Anti-catabolic drug anchored cationic exosomes for cartilage targeting and repair

用于软骨靶向和修复的抗分解代谢药物锚定的阳离子外泌体

• 批准号: 10176484
• 负责人: Ambika Goel Bajpayee
• 金额: $ 23.55万
• 依托单位: NORTHEASTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10176484
• 关键词: Antibodies; Arthralgia; Arthritis; Binding; Biochemical; Biodistribution; Biological; Biological Assay; Biological Transport; Cartilage; Cations; Cells; Charge; Chondrocytes; Chronic; Clinical; Coculture Techniques; Complex; Custom; Degenerative polyarthritis; Development; Diffuse; Dose; Drug Carriers; Drug Delivery Systems; Drug Transport; Electrostatics; Encapsulated; Engineering; Escherichia coli; Exhibits; Eye; Fibroblasts; Gene Expression; Genetic Engineering; Genetic Materials; Histology; Hybrids; Hydrophobicity; Inflammation; Inflammatory; Injections; Injury; Interleukin-1; Intervertebral disc structure; Intra-Articular Injections; Joints; Kinetics; Knee; Lipid Bilayers; Lipids; Mediating; Meniscus structure of joint; Mesenchymal Stem Cells; Modeling; Penetration; Peptides; Pharmaceutical Preparations; Process; Property; Proteins; Rattus; Recombinants; Role; Signal Transduction; Synovial Cell; Synovial Membrane; Tail; Therapeutic; Thick; Time; Tissues; Toxic effect; Translating; Treatment Efficacy; anakinra; base; biomaterial compatibility; bone; cartilage degradation; cartilage repair; cell motility; cell type; clinical translation; cytokine; density; design; engineered exosomes; exosome; in vivo; inhibitor/antagonist; injured; microCT; preservation; receptor; regeneration potential; regenerative; repaired; residence; stem cell exosomes; success; uptake

Project Summary Osteoarthritis (OA) is associated with severe joint pain, inflammation, and chronic cartilage degeneration. Mesenchymal stem cells (MSCs) derived exosomes are emerging as promising therapeutics for OA as they carry proteins and genetic materials that induce regenerative processes like cell migration, proliferation, differentiation and matrix synthesis. Their role in biological and transport crosstalk across multiple joint tissues and cell types, however, remains unclear. Additionally, the negative charge of exosome lipid bilayer hinders their penetration into the negatively charged cartilage. The high negative fixed charge density of cartilage offers a unique opportunity to utilize electrostatic interactions to enhance intra-tissue transport, uptake, and retention of exosomes by making them positively charged. We have designed an amphipathic cartilage penetrating cationic peptide (CP) that can rapidly diffuse through full tissue thickness due to their optimal charge, be up-taken by cells, and bind within for extended periods in both healthy and arthritic cartilage. This project will engineer cartilage targeting MSC-exosomes anchored with CPs and with an anti-catabolic OA biologic, IL-1Ra (IL-1 inhibitor) in optimal concentrations. Currently, extensive genetic engineering approaches are used to produce customized exosomes encapsulating biologics, which may compromise their intrinsic composition making their clinical translation complex. The project will use a simple one-step synthesis of grafting CP and IL-1Ra on exosome lipid bilayer. CP-exosomes can thus use cartilage as a drug depot and target cells thereby enhancing the availability of optimally loaded IL-1Ra to its receptors while preserving their intrinsic therapeutic potential. Aim 1 will engineer CP grafted MSC-exosome (CP-Exo) and characterize its intra-cartilage transport properties in healthy and arthritic states. Their transport crosstalk and uptake across multiple cell types using cytokine challenged chondrocyte and synovial cell co-cultures will be studied to understand whether their therapeutic benefits arise from cartilage or synovium targeting or both. Aim 2 will synthesize recombinant lipid fused IL-1Ra that will be anchored in different densities on exosome bilayer to form a hybrid vehicle, IL-1Ra-CP-Exo. Its bioactivity will be evaluated using cytokine challenged cartilage-synovium explant co-cultures and compared with free IL-1Ra and unmodified exosomes. Aim 3 will characterize joint kinetics, intra-cartilage uptake and biodistribution of CP-Exo in healthy and injured rat knees, and bio efficacy of IL1-Ra-CP-Exo in suppressing injury induced catabolic signaling will be evaluated using rat models of post traumatic OA. The project paves way for utilizing the intrinsic therapeutic potential of exosomes for cartilage repair as well as for its customizable development as a drug carrier allowing for adjustable intra-cartilage transport properties, easy drug anchoring and controllable loading of a variety of pro-chondrogenic protein drugs and antibodies. The success of this project can enable rapid clinical translation of exosomes as a cell-free, non-immunogenic platform for drug delivery to cartilage and other negatively charged tissues like meniscus, intervertebral discs, eye etc.

项目总结

项目成果

Sustained intra-cartilage delivery of interleukin-1 receptor antagonist using cationic peptide and protein-based carriers.

使用阳离子肽和基于蛋白质的载体持续软骨内递送白细胞介素 1 受体拮抗剂。

• DOI: 10.1016/j.joca.2023.01.573
• 发表时间: 2023
• 期刊: Osteoarthritis and cartilage
• 影响因子: 7
• 作者: Mehta,S;Boyer,TL;Akhtar,S;He,T;Zhang,C;Vedadghavami,A;Bajpayee,AG
• 通讯作者: Bajpayee,AG

Milk exosomes with enhanced mucus penetrability for oral delivery of siRNA.

• DOI: 10.1039/d0bm01497d
• 发表时间: 2021-06-15
• 期刊: Biomaterials science
• 影响因子: 6.6
• 作者: Warren MR;Zhang C;Vedadghavami A;Bokvist K;Dhal PK;Bajpayee AG
• 通讯作者: Bajpayee AG

Effects of polycationic drug carriers on the electromechanical and swelling properties of cartilage

聚阳离子药物载体对软骨机电和溶胀性能的影响

• DOI: 10.1016/j.bpj.2022.06.024
• 发表时间: 2022
• 期刊: Biophysical Journal
• 影响因子: 3.4
• 作者: Warren, Matthew R.;Vedadghavami, Armin;Bhagavatula, Sanjana;Bajpayee, Ambika G.
• 通讯作者: Bajpayee, Ambika G.