Photodestruction of Ovarian Cancer: ErbB3 Targeted Apta*

描述（由申请人提供）： 光敏剂纳米颗粒适体缀合物疗法（SNACT）是靶向光动力疗法（PDT）的应用，涉及施用封装在适体结合的纳米颗粒（NP）中的光敏剂（PS），然后光活化光敏剂纳米颗粒适体缀合物（SNAC）。由于适体的靶定位能力和照明的空间控制提供的双重选择性，因此与放射性和化学缀合物相关的全身毒性可以在SNACT中显著降低。本研究的目的是开发针对ErbB 3的SNACT，用于破坏微小残留卵巢癌（OVCA）。选择ErbB 3作为分子靶点是基于：（I）ErbB 3在许多癌症中过表达，包括OVCA，（ii）ErbB 3与ErbB 1和ErbB 2协同作用; ErbB 3的失活原则上可以抑制ErbB 1和ErbB 2途径，所述途径由ErbB 1的异源二聚化刺激，和（iii）公开了靶向ErbB 3的适体A30的序列，从而使合成成为可能。适体具有优于靶向剂如单克隆抗体的优势;这些优势包括更高的特异性、相对小的尺寸、易于合成和不存在免疫原性。这些项目的基本组成部分是：（一）合成和稳定SNAC，（二）在体外和体内演示SNAC的选择性光毒性，（三）开发量子点光学成像技术，作为疗效和剂量测定参数的报告者。这项研究是三名研究人员的合作，每个人都有三个组成部分之一的专业知识，据我们所知，这将是第一个使用基于适体的靶向PDT的研究;这将为高度选择性的外部激活疗法提供一个模型，这种方法可以适应其他靶点，因为试剂变得可用。所提出的适配体A30识别ErbB 3，并且PS是包封在PLGA中的苯并卟啉衍生物单酸（BPD）。BPD被批准为年龄相关性黄斑变性的一线治疗，PLGA被FDA批准用于一些临床试验。SNAC将表征光化学和生物化学性质以及与靶细胞和非靶细胞的相互作用。在体内，SNACT将在短期肿瘤减少和长期生存研究中在具有不同ErbB 3表达水平的人OVCA异种移植模型中进行研究。所设想的研究提供了基于纳米载体的、高选择性的、外部激活的多功能治疗剂，其具有有效的光学报告物。这些研究将提供一种新的方法来治疗一种生存统计数据令人沮丧的疾病，并将解决妇女严重的公共卫生问题;拟议的体内光学成像研究，如果成功的话，将提供患者定制的治疗。

DESCRIPTION (provided by applicant): PhotoSensitizer Nanoparticle Aptamer Conjugate Therapy (SNACT) is an application of targeted photodynamic therapy (PDT) involving the administration of a photosensitizer (PS) encapsulated in aptamer-bound nanoparticles (NP), followed by light activation of the PhotoSensitizer Nanoparticle Aptamer Conjugate (SNAC). The systemic toxicity associated with radio- and chemo-conjugates may thus be significantly reduced in SNACT due to the dual selectivity provided by the target localizing ability of the aptamer and the spatial control of illumination. The goal of this research is to develop SNACT targeted to ErbB3 for the destruction of minimal residual ovarian cancer (OVCA). The choice of ErbB3 as the molecular target is based on: (I) ErbB3 is overexpressed in many cancers, including OVCA, (ii) ErbB3 works in concert with ErbB1 and ErbB2; inactivation of ErbB3 could, in principle, inhibit the ErbB1 and ErbB2 pathways that are stimulated by heterodimerization with ErbB1, and (iii) the sequence for aptamer A30 targeted to ErbB3 is published, thus making the synthesis possible. Aptamers have advantages over targeting agents such as monoclonal antibodies; these include higher specificity, relatively small size, ease of synthesis, and absence of immunogenicity. The essential components of the projects are: (i) synthesis and stabilization of SNACs, (ii) demonstration of the selective phototoxicity of SNACs in vitro and in vivo, and (iii) development of optical imaging techniques with quantum dots to serve as reporters of therapeutic efficacy and of dosimetry parameters. The study is a collaboration of three investigators, each with expertise in one of the three components, and will be, to our knowledge, the first using aptamer-based targeted PDT; this will provide a model for a highly selective, externally activated therapy, an approach that can be adapted for other targets as reagents become available. The proposed aptamer A30 recognizes ErbB3, and the PS is benzoporphyrin derivative monoacid (BPD) encapsulated in PLGA. BPD is approved as the first-line therapy for age-related macular degeneration and PLGA is FDA-approved for a few clinical trials. The SNACs will be characterized for photochemical and biochemical properties and interactions with target and non-target cells. In vivo, SNACT will be investigated in xenograft models of human OVCA with different levels of ErbB3 expression in short-term tumor reduction and long-term survival studies. The envisioned studies provide nanovector-based, highly selective, externally activated multifunctional therapeutics with optical reporters of efficacy. These studies will provide a new approach for the treatment of a disease with dismal survival statistics and will address a serious public health concern for women; the proposed in vivo optical imaging studies, if successful, would provide patient-customized therapy.