ J. 62(1). 47-52 (1998)
钙拮抗剂盐酸马尼地平对异丙肾上腺素引起的左心室肥厚的影响:“Yoshiyama,M.,Takeuchi,K.,Kim,S.,Hanatani,A.,Omura,T.,Toda,I.,Akioka,
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