Photodestruction of Ovarian Cancer: ErbB3 Targeted Aptamer Nanoparticle Conjugate

卵巢癌的光破坏：ErbB3 靶向适体纳米颗粒缀合物

基本信息

批准号：
7916146
负责人：
Tayyaba Hasan
金额：
$ 15.64万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7916146
关键词：
Address Age related macular degeneration Animal Model Applications Grants Area Arterial Fatty Streak Binding Biochemical Biodegradation Biological Blindness Boston Carcinomatosis Cardiovascular Diseases Cell Line Cells Cisplatin Cities Clinical Clinical Trials Collaborations Complement Development Diagnosis Disease Disease Resistance Drug resistance ERBB2 gene Effectiveness Elderly Encapsulated Engineering Ensure Epidermal Growth Factor Receptor Event FDA approved Family Fiber Optics Figs - dietary Floor Fluorescence General Hospitals Glycolates Goals Heterodimerization Hospitals Human Image Imaging Techniques Imaging technology In Vitro Institutes Investigation Ions Kinetics Knowledge Laboratories Legal patent Letters Light Lighting Malignant - descriptor Malignant Neoplasms Malignant neoplasm of ovary Malignant neoplasm of prostate Massachusetts Measurement Mediating Methods Modality Modeling Molecular Molecular Target Monitor Monoclonal Antibodies Monoclonal Antibody C225 Mus Normal tissue morphology Nucleic Acids Operative Surgical Procedures Optical Coherence Tomography Optical reporter Optics Pathology Pathway interactions Patients Peptide antibodies Peptides Pharmaceutical Preparations Photochemistry Photochemotherapy Photosensitizing Agents Phototoxicity Play Poison Polymers Postdoctoral Fellow Preparation Principal Investigator Property Proteins Public Health Publishing Quantum Dots Radio Reaction Reagent Reporter Reporting Research Research Personnel Residual Tumors Residual state Resistance Resistance development Role Running Scientist Services Signal Transduction Singlet Oxygen Solutions Solvents Specificity Techniques Technology Testing Therapeutic Time Tissues Toxic effect Training Treatment Efficacy Treatment Protocols Tumor Burden Tumor Tissue Visible Radiation Woman Work Xenograft Model advanced disease anticancer research aptamer base cancer cell cancer therapy chemotherapy cytotoxicity design dosimetry effective therapy efficacy evaluation established cell line experience fluorescence imaging imaging modality immunogenicity in vivo in vivo Model instrument interest intraperitoneal malignant mouth neoplasm medical schools member molecular imaging nano nanoparticle nanovector novel strategies optical imaging overexpression post-doctoral training programs radiation resistance receptor research study response singlet state statistics success tumor uptake

项目摘要

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.

描述（由申请人提供）：光敏剂纳米颗粒偶联疗法（SNACT）是针对性光动力疗法（PDT）的应用，涉及在适体结合的纳米颗粒（NP）中封装的光敏剂（PS）的应用，随后光激活了光（光（NP）的光激活）。因此，由于适体的目标定位能力和照明的空间控制，与无线电和化学偶联物相关的全身毒性可能会显着降低snact。这项研究的目的是开发针对ERBB3的SNACT，以破坏最小残留卵巢癌（OVCA）。 ERBB3作为分子靶标的选择是基于：（i）在包括OVCA，（ii）ERBB3在内的许多癌症中ERBB3过表达的ERBB3与ERBB1和ERBB2一起工作； ERBB3的灭活原则上可以抑制通过与ERBB1异二聚化刺激的ERBB1和ERBB2途径，并且（iii）（iii）发布了针对ERBB3的适体A30的序列，从而发表了合成，从而使合成成为可能。适体比单克隆抗体等靶向剂具有优势。这些包括较高的特异性，相对较小的大小，易于合成以及没有免疫原性。项目的基本组成部分是：（i）SNAC的合成和稳定，（ii）证明SNAC在体外和体内的选择性光毒性，以及（iii）使用量子点开发具有量子点的光学成像技术，以作为治疗效率和Dosimetry parametry参数的记者。这项研究是由三个研究人员组成的，每个研究人员都在三个组成部分之一中具有专业知识，据我们所知，这是第一次使用基于适合APTAMER的目标PDT；这将为高度选择性，外部激活的疗法提供模型，这种方法可以在可用的情况下适用于其他靶标。提出的适体A30识别ERBB3，PS是封装在PLGA中的苯二甲胺衍生物单酸（BPD）。 BPD被批准为与年龄相关的黄斑变性的一线治疗，并且PLGA被FDA批准用于一些临床试验。 SNAC将以光化学和生化特性以及与目标和非目标细胞的相互作用进行特征。在体内，将研究在短期肿瘤减少和长期生存研究中具有不同水平ERBB3表达的人OVCA的异种移植模型。这些设想的研究提供了具有疗效的光学记者的基于纳米植物的，高度选择性的外部激活的多功能治疗剂。这些研究将为治疗疾病的生存统计数据提供新的方法，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）将提供患者的治疗。