Targeting solid-tumor vasculature with coencapsulated arsenic- and platinum-based

使用共封装的砷和铂基靶向实体瘤脉管系统

基本信息

批准号：
8642154
负责人：
Meenakshi Upreti
金额：
$ 16.08万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8642154
关键词：
Acute Address Adverse effects Amino Acids Angiogenic Peptides Antigens Arsenic Arsenic Trioxide Arsenicals Binding Biodistribution Biological Availability Blood Circulation Blood Vessels Cell Death Cisplatin Coculture Techniques Combined Modality Therapy Comorbidity Development Dose Drug Delivery Systems Drug Exposure Drug Formulations Drug resistance Drug usage Encapsulated Endothelial Cells Environment FDA approved Fluorescence Microscopy Galectin 1 Goals Half-Life In Vitro Ionizing radiation Ions Label Ligands Limb structure Liposomes Localized Malignant Neoplasm Location MEKs Malignant Neoplasms Mammary Neoplasms Modality Modeling Monitor Mus Nanotechnology Nude Mice Peptides Pharmaceutical Preparations Pharmacotherapy Pilot Projects Platinum Positron-Emission Tomography Radiation Radiation therapy Research Resistance Role Signal Transduction Site Solid Neoplasm Structure Technology Testing Therapeutic Toxic effect Translating Treatment Efficacy Tumor-Associated Vasculature Up-Regulation Vascular Endothelial Cell Vesicle angiogenesis base cancer therapy carbohydrate binding protein chemotherapy cytotoxic cytotoxicity effective therapy fluorescence imaging improved in vivo irradiation nanomaterials nanomedicine nanoparticle nanoparticulate nanosized nanovesicle neoplastic cell novel novel strategies overexpression pre-clinical public health relevance response standard care targeted delivery treatment response tumor tumor microenvironment uptake

项目摘要

DESCRIPTION (provided by applicant): A major challenge the application of nanotechnology to cancer therapy is targeting of the nanomaterials specifically to the tumor itself. Although both arsenic and platinum based drugs used in cancer therapy have displayed significant response in certain tumor types, their therapeutic applications are limited by serious systemic toxicities, limited bioavailability to the tumor site and development of drug resistance by tumor cells. We propose to address these challenges by preferentially targeting an arsenic-cisplatin nanoparticulate formulation encapsulated in liposomal vesicles called "nanobins" to the tumor site using the anti-angiogenic peptide, anginex. This peptide specifically binds to galectin-1, a tumor endothelial cell specific antigen that is induced in response to radiation. The novel nanobin formulation developed by our collaborator (O'Halloran) to be used in the present project utilizes a gradient of cisplatin ions to facilitate stable coencapsulation of Arsenic trioxide. The inclusion of the arsenic compound in the nanovesicle is expected to make the tumor targeted delivery more active against solid tumors by causing vascular damage and by overcoming resistance of tumor cells to conventional chemotherapy. The 33 amino acid, small peptide, anginex, will be the galectin-1 targeting agent to deliver arsenic and platinum drugs co-encapsulated in a single liposomal vesicle to the irradiated tumor site. It is expected that targeted delivery of liposomal cytotoxic payloads like the dual-drug nanobins via the anginex peptide to radiation-induced galectin-1 in the tumor-vasculature will increase the therapeutic ratio of such novel strategies developed against solid tumors.

描述（由申请人提供）：将纳米技术应用于癌症治疗的一个主要挑战是将纳米材料专门针对肿瘤本身。虽然两者用于癌症治疗的砷和铂基药物在某些肿瘤类型中表现出显着的反应，但其治疗应用受到严重的全身毒性、肿瘤部位的生物利用度有限以及肿瘤细胞产生耐药性的限制。我们建议通过使用抗血管生成肽anginex优先将封装在称为“纳米宾”的脂质体囊泡中的砷-顺铂纳米颗粒制剂靶向肿瘤部位来应对这些挑战。该肽与半乳糖凝集素-1 (galectin-1) 特异性结合，半乳糖凝集素-1 是一种肿瘤内皮细胞特异性抗原，可响应辐射而诱导产生。我们的合作者（O'Halloran）开发的用于本项目的新型纳米宾制剂利用顺铂离子梯度来促进三氧化二砷的稳定共封装。这纳米囊泡中包含砷化合物有望通过引起血管损伤和克服肿瘤细胞对常规化疗的耐药性，使肿瘤靶向递送对实体瘤更加有效。 33 个氨基酸、小肽、anginex 将作为 galectin-1 靶向剂，将共同封装在单个脂质体囊泡中的砷和铂药物输送到受辐射的肿瘤部位。预计通过anginex肽向肿瘤脉管系统中辐射诱导的半乳糖凝集素-1靶向递送脂质体细胞毒性有效负载（例如双药纳米粒子）将增加针对实体瘤开发的此类新策略的治疗率。