Targeted cell delivery for treatment of non-healing wounds and gangrene

靶向细胞输送用于治疗不愈合伤口和坏疽

• 批准号: 10395481
• 负责人: Sylvia Daunert
• 金额: $ 73.16万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-15 至 2023-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10395481
• 关键词: Adhesions; Amputation; Arterial Occlusive Diseases; Base Pairing; Binding; Blood Vessels; Bone Marrow; Cell Adhesion Molecules; Cell Communication; Cell Therapy; Cell Transplantation; Cell surface; Cells; Computer Assisted; Dendrimers; Destinations; Diabetes Mellitus; Diabetic Foot Ulcer; Diabetic mouse; Disease; Drug or chemical Tissue Distribution; E-Selectin; Economics; Endothelial Cells; Endothelium; Event; Family suidae; Foot Ulcer; Gangrene; Generations; Glycocalyx; Goals; Health Care Costs; Home; Homing; Isolated limb perfusion; KDR gene; Ligands; Limb structure; Mediating; Methods; Modality; Modeling; Morbidity - disease rate; Mus; Muscle Cells; Pathologic; Patients; Peripheral; Peripheral arterial disease; Physical Function; Quality of life; Recovery of Function; Role; Skeleton; Testing; Therapeutic; Therapeutic Effect; Therapy Clinical Trials; Tissues; Treatment Protocols; Ulcer; Vascular Endothelial Growth Factors; Wound models; angiogenesis; base; chemokine; chronic ulcer; chronic wound; clinically relevant; critical limb Ischemia; cytokine; design; diabetic; diabetic patient; diabetic ulcer; efficacy testing; experience; feasibility testing; healing; high risk; improved; injured; limb amputation; limb ischemia; mortality; nanocarrier; neovascularization; non-healing wounds; novel; novel strategies; novel therapeutic intervention; prevent; rational design; repaired; selective expression; skeletal muscle wasting; skin wound; stem cell therapy; stem cells; surface coating; therapeutic angiogenesis; therapy development; three dimensional structure; tissue regeneration; tissue repair; translational study; wound; wound care; wound healing

Abstract Patients suffering from limb non-healing ulcers or gangrene caused by critical limb ischemia (CLI) induced by peripheral arterial occlusive disease (PAD) or diabetes are at very high risk of major amputation and experience poor physical function and severely diminished quality of life. Particularly, CLI in diabetic patients is associated with high rates of morbidity and mortality. CLI and diabetes-associated non-healing wound and gangrene result in over 130K major limb amputations and over $2 billion health care costs in the USA every year. There is a formidable need for novel therapeutic strategies. Our goal is to develop novel therapeutic strategies that will accelerate neovascularization and tissue repair to eliminate the need for major amputation. Cell- based therapy has emerged as a promising modality that can help to heal ulcers, increase ischemic limb functional recovery, prevent major amputation, and improve quality of life and survival in patients with CLI and diabetes. Bone marrow (BM)-derived tissue repair cells (TRC) represent an alternative beneficial therapeutic option to induce therapeutic angiogenesis and promote tissue regeneration. However, targeted systemic delivery of therapeutic cells to the disease tissues, which has certain advantages to local administration approach, remains one formidable challenge. We have recently developed a nanocarrier-mediated cell delivery method by coating the surface of the cells to be delivered with dendrimer nanocarriers modified with adhesion molecules. Nanocarriers can function as `GPS' to direct infused transplanting cells reach to destination via recognition and association with the counterpart adhesion molecules highly or selectively expressed on the activated endothelium in injured tissues. Once anchored on the activated endothelium, nanocarriers-coated cells extravasate and home to the targeted tissues to execute their therapeutic role. We thus propose to test and optimize this newly-developed targeted cell delivery platform to direct TRC specifically and efficiently home to ischemic and wound tissues to achieve therapeutic angiogenesis and tissue repair. Our proposal applies novel cell surface decoration method for targeted cell delivery, new mouse gangrene and powerful pig wound models to test feasibility and efficacy of novel nanocarrier-mediated targeted cell therapy in promoting tissue neovascularization and tissue repair. The proposed study is translatable for developing and optimizing safe and effective cell-based therapies for clinical trials. It may offer a new paradigm for advancing and transforming the field of non-invasive treatment for PAD/CLI.

抽象的 患有严重肢体缺血（CLI）引起的肢体不愈合溃疡或坏疽的患者 由外周动脉闭塞性疾病（PAD）或糖尿病引起的患有重大疾病的风险非常高 截肢，身体机能较差，生活质量严重下降。 特别是，糖尿病患者的 CLI 与高发病率和死亡率相关。命令行界面 糖尿病相关的不愈合伤口和坏疽导致超过 13 万条主要肢体 美国每年有超过 20 亿美元的截肢和医疗费用。有一种强大的 需要新的治疗策略。我们的目标是开发新的治疗策略 加速新血管形成和组织修复，从而消除大截肢的需要。细胞- 基于疗法已成为一种有前途的方式，可以帮助治愈溃疡，增加 缺血肢体功能恢复，预防大截肢，提高生活质量 CLI 和糖尿病患者的生存率。骨髓 (BM) 来源的组织修复细胞 (TRC) 代表了诱导治疗性血管生成的另一种有益治疗选择，并且 促进组织再生。然而，将治疗细胞靶向全身递送至 病变组织仍然是一种相对于局部给药方法具有一定优势的 巨大的挑战。我们最近开发了一种纳米载体介导的细胞递送方法 通过用修饰的树枝状聚合物纳米载体涂覆要递送的细胞的表面 粘附分子。纳米载体可以充当“GPS”来引导输注的移植细胞到达 通过与对应的粘附分子高度识别和关联到达目的地或 选择性表达于受损组织中活化的内皮细胞上。一旦锚定在 激活的内皮细胞，纳米载体包被的细胞外渗并回到目标组织 发挥其治疗作用。因此，我们建议测试和优化这个新开发的 靶向细胞递送平台，可特异性、高效地引导 TRC 归巢至缺血性和 伤口组织以实现治疗性血管生成和组织修复。我们的建议应用新颖 用于靶向细胞递送的细胞表面修饰方法，新的小鼠坏疽和强大的猪 伤口模型测试新型纳米载体介导的靶向细胞疗法的可行性和功效 促进组织新生血管形成和组织修复。拟议的研究可转化为 开发和优化用于临床试验的安全有效的细胞疗法。它可能会提供一个 推进和转变 PAD/CLI 非侵入性治疗领域的新范例。

项目成果

Accelerating the Screening of Small Peptide Ligands by Combining Peptide-Protein Docking and Machine Learning.

• DOI: 10.3390/ijms241512144
• 发表时间: 2023-07-29
• 期刊: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
• 影响因子: 5.6
• 作者: Codina, Josep-Ramon;Mascini, Marcello;Dikici, Emre;Deo, Sapna K.;Daunert, Sylvia
• 通讯作者: Daunert, Sylvia

Gangrene, revascularization, and limb function improved with E-selectin/adeno-associated virus gene therapy.

• DOI: 10.1016/j.jvssci.2020.10.001
• 发表时间: 2021
• 期刊: JVS-vascular science
• 作者: Quiroz HJ;Parikh PP;Lassance-Soares RM;Regueiro MM;Li Y;Shao H;Vazquez-Padron R;Percival J;Liu ZJ;Velazquez OC
• 通讯作者: Velazquez OC

Targeted Bioluminescent Imaging of Pancreatic Ductal Adenocarcinoma Using Nanocarrier-Complexed EGFR-Binding Affibody-Gaussia Luciferase Fusion Protein.

• DOI: 10.3390/pharmaceutics15071976
• 发表时间: 2023-07-19
• 期刊: Pharmaceutics
• 影响因子: 5.4

Novel Gene-Modified Mesenchymal Stem Cell Therapy Reverses Impaired Wound Healing in Ischemic Limbs.

• DOI: 10.1097/sla.0000000000005949
• 发表时间: 2023-09-01
• 期刊: Annals of surgery
• 影响因子: 9

High-Resolution Three-Dimensional Imaging of the Footpad Vasculature in a Murine Hindlimb Gangrene Model.

小鼠后肢坏疽模型中足垫脉管系统的高分辨率三维成像。

• DOI: 10.3791/63284
• 发表时间: 2022
• 期刊: Journal of visualized experiments : JoVE
• 作者: Ribieras,AntoineJ;Ortiz,YulexiY;Shrestha,Sophie;Huerta,CTheodore;Shao,Hongwei;Boulina,MariaE;Vazquez-Padron,RobertoI;Liu,Zhao-Jun;Velazquez,OmaidaC
• 通讯作者: Velazquez,OmaidaC