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

摘要 严重肢体缺血（CLI）导致的肢体不愈合溃疡或坏疽患者 由外周动脉闭塞性疾病（PAD）或糖尿病引起的高血压风险非常高， 截肢和经历身体功能差和生活质量严重下降。 特别是，糖尿病患者的CLI与高发病率和死亡率相关。CLI 和糖尿病相关的不愈合伤口和坏疽导致超过130 K的主要肢体 截肢和超过20亿美元的医疗费用在美国每年。有一个强大的 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，以消除大截肢的需要。细胞- 基础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。骨髓源性组织修复细胞（TRC） 代表诱导治疗性血管生成的替代有益治疗选择， 促进组织再生。然而，将治疗性细胞靶向全身递送至肿瘤细胞是不可能的。 疾病组织，具有一定的优势，局部给药的方法，仍然是一个 艰巨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待递送的细胞的表面， 粘附分子纳米载体可以起到“GPS”的作用，以指导注入的移植细胞到达 通过识别并与对应的粘附分子结合， 选择性表达于损伤组织中活化的内皮上。一旦锚定在 活化的内皮，纳米载体包被的细胞外渗并回到靶组织， 发挥其治疗作用。因此，我们建议测试和优化这一新开发的 靶向细胞递送平台，以特异性地和有效地引导TRC归巢到缺血和 以实现治疗性血管生成和组织修复。我们的建议适用于新的 一种细胞表面修饰的靶向细胞递送方法、新鼠坏疽和强力猪 测试新型纳米载体介导的靶向细胞疗法的可行性和功效的伤口模型 促进组织新生血管形成和组织修复。拟议的研究可翻译为 为临床试验开发和优化安全有效的细胞疗法。它可以提供一个 推进和改变PAD/CLI非侵入性治疗领域的新范例。

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.