Erythrocyte-derived particles for near infrared phototherapy of port wine stains

用于近红外光疗鲜红斑痣的红细胞衍生颗粒

• 批准号: 9442689
• 负责人: BAHMAN ANVARI
• 金额: $ 33.27万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-10 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9442689
• 关键词: Acute; Animal Model; Animals; Asses; Biodistribution; Biological Assay; Biomedical Engineering; Blood; Blood Circulation; Blood Vessels; Blood capillaries; Caliber; California; Chemistry; Clinic; Clinical; Clinical Management; Dermal; Dermatology; Development; Disease; Doctor of Philosophy; Dyes; Effectiveness; Electron Microscopy; Encapsulated; Engineering; Epidermis; Erythro; Erythrocytes; Evaluation; FDA approved; Fluorescence Spectroscopy; Formulation; Generations; Grant; Heating; Human; Human Resources; Impairment; Incineration; Individual; Indocyanine Green; Injury; Institutes; Lasers; Leadership; Light; Location; Low-Level Laser Therapy; Medical; Melanins; Melanosomes; Membrane; Methods; Modeling; Mus; Optics; Oryctolagus cuniculus; Pathologic; Patients; Penetration; Phototherapy; Physician Executives; Physiologic pulse; Pigmentation physiologic function; Pigments; Port-Wine Stain; Positioning Attribute; Production; Property; Quality of life; Serum; Skin; Stains; Supervision; Surface; Temperature; Theoretical Studies; Therapeutic; Time; Toxic effect; Transducers; Universities; Vesicle; Work; absorption; base; biomaterial compatibility; chromophore; clinically relevant; cytokine; design; experimental study; heat injury; immunogenic; immunogenicity; in vivo; irradiation; light scattering; malformation; mathematical model; nanosized; novel therapeutic intervention; particle; physical property; professor; psychologic; public health relevance; response; skin color; skin disorder; therapy outcome

 DESCRIPTION (provided by applicant): Port wine stains (PWSs) are congenital and progressive malformations of dermal capillaries. Histopathologically, PWSs are characterized by ectatic capillaries with diameters that can range from about 10 µm to as large as ≈ 600 µm, and usually located in depths of ≈ 300-500 µm below the skin surface. PWS is a disease with potentially devastating psychological and physical complications that greatly impairs the quality of life for the afflicted individuals. Currently, the only viable treatment approach is based on laer irradiation, using visible wavelengths, to thermally destroy the abnormal vasculature. However, may stains are resistive to current laser treatment methods since the visible laser irradiation parameters do not achieve the critical core temperature necessary to irreversibly destroy blood vessels, particularly at the deeper skin locations (>300 µm), necessitating many therapeutic sessions to achieve complete fading, if at all. Furthermore, a large segment of patients with moderate to heavy pigmentation (moderate brown to black skin) cannot benefit from laser therapy due to non-specific heating of the overlying epidermis. Our ultimate objective is to develop a laser-based approach that can be used to treat resistive stains, and all patients with PWS regardless of their skin types. Our proposed approach is based on the use of optical vesicles composed of the FDA-approved near infrared (NIR) chromophore, indocyanine green (ICG), encapsulated by membranes derived from erythrocytes. We refer to these vesicles as near infrared erythrocyte-mimicking transducers (NETs). Once activated by NIR laser irradiation, these vesicles transduce the light energy to heat, leading to thermal destruction of blood vessels. We refer to this approach as laser- erythro-therapy (LET). The advantage of NIR laser irradiation is that it allows for deeper penetration of light into the skin, and reduces the isk of non-specific epidermal heating due to reduced absorption by melanosomes. The potential advantages of NETs as an exogenous chromophore to enhance NIR absorption within the blood vessels are in their potentially long circulation time within the vasculature to extend the therapeutic window of time during which LET can be performed, and their expected biocompatibility. The overall subject of this application is to determine the appropriate formulations of NETs, based on identifying the optimal ICG content, diameter, and relative number concentration, that will result in maximum vascular retention time with appropriate optical properties, as well as optimal NIR irradiation parameters that will result in deep vascular injury without non-specific thermal injury to the epidermis. To do so, our approach will be centered upon physical characterizations of various formulation of NETs, quantification of their optical properties, their biodistributions in healthy mice, mathematical models to predict light an temperature distributions in response to NIR laser irradiation due to these formulations, and finally in-vivo NIR laser irradiation studies involving the rabbit earlobe vasculature as an animal model of PWSs injected with such NETs formulations. We will also evaluate the potential toxicity and immunogenic effects of these formulations in mice. Upon completion of this project, we will have identified the appropriate formulations of NETs, and be in a position to use that information in guiding our human experimental studies in the next grant period following this application. This Multi-PI application will be performed under the leaderships of Dr. Bahman Anvari, Professor of Bioengineering at University of California, Riverside (UCR), and Dr. J. S. Nelson, Medical Director of the Beckman Laser Institute and Medical Clinic (BLIMC), University of California, Irvine (UCI). Dr. Anvari will oversee the entire project, and have overall responsibiliy to coordinate and administer the project. Fabrication and characterization of the NETs, biodistribution, toxicity, and immunogenicity studies will be performed under his supervision. He will also work closely with Dr. Nelson's group on quantification of the optical properties, development of mathematical models and in-vivo animal laser irradiation studies. Other key collaborating personnel are David Lo, MD, PhD (UC Riverside) who will provide the expertise in the design of the immunogenic studies in mice, and evaluating those results; Wangcun Jia, PhD (UC Irvine) who will be involved in quantification of optical properties, development of the mathematical models, and in vivo laser irradiation of the rabbits; and Stephen Griffey, PhD, DVM (UC Davis) who will support us in our toxicity evaluations of the NETs using hematological profiling, serum chemistry, and histopathological evaluations.

 描述（由申请人提供）：葡萄酒色斑（PWS）是先天性和进行性皮肤毛细血管畸形。在组织学上，PWS的特征是毛细血管扩张，直径范围从约10 µm到约600 µm， 通常位于皮肤表面以下300-500 µm的深度。PWS是一种具有潜在破坏性心理和身体并发症的疾病，极大地损害了受折磨个体的生活质量。目前，唯一可行的治疗方法是基于使用可见波长的莱尔照射，以热破坏异常脉管系统。然而，由于可见激光照射参数不能达到不可逆地破坏血管所需的临界核心温度，特别是在较深的皮肤位置（>300 µm），因此可能的污渍对当前的激光治疗方法具有抵抗力，如果有的话，则需要许多治疗疗程来实现完全褪色。此外，由于上覆表皮的非特异性加热，大部分具有中度至重度色素沉着（中度棕色至黑色皮肤）的患者不能从激光治疗中受益。我们的最终目标是开发一种基于激光的方法，可用于治疗抵抗性色斑，以及所有PWS患者，无论其皮肤类型如何。我们提出的方法是基于使用的光学囊泡组成的FDA批准的近红外（NIR）发色团，吲哚菁绿色（ICG），封装膜来自红细胞。我们将这些囊泡称为近红外红细胞模拟换能器（NET）。一旦被近红外激光照射激活，这些囊泡将光能转化为热量，导致血管的热破坏。我们将这种方法称为激光红细胞疗法（LET）。NIR激光照射的优点是它允许光更深地穿透到皮肤中，并且由于黑素体的吸收减少而降低了非特异性表皮加热的风险。NET作为外源性发色团以增强血管内NIR吸收的潜在优势在于其在脉管系统内的潜在长循环时间以延长可以进行LET的治疗时间窗，以及其预期的生物相容性。本申请的总体主题是基于识别最佳ICG含量、直径和相对数量浓度来确定NET的适当制剂，其将导致具有适当光学性质的最大血管保留时间，以及确定将导致深血管保留时间的最佳NIR照射参数。 无表皮非特异性热损伤的损伤。为此，我们的方法将集中在各种NET制剂的物理表征，其光学性质的量化，其在健康小鼠中的生物分布，预测由于这些制剂引起的近红外激光照射响应的光和温度分布的数学模型，以及最后涉及兔耳垂脉管系统的体内近红外激光照射研究 注入这种NET制剂的PWS模型。我们还将评估这些制剂在小鼠中的潜在毒性和免疫原性作用。待这项研究计划完成后，我们便会找到合适的NET配方，并可利用这些数据，在申请拨款后的下一个资助期内，指导我们的人体实验研究。本Multi-PI申请将在加州大学滨江分校（UCR）生物工程教授Bahman Anvari博士和J. S.纳尔逊，贝克曼激光研究所和医疗诊所（BLIMC），加州大学欧文分校（UCI）的医学主任。Anvari博士将监督整个项目，并全面负责协调和管理该项目。将在他的监督下进行NET的制造和表征、生物分布、毒性和免疫原性研究。他还将与纳尔逊博士的小组密切合作，对光学特性进行量化，开发数学模型和体内动物激光照射研究。其他主要合作人员是大卫罗，医学博士，博士（加州大学滨江分校），将在小鼠免疫原性研究的设计和评估这些结果方面提供专业知识; Wangcun Jia，博士（UC Irvine），其将参与光学性质的量化、数学模型的开发以及兔子的体内激光照射;和Stephen Griffey博士，DVM（加州大学戴维斯分校），他将支持我们使用血液学分析、血清化学和组织病理学评价对NET进行毒性评价。