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

X射线

• 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
• 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

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）：外周动脉疾病（PAD）影响大约800 - 1200万美国人。许多患者不是常规治疗的候选人，例如，外科搭桥术或血管成形术，由于其疾病的范围和分布模式。闭塞性PAD不仅可能导致休息时或行走时疼痛（跛行），而且如果足够严重，可能导致肢体远端溃疡，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。因为新血管形成的线索是错误的（由于最缺血的区域发生在远端肢体，即，足部，而狭窄或闭塞的动脉更近，即，髂或股疾病），外源性细胞疗法提供了一种将细胞施用到它们可能最有帮助的区域的方法。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辅助新血管形成来实现。由于患者的天然干细胞通常功能障碍，异基因干细胞可能提供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将需要以非侵入性方式监测递送、植入和治疗益处的方法。此外，目前的细胞疗法都遭受极低的植入，主要是由于在施用后的前24小时内细胞的破坏。因此，保护干细胞免于早期破坏并且还免疫保护患者免于排斥同种异体细胞疗法的方法将具有巨大的益处，所述方法可以非侵入性地监测。在目前的建议中，我们将开发一种新的方法，结合不透射线，MR可见的微囊化（XMRCap）的同种异体间充质干细胞（MSC），可以提供和跟踪非侵入性使用X射线荧光透视，计算机断层扫描（CT），磁共振成像（MRI）。对于R21阶段的应用程序，我们将专注于三个具体目标：1。维持细胞活力的优化的XMRCap的制剂是生物相容的，并且证明对于用于递送的非侵入性成像具有足够的灵敏度; 2.）证明用CT连续跟踪XMRCaps的能力;以及3.）证明XMRCaps具有免疫保护性并增强细胞存活。在实现R21里程碑后，R33应用将通过在后肢缺血的相关兔模型中相对于裸MSC增强动脉生成的能力来确定在施用后7天增强的植入程度和治疗功效。由于XMRCaps由临床级产品组成，我们预计这些临床前数据将成为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供体的干细胞，这些干细胞可以通过X射线成像和磁共振成像（MRI）看到，以便在患者中精确递送和跟踪。微胶囊化将：1.）防止排斥外来细胞; 2.）与未被包裹的细胞相比，增强细胞的存活;和3.）使干细胞能够帮助动脉狭窄或闭塞且无法用常规手术或药物治疗的患者形成新血管。

项目成果

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.

• DOI: 10.2217/iim.11.33
• 发表时间: 2011-08-01
• 期刊: Imaging in medicine
• 作者: Fu Y;Azene N;Xu Y;Kraitchman DL
• 通讯作者: Kraitchman DL

Recent developments and future challenges on imaging for stem cell research.

• DOI: 10.1007/s12265-009-9158-x
• 发表时间: 2010-02
• 期刊: JOURNAL OF CARDIOVASCULAR TRANSLATIONAL RESEARCH
• 影响因子: 3.4
• 作者: Fu, Yingli;Kedziorek, Dorota;Kraitchman, Dara L.
• 通讯作者: Kraitchman, Dara L.