Combined magnetophoresis and photodynamic therapy for the treatment of TNBC

三阴性乳腺癌（TNBC）对一些最有效的治疗方法没有反应， 乳腺癌的治疗即使是积极的手术，即乳房切除术，也不能改善结果。事实上，患者 接受保乳手术（BCS）和放射治疗的乳腺癌患者表现出更好的特异性和整体 对于转移性和非转移性疾病，生存率高于接受乳房切除术的患者。这是 被认为是由于辐射引起的远位效应。因此，我们假设， 治疗既能改善BCS期间的局部区域控制，又能增强远端效应， 目前的护理标准。一种这样的选择是光动力疗法（PDT）。我们将利用间皮素靶向 光敏剂（PS）。我们以前已经发现，间皮素在大多数TNBC中强烈表达， 并且表达与总体存活率和疾病特异性存活率高度相关。 由于大多数PS是亲脂性的，因此它们通常被封装在纳米颗粒内以改善它们的溶解性并 促进全身递送。纳米颗粒可以设计成携带高PS有效载荷，延长PS循环 时间，改善肿瘤积聚，并通过最小化健康组织中的PS摄取来减少脱靶光毒性。 然而，为了最大化纳米颗粒的益处，必须开发新的纳米制剂， 使活性氧物质产生的自猝灭最小化。此外，新战略必须 建立了有助于促进PS负载的纳米颗粒渗透到肿瘤中。 最近，我们发现两亲性光敏剂二氢卟酚e6（Ce 6）能够形成稳定的水溶性 超顺磁性氧化铁纳米颗粒（SPION）的纳米团簇上的涂层。由于独特的方向 的Ce 6在SPION表面上，很少或没有观察到单线态氧产生的淬灭。这导致 在TNBC的鼠模型中有效使用Ce 6-涂覆的SPION纳米团簇（CSN）作为PDT剂， 肿瘤生长的显著减缓。本提案的总体目标是通过以下方式改进这项工作： 将CSN与间皮素靶向和磁电泳结合以提高特异性、积累， 渗透性和CSN在治疗TNBC中的功效。将使用自定义磁性材料应用磁泳， 该装置可以径向地 深刻 从活体的任何位置分散CSN。这项创新技术将 提高CSN达到预定目标的能力。这项建议的具体目标是 目标1.合成和表征间皮素靶向的Ce 6-包覆的物理化学性质 SPION纳米团簇（CSN）和表征第二代磁性器件;目的2。评估肿瘤 CSN在TNBC鼠模型中的积累和渗透;目的3.评价的疗效和毒性 在TNBC的鼠模型中用CSN进行PDT。

Triple negative breast cancer (TNBC) does not respond to some of the most effective therapies available for breast cancer treatment. Even aggressive surgery, i.e. mastectomy, does not improve outcome. In fact, patients receiving breast conserving surgery (BCS) and radiation therapy exhibit better breast cancer specific and overall survival than patients that undergo a mastectomy, for both metastatic and non-metastatic disease. This is thought to be due to the radiation-induced abscopal effect. Therefore, we hypothesize that and adjuvant treatment that can both improve local regional control during BCS and enhance the abscopal effect could improve the current standard of care. One such option is photodynamic therapy (PDT). We will utilize mesothelin-targeted photosensitizers (PS). We have previously found that mesothelin is strongly expressed in the majority of TNBCs and expression is highly associated with both overall and disease-specific survival. Since most PS are lipophilic, they are often encapsulated within nanoparticles to improve their solubility and to facilitate systemic delivery. Nanoparticles can be designed to carry high PS payloads, extend the PS circulation time, improve tumor accumulation, and reduce off-target phototoxicity by minimizing PS uptake in healthy tissue. However, in order to maximize the benefit of nanoparticles, new nanoformulations must be developed that minimize the self-quenching of reactive oxygen species generation. Moreover, new strategies must be established to help facilitate the penetration of PS-loaded nanoparticles into tumors. Recently, we found that the amphiphilic photosensitizer Chlorin e6 (Ce6) was able to form a stable, water-soluble coating on nanoclusters of superparamagnetic iron oxide nanoparticles (SPIONs). Due to the unique orientation of Ce6 on the SPION surface, little to no quenching of singlet oxygen production was observed. This led to the effective use of the Ce6-coated SPION nanoclusters (CSNs) as a PDT agent in a murine model of TNBC, leading to a significant slowing of tumor growth. The overall goal of this proposal is to improve upon this work by combining CSNs with mesothelin-targeting and magnetophoresis to improve the specificity, accumulation, penetration, and efficacy of CSNs in treating TNBC. Magnetophoresis will be applied using a custom magnetic device that can radially profoundly disperse CSNs from any location in a living subject. This innovative technology will improve the ability of CSNs to reach their intended targets.The specific aims for this proposal are as follows: Aim 1. Synthesize and characterize the physical-chemical properties of mesothelin-targeted, Ce6-coated SPION nanoclusters (CSNs) and characterize a 2nd generation magnetic device; Aim 2. Evaluate the tumor accumulation and penetration of CSNs in a murine model of TNBC; Aim 3. Evaluate the efficacy and toxicity of PDT with CSNs in a murine model of TNBC.