Immunotargeting of reparative cells and theranostic nanosomes to cartilage lesions
修复细胞和治疗诊断纳米体对软骨损伤的免疫靶向
基本信息
- 批准号:10266752
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-01-01 至 2021-12-31
- 项目状态:已结题
- 来源:
- 关键词:Adipose tissueAffectAntibodiesAreaArthroscopyAvidinBindingBiotinBone MarrowCartilageCartilage MatrixCartilage injuryCellsChondrocytesCollagenCollagen Type IICoupledDefectDegenerative polyarthritisDetectionDevelopmentDiagnosisDiseaseDisease ProgressionDomestic PigDrug Delivery SystemsEarly DiagnosisEarly treatmentEncapsulatedExtracellular Matrix DegradationFamily suidaeGene ExpressionGlycoproteinsHistopathologyHumanImmunologicsIndividualInjuryIntra-Articular InjectionsJointsKneeKnee jointLabelLesionLigandsLiposomesMatrix MetalloproteinasesMeniscus structure of jointMesenchymalMesenchymal Stem CellsMethodsModelingMonitorMonoclonal AntibodiesMorbidity - disease rateNF-kappa BOperative Surgical ProceduresPainPathway interactionsPharmaceutical PreparationsPlayProceduresProductionProteinsProteoglycanReagentReplacement ArthroplastyReverse Transcriptase Polymerase Chain ReactionRiskRoleSiteSurfaceSurgical ModelsSynovitisSystemThickTimeTissuesTraumatic injuryTreatment EfficacyVeteransVisualizationWeight-Bearing statearthropathiesarticular cartilagecartilage degradationcartilage repaircell injurydisabilitydrug candidatefluorescence imagingin vivoinhibitor/antagonistinnovationjoint functionjoint injurymeniscus injurynanoscalenovelporcine modelpreventrecruittargeted deliverytargeted treatmenttheranosticstraumatic eventtreatment planning
项目摘要
The ability to detect early cartilage damage in traumatic injury or degenerative arthritis has been limited,
preventing treatment when therapies may be more beneficial. Depletion of proteoglycans/glycoproteins on the
surface of the cartilage in these disorders results in unmasking of the underlying type II collagen (CII). This
allows CII to serve as an immunologically recognizable target for monoclonal antibody to type II collagen
(MabCII). MabCII can be fluorescently labeled for diagnosis of cartilage injury or cartilage degeneration or may
be directly coupled to nanosomes encapsulating drugs for localized delivery to the cartilage lesion. Preliminary
evidence shows a similar strategy can be used to target and recruit reparative chondrocytes and mesenchymal
stem cells to the damaged site. In this application, MabCII will be used in a comprehensive treatment plan for
directing reparative cells to lesions of the articular cartilage and meniscal cartilages. The therapeutic efficacy
for repairing these cartilages will be monitored by an innovative fluorescent arthroscopy. In addition, we will
optimize the recruitment and integration of the reparative cells in the cartilage lesions by reducing MMP
production in the joint by intra-articular injection of an inhibitor of activation of the nuclear factor kappa B (NF-
KB) pathway encapsulated in MabCII-targeted nanosomes. These procedures are extremely novel and
paradigm shifting for the diagnosis and treatment of joint injury and disease. Our aims are: (1). To diagnose
and characterize damaged and degenerative areas of articular surface and meniscal cartilages in the
pig knee using a sensitive, MabCII antibody-guided method of fluorescent arthroscopy (FA). The knee
of the domestic pig closely resembles a human joint in terms of joint size, weight-bearing requirements, and
cartilage thickness and will be used in the characterization of surgically-induced injuries to meniscal and
articular cartilages. The damage will be visualized through its binding to fluorescent MabCII using fluorescent
arthroscopy, a new procedure that we have developed, and confirmed by histopathology. After FA
characterization of the injury, (2) MabCII antibody will be used to target delivery and recruitment of
reparative cells to the damaged areas of the knee joint cartilages. We will investigate the therapeutic
efficacy of fluorescent, MabCII-targeted chondrocytes or mesenchymal stem cells derived from bone marrow
and adipose tissues intra-articularly injected into joints where articular or meniscal cartilages have been
surgically damaged monitoring the cellular localization and persistence by FA. Cell to cell recruitment at the
cartilage lesion in the knee will be facilitated by an innovative system of biotin/avidin ligands on the surface of
the reparative cells and multivalent antibody recruitment of cells binding type II collagen. Reparative tissues will
be analyzed over time by histopathology and gene expression by RT-PCR. We will (3) further optimize the
recruitment and integration of replacement cells in the cartilage lesion by treatment with MabCII
targeted nanosomes loaded with an inhibitor of the activation of the NF-κB pathway. The production of
matrix metalloproteinases (MMP) is known to be a factor in degradation of cartilage matrices. Diminishing
MMP production will be a prototypic target for enhancing reparative efforts. The MabCII-targeted nanosomes
encapsulating a selective inhibitor of human IKK-2, an activator of the NF-κB pathway, will be used as a local
delivery system to reduce production of MMPs in damaged cartilage lesions prior to treatment with reparative
cells. !
!
!
在创伤性损伤或退行性关节炎中检测早期软骨损伤的能力有限,
当治疗可能更有益时阻止治疗。蛋白聚糖/糖蛋白的消耗
在这些疾病中,软骨表面的损伤导致下面的II型胶原(CII)的暴露。这
允许CII作为针对II型胶原的单克隆抗体的免疫学可识别的靶标
(MabCII)。MabCII可以被荧光标记用于诊断软骨损伤或软骨变性,或者可以
直接偶联到包封药物的纳米体上,用于局部递送到软骨损伤处。初步
有证据表明,类似的策略可用于靶向和招募修复性软骨细胞和间充质细胞。
干细胞移植到受损部位在本申请中,MabCII将用于综合治疗计划,
将修复细胞导向关节软骨和关节软骨的损伤。疗效
将通过创新的荧光关节镜来监测这些软骨的修复情况。此外,我们会
通过减少MMP,优化软骨损伤中修复细胞的募集和整合
通过关节内注射核因子κ B(NF-κ B)活化的抑制剂在关节中产生
KB)途径包封在MabCII靶向纳米体中。这些程序非常新颖,
关节损伤和疾病的诊断和治疗的范式转变。我们的目标是:(1)。诊断
并表征关节表面和关节软骨的损伤和退行性区域,
使用灵敏的MabCII抗体引导的荧光关节镜检查(FA)方法,膝
家猪的关节在关节尺寸、承重要求和
软骨厚度,并将用于表征骨关节炎引起的骨关节损伤,
关节软骨损伤将通过其与荧光MabCII的结合使用荧光标记可视化。
关节镜检查,我们已经开发的一种新的程序,并通过组织病理学证实。FA后
(2)MabCII抗体将用于靶向递送和募集
修复细胞的膝关节软骨的受损区域。我们将研究
来源于骨髓的荧光、MabCII靶向软骨细胞或间充质干细胞的功效
和脂肪组织关节内注射到关节或关节软骨已经
通过FA监测细胞定位和持久性。细胞间的招募
膝关节的软骨损伤将通过生物素/抗生物素蛋白配体的创新系统促进,
修复细胞和结合II型胶原的细胞的多价抗体募集。修复组织将
通过组织病理学和通过RT-PCR的基因表达随时间进行分析。我们将(3)进一步优化
通过用MabCII治疗在软骨损伤中募集和整合替代细胞
载有NF-κ B通路活化抑制剂的靶向纳米体。生产
已知基质金属蛋白酶(MMP)是软骨基质降解的一个因子。递减
微型企业方案的生产将是加强修复努力的一个原型目标。MabCII靶向纳米体
包封人IKK-2的选择性抑制剂(NF-κ B通路的激活剂)将被用作局部抑制剂,
在用修复剂治疗之前减少受损软骨病变中MMPs产生的递送系统
细胞!
!
!
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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KAREN A. HASTY其他文献
KAREN A. HASTY的其他文献
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{{ truncateString('KAREN A. HASTY', 18)}}的其他基金
Stimulation of Native Joint-resident Precursors for Cartilage Repair in Osteoarthritis
刺激天然关节前体促进骨关节炎软骨修复
- 批准号:
10731660 - 财政年份:2020
- 资助金额:
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