X-ray & MR-visible Microencapsulation of Allogeneic Arteriogenic Cell Therapeutic

X射线

基本信息

批准号：
7473947
负责人：
DARA L KRAITCHMAN
金额：
$ 40.99万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-23 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7473947
关键词：
Adoption Affect Aging Alginates Allogenic American Amputation Anatomy Angiography Angioplasty Animal Model Animals Area Arteries Barium Biocompatible Blood Substitutes Blood Vessels Bypass Cancer Patient Carrying Capacities Cell Survival Cells Clinical Clinical Trials Confocal Microscopy Contrast Media Conventional Surgery Count Cues Data Development Diagnostic radiologic examination Digital Photography Disease Distal Drug Formulations Encapsulated Engraftment Fluorocarbons Fluoroscopy Functional disorder Goals Hindlimb Hour Image Imagery Injection of therapeutic agent Invasive Ischemia Label Lead Limb structure Location Magnetic Resonance Imaging Measurement Measures Medial Medical Mesenchymal Stem Cells Methods Microcapsules drug delivery system Microencapsulations Modeling Monitor Multimodal Imaging Numbers Nutrient Operative Surgical Procedures Oryctolagus cuniculus Oxygen Pain Patients Pattern Perfusion Peripheral arterial disease Pharmacologic Substance Phase Population Propidium Diiodide Quality of life Radiation Radionuclide Imaging Relative (related person)Rest Roentgen Rays Safety Saline Scanning Score Site Staining method Stains Standards of Weights and Measures Stem cells Surgical Models Techniques Testing Therapeutic Thigh structure Thinking Time Tracer Translations Treatment Efficacy Ulcer United States Food and Drug Administration Walking Week X-Ray Computed Tomography base capsule claudication concept cytokine day desire experience foot improved neovascularization novel paracrine poly-L-lysine alginate pre-clinical prevent sample fixation stem cell therapy

项目摘要

DESCRIPTION (provided by applicant): Peripheral arterial disease (PAD) affects approximately 8-12 million Americans. Many patients are not candidates for conventional treatments, e.g., surgical bypass or angioplasty, due to the extent and distribution pattern of their disease. Occlusive PAD may not only lead to pain at rest or with walking (claudication), but, if severe enough, may lead to distal limb ulceration and, ultimately, the need for amputation. Moreover, patients with critical limb ischemia have quality of life scores that are comparable to terminal cancer patient. Because the cues for new vessel formation are misplaced (due to the most ischemic areas occurring in the distal limb, i.e., foot, whereas the stenotic or occlusive artery is more proximal, i.e., iliac or femoral disease), exogenous cellular therapy offers a means to administer cells to the regions where they might be most helpful. This can be accomplished by either direct differentiation into blood vessels or by the release the appropriate cytokines to assist in neovascularization. Because patients' native stem cells are often dysfunction, allogeneic stem cells may offer the best choice of cellular products to provide off-the-shelf, high quality, cellular therapy for PAD patients. Clinical trials of cellular therapy will require methods to monitor delivery, engraftment, and therapeutic benefit in a non-invasive manner. In addition, current cellular therapies all suffer from extremely low engraftment primarily due to destruction of the cells in the first 24 hours after administration. Therefore, methods to protect stem cells from early destruction and also immunoprotect the patient from rejection of allogeneic cellular therapies that could be monitored non-invasively would be of tremendous benefit. In the current proposal, we will develop a novel method of combined radiopaque, MR-visible microencapsulation (XMRCap) of allogeneic mesenchymal stem cells (MSCs) that can be delivered and tracked non-invasively using x-ray fluoroscopy, computed tomography (CT), and magnetic resonance imaging (MRI). For the R21 phase of the application, we will focus on three specific aims: 1.) the formulation of an optimized XMRCap that maintains cellular viability, is biocompatible, and demonstrates sufficient sensitivity for non-invasive imaging for delivery; 2.) demonstrate the ability to serially track XMRCaps with CT; and 3.) demonstrate that XMRCaps are immunoprotective and enhance cell survival. After achieving the R21 milestones, the R33 application will determine the degree of enhanced engraftment at 7 days post- administration and therapeutic efficacy by the ability to enhance arteriogenesis relative to naked MSCs in a relevant rabbit model of hindlimb ischemia. Because XMRCaps are composed of clinical grade products, we anticipate that these preclinical data will form the basis of safety and activity data for the FDA for translation of XMRCaps to therapeutic arteriogenesis clinical trials in PAD. Using a novel microencapsulation technique with clinical grade pharmaceuticals, the goal of the current application is to encapsulate stem cells from unrelated donors that can be seen by X-ray imaging and magnetic resonance imaging (MRI) for precise delivery and tracking in patients. The microencapsulation will: 1.) prevent the rejection of foreign cells; 2.) enhance the survival of the cells compared to cells that are not encapsulated; and 3.) enable the stem cells to assist in the development of new vessels in patients whose arteries that are narrowed or occluded and who cannot be treated with conventional surgery or medical therapies.

描述（由申请人提供）：周围动脉疾病 (PAD) 影响大约 8-1200 万美国人。由于疾病的程度和分布模式，许多患者不适合接受传统治疗，例如外科搭桥术或血管成形术。闭塞性 PAD 不仅可能导致休息时或行走时疼痛（跛行），而且如果严重的话，可能会导致远端肢体溃疡，最终需要截肢。此外，严重肢体缺血患者的生活质量评分与晚期癌症患者相当。由于新血管形成的线索错位（由于缺血最严重的区域发生在远端肢体，即足部，而狭窄或闭塞的动脉更近端，即髂或股骨疾病），外源细胞治疗提供了一种手段将细胞注射到它们可能最有帮助的区域。这可以通过直接分化成血管或通过释放适当的细胞因子来协助新血管形成来实现。由于患者的天然干细胞通常存在功能障碍，因此同种异体干细胞可能是细胞产品的最佳选择，为 PAD 患者提供现成的高质量细胞治疗。细胞疗法的临床试验需要以非侵入性方式监测递送、植入和治疗效果的方法。此外，目前的细胞疗法都存在着入极低的问题，这主要是由于细胞在给药后的前 24 小时内被破坏。因此，保护干细胞免遭早期破坏并免疫保护患者免受可非侵入性监测的同种异体细胞疗法排斥的方法将具有巨大的益处。在当前的提案中，我们将开发一种结合不透射线、MR 可见微囊化 (XMRCap) 的同种异体间充质干细胞 (MSC) 的新方法，该方法可以使用 X 射线透视、计算机断层扫描 (CT) 进行非侵入性输送和跟踪和磁共振成像 (MRI)。对于该应用的 R21 阶段，我们将重点关注三个具体目标：1.）优化 XMRCap 的配方，该 XMRCap 可以保持细胞活力、具有生物相容性，并且对用于输送的非侵入性成像表现出足够的灵敏度； 2.) 展示使用 CT 连续跟踪 XMRCap 的能力； 3.) 证明 XMRCap 具有免疫保护作用并增强细胞存活率。实现 R21 里程碑后，R33 应用将通过在相关兔后肢缺血模型中相对于裸 MSC 增强动脉生成的能力来确定给药后 7 天增强植入的程度和治疗效果。由于 XMRCaps 由临床级产品组成，我们预计这些临床前数据将构成 FDA 将 XMRCaps 转化为 PAD 治疗性动脉生成临床试验的安全性和活性数据的基础。使用临床级药物的新型微囊化技术，当前应用的目标是封装来自无关捐赠者的干细胞，这些干细胞可以通过 X 射线成像和磁共振成像 (MRI) 看到，以便在患者体内进行精确输送和跟踪。微囊化将： 1.) 防止外来细胞的排斥； 2.) 与未封装的细胞相比，提高细胞的存活率； 3.) 使干细胞能够帮助动脉狭窄或闭塞且无法通过传统手术或药物疗法治疗的患者形成新血管。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（1）

Using C-arm x-ray imaging to guide local reporter probe delivery for tracking stem cell engraftment.

DOI：
10.7150/thno.6943
发表时间：
2013
期刊：
Theranostics
影响因子：
12.4
作者：
Kedziorek DA;Solaiyappan M;Walczak P;Ehtiati T;Fu Y;Bulte JW;Shea SM;Brost A;Wacker FK;Kraitchman DL
通讯作者：
Kraitchman DL

Stem cell labeling for noninvasive delivery and tracking in cardiovascular regenerative therapy.

DOI：
10.1586/erc.10.106
发表时间：
2010-08
期刊：
Expert review of cardiovascular therapy
影响因子：
2
作者：
Fu Y;Kraitchman DL
通讯作者：
Kraitchman DL

Fused X-ray and MR imaging guidance of intrapericardial delivery of microencapsulated human mesenchymal stem cells in immunocompetent swine.

DOI：
10.1148/radiol.14131424
发表时间：
2014-08
期刊：
Radiology
影响因子：
19.7
作者：
Fu Y;Azene N;Ehtiati T;Flammang A;Gilson WD;Gabrielson K;Weiss CR;Bulte JW;Solaiyappan M;Johnston PV;Kraitchman DL
通讯作者：
Kraitchman DL

Tracking stem cells for cardiovascular applications in vivo: focus on imaging techniques.