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）影响约8-1200万美国人。由于其疾病的程度和分布模式，许多患者不是常规治疗的候选者，例如手术旁路或血管成形术。闭塞垫不仅可能导致休息时或步行（laurauration）疼痛（如果足够严重，可能会导致远端肢体溃疡，最终导致截肢的需求。此外，临界肢体缺血的患者具有与晚期癌症患者相当的生活质量评分。由于新血管形成的提示是放错了位置的（由于远端肢体发生的最缺血区域，即脚部，而狭窄或闭塞性动脉更近近，即iLiac或股骨病），外源性的细胞治疗为其提供了最有帮助的区域的手段。这可以通过直接分化为血管或释放适当的细胞因子来帮助新血管形成来实现。由于患者的天然干细胞通常是功能障碍，因此同种异体干细胞可能会提供最佳的细胞产物选择，可为PAD患者提供现成，高质量的细胞疗法。细胞疗法的临床试验将需要以非侵入性方式监测输送，植入和治疗益处的方法。此外，当前的细胞疗法均主要是由于在给药后的头24小时内遭受了极低的植入。因此，保护干细胞免受早期破坏的方法，并免疫保护患者免受可非侵入性监测的同种异细胞疗法的排斥，这将是巨大的好处。在当前的提案中，我们将开发一种新型的放射性放射性，可见的，可见的微囊化（XMRCAP）的方法，可以使用X射线荧光镜检查，计算机术（CT）和磁共振（MRI），可以使用X射线荧光镜，计算机术（CT）进行非侵袭性地传递和跟踪，该方法可以非侵入性地传递和跟踪。对于应用程序的R21阶段，我们将重点关注三个特定目的：1。）配方保持细胞生存力的优化XMRCAP是生物相容性的，并且表现出对非侵入性成像的足够敏感性； 2.）演示使用CT串行跟踪XMRCAP的能力； 3.）证明XMRCAP是免疫保护并增强细胞存活的。达到R21里程碑后，R33应用将确定在给药后7天和治疗功效时通过增强动脉生成相对于裸MSC在Hindimb Ischemia相关兔模型中的能力。由于XMRCAP是由临床级产品组成的，因此我们预计这些临床前数据将构成FDA的安全性和活动数据的基础，用于将XMRCAP转换为PAD中的XMRCAP为治疗性动脉生成临床试验。使用新型的微型塑料技术与临床级药物，当前应用的目的是将干细胞封装在无关供体中的干细胞，这些干细胞可以通过X射线成像和磁共振成像（MRI）来看待患者的精确输送和跟踪。微囊化将：1。）防止外国细胞排斥； 2.）与未封装的细胞相比，增强细胞的存活；和3.）使干细胞能够帮助开发狭窄或遮挡且无法接受常规手术或医疗疗法治疗的动脉的患者的新血管。

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.