Nanoparticle Therapy for Targeted Drug Delivery in Organ Transplantation

器官移植中靶向药物输送的纳米颗粒疗法

基本信息

批准号：
9225201
负责人：
SATISH N NADIG
金额：
$ 19.57万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9225201
关键词：
Acute Address Adoptive Transfer Adverse effects Allogenic Allografting Antigen Presentation Area Attenuated Binding Biological Biomedical Engineering C3bi Cardiac Caring Chronic Clinical Complement Complement 3d Complement 3d Receptors Complement Activation Complement Receptor Data Deposition Development Devices Disease Dose Drug Delivery Systems Drug Targeting Effector Cell Encapsulated Endothelial Cells Eragrostis Event Future Glare Goals Graft Survival Histology Homing Human Immune system Immunity Immunohistochemistry Immunologics Immunologist Immunosuppression Immunosuppressive Agents In Vitro Inbred BALB C Mice Infection Inflammatory Lead Legal patent Life Longevity Malignant Neoplasms Measures Mechanics Mediating Mentors Metabolic Methods Micelles Modeling Modern Medicine Mus Organ Organ Survival Organ Transplantation Outcome Patients Perioperative Pharmaceutical Preparations Pharmacotherapy Phenotype Property Publishing Recombinants Regulatory T-Lymphocyte Reperfusion Injury Reperfusion Therapy Research Personnel Risk Savings Science Seminal Serum Side Sirolimus Skin Solid System T-Cell Activation T-Lymphocyte Therapeutic Therapeutic immunosuppression Tissue Grafts Transplant Recipients Transplantation Transplanted Organ Complication Umbilical vein Vascular Diseases Vitronectin Work Wound Healing allograft rejection base cell type clinically relevant clinically translatable complement C3d,g cytokine design design and construction drug preservation efficacy testing experience experimental study fluorophore genetic regulatory protein heart allograft imaging study immunosuppressed improved in vivo isoimmunity nanoparticle nanotherapy novel organ transplant rejection prevent public health relevance receptor mediated endocytosis response targeted delivery targeted treatment therapeutic target uptake vascular smooth muscle cell proliferation

项目摘要

DESCRIPTION (provided by applicant): Organ transplantation is an accepted therapy for various end-stage organ diseases. Systemic immunosuppression is required to prevent immunologic rejection in transplanted allografts. However, side- effects such as infections, cancers, and metabolic derangements are among the list of complications that organ transplant recipients suffer while on the necessary organ saving immunosuppressant medication. While significant advancements have been made with the design and efficacy of newer immunosuppressive medications, many carry heightened systemic risk profiles. In particular, rapamycin, has been shown to be an effective immunosuppressant, but carries an increased risk of infection, wound healing problems and metabolic side-effects1. Recent studies have shown that utilization of sub-therapeutic doses of rapamycin (insufficient to inhibit graft rejectin) combined with a systemic increase in ex-vivo expanded, adoptively transferred regulatory T cells (Treg) may prevent graft rejection2. These seminal studies suggest that combined low dose rapamycin with standard immunosuppressive care may prolong graft survival by inducing the recipient's immune system to `self-immunosuppress'. A potential way to further circumvent the systemic side-effects of rapamycin administration is to develop strategies to specifically deliver rapamycin directly to the grafted tissues. Many of the priming events that lead to the development of an alloimmune response have been shown to occur at the level of the graft3. Thus, while current practice utilizes systemic immunosuppression to modulate host immunity there is a growing appreciation that immune suppression at the graft level may have more profound effects on alloimmunity whilst sparing the recipient from the complications of systemic immunosuppression. Here, we propose to use novel graft targeting self-assembling micelle nanoparticles to attenuate both acute and chronic rejection. To facilitate graft targeting, we will conjugate these Targeted Rapamycin Micelles (TRaM) to soluble recombinant complement receptor 2 (CR2), a targeting moiety we have extensively characterized4. CR2 binds to long lived cleavage fragments of complement protein C3 (iC3b, C3dg, and C3d), which we have shown to deposit in cardiac allografts early post-transplantation as a response to ischemia- reperfusion injury, an unavoidable event in all solid organ transplants5. In addition to rapamycin loading and CR2 targeting moiety coating, micelles will contain near infrared (NIR) fluorophores for homing and tracking imaging studies. The feasibility of CR2 mediated targeting has previously been demonstrated and successful delivery of complement regulatory proteins utilizing this targeting moiety has been achieved6. By utilizing the novel targeting capabilities o CR2 we will be able to deliver rapamycin directly to the grafted organ. We hypothesize that rapamycin may be packaged within a biologically inert nanoparticle, tracked, targeted to, and released at the level of a transplanted allograft as a means for drug delivery and local immunosuppression.

描述（由申请人提供）：器官移植是治疗各种终末期器官疾病的公认疗法，需要全身免疫抑制来预防移植同种异体移植物的免疫排斥反应，但其中包括感染、癌症和代谢紊乱等副作用。移植器官受者在接受必要的器官保存免疫抑制药物治疗时遭受的并发症列表虽然新型免疫抑制药物的设计和功效取得了重大进展，但许多药物都具有全身性。特别是雷帕霉素，已被证明是一种有效的免疫抑制剂，但会增加感染、伤口愈合问题和代谢副作用的风险1。最近的研究表明，使用亚治疗剂量的雷帕霉素（不足以抑制移植物排斥2）。）与体外扩增、过继转移的调节性 T 细胞 (Treg) 的系统性增加相结合，可能会预防移植物排斥2。免疫抑制治疗可以通过诱导受体的免疫系统“自我免疫抑制”来延长移植物的存活率，进一步避免雷帕霉素给药的全身副作用的潜在方法是制定将雷帕霉素直接递送至移植组织的策略。导致同种免疫反应发生的启动事件已被证明发生在移植物水平3。因此，虽然目前的实践利用全身免疫抑制来调节宿主免疫。人们越来越认识到移植物水平的免疫抑制可能对同种免疫产生更深远的影响，同时使受者免受全身免疫抑制的并发症。在这里，我们建议使用新型移植物靶向自组装胶束纳米颗粒来减轻急性和慢性排斥反应。为了促进移植目标，我们将将这些靶向雷帕霉素胶束 (TRaM) 与可溶性重组补体受体 2 (CR2) 结合，CR2 是我们广泛表征的靶向部分，可与补体蛋白 C3（iC3b、C3dg 和 C3d）的长寿命裂解片段结合。已显示在移植后早期沉积在同种异体心脏移植物中，作为对缺血再灌注损伤（不可避免的事件）的反应在所有实体器官移植中，除了雷帕霉素负载和 CR2 靶向部分涂层外，胶束还将包含用于归巢和跟踪成像研究的近红外 (NIR) 荧光团，CR2 介导的靶向的可行性已被证明并成功递送补体调节蛋白。利用该靶向部分已经实现6。通过利用 CR2 的新型靶向功能，我们将能够将雷帕霉素直接递送至移植器官。生物惰性纳米颗粒，在移植的同种异体移植物水平上进行跟踪、靶向和释放，作为药物输送和局部免疫抑制的手段。