Raising the Therapeutic Index of Photodynamic Therapy with Targeted Nanosyringes

摘要 目前临床光动力疗法(PDT)是一种有效的非侵入性、低成本的肿瘤治疗方法。 成本，但它尚未成为主流的一线治疗。光动力疗法治疗实体瘤的临床疗效 取决于光敏剂(PS)在肿瘤部位的显著积累，附近氧气的可获得性 光敏剂，以及药物-光组合的有效剂量。我们的新交付平台和 光敏剂的成像，名为纳米使能光动力疗法(NePDT)，将增强所有这三个区域，提高 光动力疗法的治疗指标，使光动力疗法充分发挥其临床潜力。 NePDT由含吲哚青绿(Icg)的富氧液体全氟碳(Pfc)组成。 由含有光敏剂(PS)的脂壳稳定的染料，也为癌症提供结合部位 细胞靶向抗体。ICG染料用于触发PFC的液-气相转变 有两个用途：(1)它将PS和额外的O2输送到细胞胞浆(充当纳米注射器)和(2) 汽化事件产生了一个巨大的声音瞬变，可以使用组合光声和 超声(PAUS)成像，用于可视化药物在肿瘤部位的分布。从 Paus成像接收到丰富的三维空间信息的药物分布、光照强度和持续时间 有效光动力疗法的剂量学可以计算出来。这种个性化的剂量测定将确保患者获得 为他们的肿瘤量身定制正确的治疗剂量。 光动力疗法承诺提供局部治疗，将对健康的残余损害或副作用降至最低 组织是值得注意的。我们很高兴推出这一新的nePDT平台，它将增强特定的交付 PS对肿瘤的作用，通过氧气输送提高治疗效果(特别是对缺氧肿瘤)，以及 最终创建由Paus成像实现的个性化患者特定剂量。而光动力疗法有潜力 为了治疗各种疾病，我们选择了头颈癌，特别是口腔癌，作为 最初的目标应用是由于临床上未满足的最小干预需求，最小限度减少疤痕 美容和功能缺陷，以及这些肿瘤的表面位置，提供了光线可及性。 NePDT是一种革命性的新纳米平台，能够消除广泛治疗的障碍 光动力疗法的疗效和临床成功。

ABSTRACT Current clinical photodynamic therapy (PDT) is an effective cancer treatment that is non-invasive and low- cost, but it has yet to become a mainstream, frontline treatment. The clinical efficacy of PDT in solid tumors depends on significant accumulation of the photosensitizer (PS) at the tumor site, availability of oxygen near the photosensitizer, and effective dosing of the drug-light combination. Our new platform for delivery and imaging of photosensitizers, entitled nano-enabled PDT (nePDT), will enhance all three of these areas, raising PDT’s therapeutic index and enabling PDT to reach its full clinical potential. nePDT comprises a core of oxygen-rich liquid perfluorocarbon (PFC) containing indocyanine green (ICG) dye stabilized by a lipid shell which houses the photosensitizer (PS) and also provides binding sites for cancer cell targeting antibodies. The ICG dye is used to trigger a liquid to gas phase change of the PFC which serves two purposes: (1) it delivers PS and additional O2 to the cell cytosol (acting as a nanosyringe) and (2) the vaporization event creates a giant acoustic transient which can be detected using combined photoacoustic and ultrasound (PAUS) imaging and used to visualize the distribution of drug delivery at the tumor site. From the rich 3D spatial information received by PAUS imaging of the drug distribution, light intensity and duration dosimetry for effective PDT can be calculated. This personalized dosimetry will ensure patients receive the correct therapy dose customized for their tumor. The promise of PDT to provide localized therapy with minimal residual damage or side effects to healthy tissues is remarkable. We are excited to introduce this new nePDT platform that will enhance specific delivery of PS to the tumor, increase efficacy of therapy through O2 delivery (especially to hypoxic tumors), and ultimately create a personalized patient specific dose enabled by PAUS imaging. While PDT has the potential to treat a variety of diseases, we chose head and neck cancer generally, and specifically oral cancer, for an initial target application due to the unmet clinical need for minimal intervention, minimal scarring to reduce cosmetic and functional defects, and the superficial location of these tumors which provides light accessibility. nePDT is a revolutionary new nanoplatform capable of removing the roadblocks to widespread therapeutic efficacy and clinical success for PDT.