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

鲜红斑痣是一种先天性进行性皮肤毛细血管畸形。 在585-600 nm的可见波长范围内的脉冲染料激光（POL）照射仍然存在 作为治疗的黄金标准。基本的治疗原则是基于 通过血红蛋白吸收POL光以诱导不可逆的光热凝固， 脉管系统然而，由于不充分的免疫原性，使用POL的治疗功效仍然有限。 光在皮肤中的穿透以及表皮黑色素的非特异性吸收。 只有约20%的患者达到临床可接受的结果，且收益递减 超过五个疗程。我们的长期目标是开发一种新的治疗方法 一种基于光学微粒血管内给药的方法， 红细胞，作为在755 nm处的脉冲近红外（NIR）激光治疗的目标。这些 微粒掺杂有吲哚菁绿色（ICG），其是唯一经FOA批准的NIR发色团。的 基本前提是基于黑色素对光的吸收减少，强烈的ICG吸收， 以及755 nm皮肤激光的可用性。一个特别创新的特点， 这些微粒的一个重要原因是它们的膜富含胆固醇， 磷脂酰丝氨酸从膜的内叶到外叶， 否则用作从脉管系统中去除颗粒的信号。我们称这些 微粒子作为c- μ NET。通过使用c-μ NET，我们旨在延长ICG的循环时间， 增加其在病变血管系统中的可用性，以便可以治疗更多部位 在给定的会话期间，最终导致最小的治疗会话以清除 污点另一个创新方面是使用转基因小鼠，其黑色素含量可以 以可控的方式变化，以模拟PWS的表皮反应， 不同的色素对755 nm激光照射。我们将用这些老鼠来确定 激光辐射对表皮和血管损伤的阈值 光凝结合c-μ NET。我们还将使用兔子模型， 表征c-μ NET的循环和生物分布动力学，确定 使用c型-µ NET时的治疗时间窗，并评估相关的血管反应 激光辐照参数和c-μ NET剂量。SA 1：制造和表征c-μ NET。SA 图2：描述c-μ NET的循环和生物分布动力学。SA 3：评价 c-µ NET结合脉冲NIR激光照射的治疗效果。一个关键 我们建议的研究结果是，我们将知道最长的时间， 当使用c-μ NET时，可以实现有效的血管光凝，此外， 寻找皮肤血管光凝的适当辐射暴露水平 有各种色素这方面的知识目前尚不具备，但却是必要的 为PWS患者的激光治疗制定安全有效的方案。提出 研究与NIAMS在开发有效疗法方面的科学主题一致， PWS。

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.