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

鲜红斑点(PWS)是一种先天性进行性皮肤毛细血管畸形。 585-600 nm可见波长范围内的脉冲染料激光(POL)照射 作为治疗的黄金标准。基本的治疗原则是基于 血红蛋白对POL光的吸收诱导不可逆的光热凝血 脉管系统。然而，由于治疗效果的不足，POLS的治疗效果仍然有限。 光在皮肤中的穿透性，以及表皮黑色素的非特异性吸收。 只有大约20%的患者获得了临床可接受的结果，但收益递减。 超过五次治疗疗程。我们的长期目标是开发一种新的治疗方法 基于血管内给药光学微粒的方法，由 红细胞，作为755 nm脉冲近红外(NIR)激光治疗的目标。这些 微粒中掺杂了吲哚青绿(ICG)，这是FOA批准的唯一近红外发色团。这个 潜在的前提是黑色素对光的吸收减少，ICG吸收强烈， 以及皮肤科755 nm激光的可用性。的一个特别创新的功能 这些微粒是因为它们的膜上富含胆固醇，以防止翻转 从膜的内叶到外叶的磷脂酰丝氨酸，这将 否则用作从血管系统中移除颗粒的信号。我们指的是这些 微粒子为c⁺-µNet。通过使用c⁺-µNet，我们的目标是延长ICG的循环时间，并 增加其在病变血管系统中的可用性，以便可以治疗更多的部位 在给定的疗程中，最终导致最少的治疗疗程以清除 污渍。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 对755 nm激光照射不同的着色剂。我们将用这些老鼠来确定 激光照射对皮肤损伤和血管损伤的阈值 结合c-⁺-微网进行光凝治疗。我们还将使用兔子模型来 表征c⁺-uNet的循环和生物分布动力学，确定 使用c⁺-µNet时的治疗时间窗，并评估相关的血管反应 C⁺-µNet的激光照射参数和剂量。SA 1：c⁺-µNet的制造和表征。Sa 2：表征c⁺-µNet的循环和生物分布动力学。回答3：评估 C⁺-µNet联合脉冲近红外激光照射的疗效观察一把钥匙 我们建议的研究结果是，我们将知道 使用c⁺-µNet时，除了 寻找皮肤中血管光凝的适当辐射曝光量 有各种各样的色素沉着。这方面的知识目前还不可用，但很重要。 开发安全有效的激光治疗PWS患者的方案。建议 在开发有效的治疗方法方面，研究与NIAMS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.