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

基本信息

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
项目类别：
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

项目摘要

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（由应用程序提供）：港口葡萄酒污渍（PWSS）是真皮毛细血管的先天性和渐进性畸形。从组织病理学上讲，PWS的特征是直径的直肠毛细血管的特征，其直径的范围从约10 µm到大至≈600µm，并且通常位于皮肤表面以下300-500 µm的深度。 PWS是一种潜在的心理和身体并发症的疾病，极大地损害了受苦的人的生活质量。当前，唯一可行的治疗方法是基于使用可见波长的Laer辐照，以热破坏异常的脉管系统。但是，可能的污渍对当前的激光治疗方法具有抗药性，因为可见的激光辐射参数并不能达到不可逆地破坏血管所必需的关键核心温度，尤其是在更深的皮肤位置（> 300 µm），这对于许多治疗性治疗所必需的，以达到完全褪色的效果。此外，由于上覆的表皮的非特异性加热，大量具有中度至重色素（中度棕色至黑色皮肤）的患者无法受益于激光治疗。我们的最终目标是开发一种基于激光的方法，该方法可用于治疗电阻污渍，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由FDA批准的近红外（NIR）发色团，吲哚氰胺绿（ICG）组成的光学蔬菜，该蔬菜由源自红细胞的膜封装。我们将这些蔬菜称为近红外红细胞模拟传感器（NETS）。一旦通过NIR激光辐射激活，这些蔬菜将光能转化为热量，从而导致血管的热破坏。我们将这种方法称为激光疗法（LET）。 NIR激光照射的优势在于，它可以使光更深地渗透到皮肤中，并减少由于黑色素肌瘤吸收降低而导致非特异性表皮加热的ISK。网络作为增强血管内NIR吸收的外源性发色团的潜在优势是在脉管系统内的潜在较长循环时间，以扩展可以进行允许进行治疗的时间窗口，并可以进行预期的生物相容性。该应用程序的总体主题是确定基于确定最佳ICG含量，直径和相对数量浓度的网络的适当公式，这将导致具有适当的光学特性的最大血管保留时间，以及最佳的NIR辐照参数，从而导致深层血管辐射参数没有对表皮的非特异性热损伤的损伤。为此，我们的方法将集中在各种网络的物理特征上，其光学特性的量化，其在健康小鼠中的生物分布，数学模型，以预测因这些配方而导致的NIR激光照射的温度分布，以及由于这些公式而导致的，以及最终涉及Rabbit Ellobe Ellobe Ellobe Ellobe EllobeTator In-Vivo In-Vivo Nir Laser Interabe PWSS的模型注入了此类网络公式。我们还将评估这些公式在小鼠中的潜在毒性和免疫原性。该项目完成后，我们将确定网络的适当公式，并可以在本申请后的下一个赠款期间使用该信息指导我们的人类实验研究。该多PI应用程序将在加利福尼亚大学（UCR）生物工程教授巴曼·安瓦里（Bahman Anvari）的领导下以及贝克曼·激光学院（Beckman Laser Institute and Medical Clinic（Blimc））的医疗总监J. S. Nelson博士（Blimc），加利福尼亚大学（UCI）。 Anvari博士将监督整个项目，并总体上负责协调和管理该项目。在他的监督下将进行网络的制造和表征，生物分布，毒性和免疫原性研究。他还将与尼尔森博士的小组紧密合作，以定量光学性质，数学模型的发展和体内动物激光照射研究。其他主要合作人员是医学博士David LO（UC Riverside），他们将在小鼠的免疫原性研究设计方面提供专业知识，并评估这些结果； Wangcun Jia博士（UC Irvine）将参与量化光学性质，数学模型的发展以及兔子的体内激光照射；以及Stephen Griffey博士，DVM（UC Davis），他们将使用血液学分析，血清化学和组织病理学评估来支持我们对网络的毒性评估。