Photodestruction of Ovarian Cancer: ErbB3 Targeted Aptamer Nanoparticle Conjugate

描述(由申请人提供)： 光敏剂纳米颗粒适体结合疗法(SNACT)是靶向光动力疗法(PDT)的一种应用，包括给药包裹在适体结合纳米粒(NP)中的光敏剂(PS)，然后光激活光敏剂纳米颗粒适体结合疗法(SNAC)。因此，由于适体的靶点定位能力和光照的空间控制提供的双重选择性，SNACT中与放射和化学结合物相关的全身毒性可能会显著降低。本研究的目标是开发针对ErbB3的SNACT，用于破坏微小残留卵巢癌(OVCA)。选择ErbB3作为分子靶点是基于：(I)ErbB3在许多癌症中过表达，包括OVCA；(Ii)ErbB3与ErbB1和ErbB2协同工作；原则上，失活ErbB3可以抑制由ErbB1异源二聚刺激的ErbB1和ErbB2途径，以及(Iii)靶向ErbB3的适体A30的序列被公布，从而使合成成为可能。与单抗等靶向试剂相比，适配子具有更高的特异性、相对较小的尺寸、易于合成以及没有免疫原性等优点。这些项目的基本组成部分是：(I)SNAC的合成和稳定，(Ii)SNAC在体外和体内的选择性光毒性的演示，以及(Iii)用量子点作为治疗效果和剂量学参数的报告的光学成像技术的发展。这项研究是由三名研究人员合作进行的，每名研究人员都拥有三种成分中的一种专业知识，据我们所知，这将是第一次使用基于适体的靶向PDT；这将为高度选择性的外部激活疗法提供一个模型，这种方法可以随着试剂的出现而适用于其他靶点。所提出的适体A30识别ErbB3，PS是包裹在PLGA中的苯并卟啉衍生物一酸(BPD)。BPD被批准为治疗老年性黄斑变性的一线药物，PLGA被FDA批准用于几项临床试验。SNAC将被表征为光化学和生化特性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，在具有不同水平ErbB3表达的人OVCA异种移植模型中进行研究。这些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方法，并提供了疗效的光学报告。这些研究将为治疗存活率低的疾病提供一种新的方法，并将解决女性面临的一个严重的公共卫生问题；拟议的体内光学成像研究如果成功，将提供患者定制的治疗方法。

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.