Engineering the next generation nanoparticle-cyclosporine A therapy in lupus
设计下一代纳米颗粒环孢素 A 狼疮疗法
基本信息
- 批准号:10098822
- 负责人:
- 金额:$ 8.11万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-09-21 至 2021-01-13
- 项目状态:已结题
- 来源:
- 关键词:AffectAutoimmune DiseasesB-LymphocytesBenchmarkingBenefits and RisksBiologicalBiological AvailabilityBlood flowCD3 AntigensCXCL12 geneCXCR4 geneCarbonCellsChronicClinicClinical ResearchComplementCustomCyclosporineCytostaticsDataDiagnosisDiseaseDoseDrug Delivery SystemsEngineeringEvaluationFDA approvedFormulationGlomerulonephritisGoalsGrantGut associated lymphoid tissueHumanHuman CharacteristicsImmuneImmune systemImmunoglobulin GImmunologicsIndividualInflammatoryIntestinesKidneyKnowledgeLaboratory FindingLengthLigandsLupusLupus NephritisLymphLymphaticLymphatic SystemLymphocyteLymphoidLymphoid CellLymphoid TissueMS4A1 geneModelingMusNucleosome Core ParticleOralOrganPatientsPeriodicityPeripheral Blood Mononuclear CellPersonsPharmaceutical PreparationsPlasmaPolyestersPortal vein structureRegimenSerumSeveritiesSigns and SymptomsSiteSpleenSteroidsStructure-Activity RelationshipSurvival RateSymptomsSystemic Lupus ErythematosusT-LymphocyteTFRC geneTechnologyTestingTherapeuticTimeToxic effectTranslatingWorkcapsulecell mediated immune responsechemokinechemokine receptorcytokinedensitydesignds-DNAeffective therapyhuman diseaseimprovedin vivoinnovationlymph nodesmouse modelnanomedicinenanoparticlenanosystemsnephrotoxicitynext generationparticlepreventprophylacticreceptorside effectsuccesstherapeutic targettherapy outcomeuptake
项目摘要
Project Summary
Systemic lupus erythematosus (SLE) is a debilitating autoimmune disease that can affect almost every organ
in the body. Current treatments for SLE are often inadequate because they involve the chronic use of non-
specific, steroidal and cytostatic drugs that are associated with a wide spectrum of side-effects. However,
notwithstanding ongoing efforts to develop better therapies, there has only been one new, FDA-approved drug
for SLE in more than five decades. In this context, cyclosporine (CsA), a powerful suppressor of both humoral
and cell-mediated immune responses can be a potential candidate, but its efficacy as a stand-alone treatment
for SLE has never been demonstrated and often used to steroid tampering. Acknowledged reason for the lack
of success with the current commercial CsA formulations is due to poor/variable target (lymphoid) tissue
bioavailability with consequently differing biological activity and toxic to the kidneys. Targeting the lymphoid
tissue potentially enables rational design of therapeutics to modulate the immune system, representing an
innovative approach to treating lupus due to the fact that more than 75 percent of immune cells reside in the
GUT-associated lymphoid tissues (GALT). Moreover, GALT in lupus is larger compared to the healthy
individuals, making it an attractive site for targeting. The proposed study will generate paradigm-shifting, new
knowledge in the field of nano-medicines using unique periodic-functional-polyesters (P2s, unlike commercial
PLA/PLGA that are terminal functional), and investigate how the ligand density and composition influence the
CsA delivery to lymphoid tissue. The work is enabled by previous findings, in which highly potent lymphatic
system-targeting nanoparticle-CsA (called P2Ns-GA-CsA) specific to CD71 (transferrin receptor 1, TfR-1) on
lymphoid cells (T and B-cells) have outperformed ligand-free controls and commercial CsA product, leading to
better therapeutic outcomes. In this project, the technology is further developed by investigating how the
spatial size and composition of the spacer molecules affect the intestinal-receptor interaction and transport of
the nanoparticles facilitating customized dose-regimens. The project comprises of the following three aims,
Aim#1, to establish structure-activity relationships for P2Ns-GA-CsA in a murine lupus and TfR KO models.
Aim#2, to define the therapeutic dose of P2Ns-GA-CsA in a murine lupus model and Aim#3, to establish
survival rates in murine lupus models using the most efficacious P2Ns-GA-CsA.
项目摘要
系统性红斑狼疮(SLE)是一种使人衰弱的自身免疫性疾病,几乎可以影响到所有器官。
在身体里。目前对系统性红斑狼疮的治疗通常是不够的,因为它们涉及到长期使用非
具有广泛副作用的特效药、类固醇药和细胞抑制药。然而,
尽管不断努力开发更好的治疗方法,但只有一种新药获得了FDA的批准
对于50多年来的系统性红斑狼疮。在这方面,环孢素(CsA),一种对体液和体液都有强大抑制作用的药物
细胞介导的免疫反应可能是一个潜在的候选者,但作为一种独立的治疗方法,它的有效性
因为系统性红斑狼疮从来没有被证明过,而且经常用于类固醇干预。公认的缺乏的原因
目前的商业CsA制剂的成功是由于较差的/可变的靶(淋巴)组织
生物利用度,因此具有不同的生物活性和对肾脏的毒性。靶向淋巴组织
组织可能使合理的治疗设计成为可能,以调节免疫系统,代表着
治疗狼疮的创新方法,因为超过75%的免疫细胞驻留在
肠道相关淋巴组织(GALT)。此外,狼疮患者的GALT较健康人大
个人,使其成为一个有吸引力的目标网站。拟议中的研究将产生范式转变、新的
使用独特的周期性功能聚酯(与商用不同)的纳米药物领域的知识
具有末端功能的PLA/PLGA),并研究配体密度和组成如何影响
CsA递送至淋巴组织。这项工作得到了之前的发现的支持,在这些发现中,高度有效的淋巴
针对CD71(转铁蛋白受体1,TFR-1)的系统靶向纳米CsA(称为P2NS-GA-CsA)
淋巴样细胞(T和B细胞)的表现优于无配体对照和商业CsA产品,导致
更好的治疗效果。在这个项目中,这项技术通过调查如何
间隔物分子的空间大小和组成影响肠道-受体相互作用和转运
纳米颗粒促进了定制的剂量方案。该项目包括以下三个目标:
目的#1,在小鼠狼疮模型和转铁蛋白受体KO模型中建立P2NS-GA-CsA的构效关系。
目的#2,确定P2NS-GA-CsA在小鼠狼疮模型中的治疗剂量,目的#3,建立
最有效的P2NS-GA-CsA对狼疮小鼠模型的存活率。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Meenakshi Arora其他文献
Meenakshi Arora的其他文献
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{{ truncateString('Meenakshi Arora', 18)}}的其他基金
Urolithin A nanoparticle therapy for acute kidney injury
尿石素A纳米颗粒治疗急性肾损伤
- 批准号:
10396628 - 财政年份:2021
- 资助金额:
$ 8.11万 - 项目类别:
Urolithin A nanoparticle therapy for acute kidney injury
尿石素A纳米颗粒治疗急性肾损伤
- 批准号:
10193296 - 财政年份:2021
- 资助金额:
$ 8.11万 - 项目类别:
Urolithin A nanoparticle therapy for acute kidney injury
尿石素A纳米颗粒治疗急性肾损伤
- 批准号:
10597045 - 财政年份:2021
- 资助金额:
$ 8.11万 - 项目类别:
Engineering the next generation nanoparticle-cyclosporine A therapy in lupus
设计下一代纳米颗粒环孢素 A 狼疮疗法
- 批准号:
10373827 - 财政年份:2020
- 资助金额:
$ 8.11万 - 项目类别:
Engineering the next generation nanoparticle-cyclosporine A therapy in lupus
设计下一代纳米颗粒环孢素 A 狼疮疗法
- 批准号:
10461983 - 财政年份:2020
- 资助金额:
$ 8.11万 - 项目类别:
Engineering the next generation nanoparticle-cyclosporine A therapy in lupus
设计下一代纳米颗粒环孢素 A 狼疮疗法
- 批准号:
10267718 - 财政年份:2020
- 资助金额:
$ 8.11万 - 项目类别:
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