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

用于鲜红斑痣近红外光疗的红细胞衍生颗粒。

• 批准号: 10580669
• 负责人: BAHMAN ANVARI
• 金额: $ 51.52万
• 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 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10580669
• 关键词: Animal Model; Animals; Biodistribution; Biological Assay; Blood; Blood Vessels; Blood capillaries; Characteristics; Cholesterol; Circulation; Clinical; Coagulation Process; Darkness; Dermal; Dermatologic; Deterioration; Development; Dorsal; Dose; Dyes; Ensure; Erythrocytes; Euthanasia; Excision; Fluorescence; Half-Life; Hemoglobin; Histologic; Histology; Hour; Human; Indocyanine Green; Injections; Injury; Knowledge; Laser Speckle Imaging; Lasers; Length; Lesion; Light; Light Coagulation; Measurement; Measures; Melanins; Membrane; Modeling; Mus; National Institute of Arthritis, and Musculoskeletal, and Skin Diseases; New Zealand; Optics; Organ; Oryctolagus cuniculus; Outcome; Patients; Penetration; Phosphatidylserines; Phototherapy; Physiologic pulse; Pigmentation physiologic function; Pigments; Port-Wine Stain; Protocols documentation; Quality Control; Reproducibility; Research Personnel; Signal Transduction; Site; Skin; Stains; Temperature; Therapeutic; Time; Tissues; Transgenic Mice; Treatment Effectiveness; Treatment Efficacy; Visualization; absorption; chromophore; clinical application; effective therapy; effectiveness evaluation; efficacy evaluation; experimental study; fluorescence imaging; innovation; irradiation; malformation; novel therapeutic intervention; particle; patient population; prevent; psychologic; response; skin color; skin disorder; standard care; zeta potential

Port wine stain (PWS) is a congenital and progressive malformations of the dermal capillaries. Pulsed dye laser (POL) irradiation in the visible wavelength range of 585-600 nm remains as the gold standard of treatment. The underlying treatment principle is based on the absorption of POL light by hemoglobin to induce irreversible photothermal coagulation of the vasculature. However, therapeutic efficacy with POLs remains limited due to insufficient penetration of light in skin, and non-specific absorption by the epidermal melanin pigments. Clinically acceptable outcomes are achieved in only about 20% of patients with diminishing returns beyond five treatment sessions. Our long-term objective is the development of a new therapeutic approach based on intravascular administration of optical micro-particles, fabricated from erythrocytes, as targets for pulsed near infrared (NIR) laser treatment at 755 nm. These micro-particles are doped with indocyanine green (ICG), the only FOA-approved NIR chromophore. The underlying premise is based on reduced absorption of light by melanin, strong ICG absorption, and availability of dermatological lasers at 755 nm. A particularly innovative feature of these micro-particles is that their membrane is enriched with cholesterol to prevent the flipping of phosphatidylserine from the inner to the outer leaflet of the membrane, which would otherwise serve as a signal for removal of the particles from the vasculature. We refer to these micro-particles as c⁺- µNETs. By using c⁺-µNETs, we aim to prolong the circulation time of ICG, and increase its availability in the lesion vasculature so that more sites can be treated during a given session, ultimately leading to minimal therapeutic sessions to clear the stain. Another innovative aspect is the use of transgenic mice whose melanin content can be varied in a controllable manner to simulate the epidermal response of PWS with different pigmentations to 755 nm laser irradiation. We will use these mice to determine the threshold values of the laser radiant exposures for epidermal injury and blood vessels photocoagulation in conjunction with c⁺-µNETs. We will also use a rabbit model to characterize the circulation and biodistribution dynamics of c⁺-µNETs, determine the therapeutic window of time when using c⁺-µNETs, and evaluate the vascular response as it relates to laser irradiation parameters and dose of c⁺-µNETs. SA 1: Fabricate and characterize c⁺-µNETs. SA 2: Characterize the circulation and biodistribution dynamics of c⁺-µNETs. SA 3: Evaluate the therapeutic efficacy of c⁺-µNETs in conjunction with pulsed NIR laser irradiation. A key outcome of our proposed studies is that we will know the maximum length of time over which effective blood vessels photocoagulation can be achieved when using c⁺-µNETs, in addition to finding the appropriate radiant exposure levels for vascular photocoagulation in skins with various pigmentations. This knowledge is not currently available, but is essential towards development of safe and effective protocols for laser treatment of PWS patients. Proposed studies are consistent with the scientific themes of NIAMS in developing effective therapies for PWS.

葡萄酒污染（PWS）是真皮毛细血管的先天性和渐进性畸形。 脉冲染料激光（POL）在可见波长范围为585-600 nm的可见范围 作为黄金治疗标准。基础治疗原则是基于 血红蛋白吸收pol光，以诱导不可逆的光热凝血 脉管系统。但是，由于不足 皮肤中光的渗透以及表皮黑色素色素的非特异性滥用。 临床上可接受的结果仅在约20％的回报率下降的患者中实现 超出五个治疗课程。我们的长期目标是开发新的治疗性 基于光学微粒的血管内给药的方法，由 红细胞作为755 nm的红外（NIR）激光处理的脉冲靶标。这些 微粒子与吲哚烷绿色（ICG）掺杂，这是唯一的FOA批准的NIR发色团。这 潜在的信念是基于黑色素的光线遗憾，强烈的ICG遗憾， 以及755 nm的皮肤激光器的可用性。一个特别创新的特征 这些微粒子是它们的膜富含胆固醇，以防止翻转 磷脂酰丝氨酸从膜的内部到外小叶，将 否则用作从脉管系统中去除颗粒的信号。我们指的是这些 微粒作为c⁺-µnet。通过使用c⁺-µnet，我们旨在延长ICG的循环时间，并 增加其在病变脉管系统中的可用性，以便可以治疗更多的站点 在给定的课程中，最终导致最少的治疗课程清除 弄脏。另一个创新的方面是使用黑色素含量的转基因小鼠的使用 以受控方式变化，以模拟PW的表皮反应 不同的色素到755 nm激光照射。我们将使用这些小鼠来确定 激光辐射暴露于表皮损伤和血管的阈值 与C⁺-µNets结合的光凝。我们还将使用兔子模型 表征C⁺-µNets的循环和生物分布动力学，确定 使用C⁺-µNET时的治疗时间窗口，并评估血管反应 到激光辐照参数和C⁺-µNets的剂量。 SA 1：制造并表征C⁺-µNet。 SA 2：表征C⁺-µNets的循环和生物分布动力学。 SA 3：评估 C⁺-µNet的治疗效率与脉冲NIR激光照射结合使用。钥匙 我们提出的研究的结果是，我们将知道 当使用C⁺-µNets时，还可以实现有效的血管光血管 在皮肤中找到适当的辐射暴露水平以进行血管光凝水平 带有各种色素。这些知识目前尚不可用，但至关重要 拟议开发用于PWS患者激光治疗的安全有效方案。 研究与NIAM的科学主题一致，开发​​有效的疗法 PWS。