Active Delivery of Platinum Nanoimmunoconjugates to Improve Breast Cancer Therapy

主动递送铂纳米免疫缀合物以改善乳腺癌治疗

• 批准号: 9893830
• 负责人: Bogdan Olenyuk
• 金额: $ 46.4万
• 依托单位: PROTEOGENOMICS RESEARCH INSTIT/SYS/ MED
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-10 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9893830
• 关键词: Address; Annexin A1; Antibodies; Antibody-drug conjugates; Applications Grants; Attenuated; Binding; Biological; Blood; Blood Cells; Blood Vessels; Breast Cancer Model; Breast Cancer Treatment; Breast Cancer therapy; Carboplatin; Caveolae; Cell Death; Cell Wall; Cell surface; Chemicals; Cisplatin; Cleaved cell; Complex; DNA; DNA Binding; DNA lesion; Data; Dextrans; Dose; Dose-Limiting; Drug Delivery Systems; Drug Kinetics; Drug resistance; ERBB2 gene; Endothelial Cells; Endothelium; Fluorescence; Fluorescence Microscopy; Fostering; Goals; Half-Life; Health; Human; Immunoconjugates; Infection; Injections; Intravenous; Maximum Tolerated Dose; Membrane; Microfilaments; Mission; Modeling; Monitor; Mus; Myelosuppression; Neoplasm Metastasis; Normal tissue morphology; Organ; Pathway interactions; Patients; Penetration; Pharmaceutical Preparations; Phospholipids; Platinum; Property; Proteins; Publishing; Pump; RNA; Renal clearance function; Research; Risk; Shapes; Side; Solid Neoplasm; Specificity; Speed; System; Testing; Therapeutic; Time; Toxic effect; Translating; Treatment Efficacy; United States National Institutes of Health; Vascular Endothelial Cell; animal imaging; anti-cancer therapeutic; antitumor drug; base; cancer therapy; carcinogenicity; chemotherapy; clinical efficacy; design; drug candidate; drug development; improved; in vivo; innovation; intravital microscopy; iterative design; malignant breast neoplasm; nanoparticle; neoplastic cell; nephrotoxicity; novel; oxaliplatin; pre-clinical; self assembly; side effect; single photon emission computed tomography; systemic toxicity; targeted delivery; targeted treatment; therapeutic effectiveness; treatment response; tumor; uptake; vascular endothelium permeability

The overall objective of the proposed research is to utilize a newly discovered, active transendothelial transport pathway, the caveolae pumping system, in order to provide an effective solution to the delivery and toxicity problem of Pt(II)-based chemotherapeutics in breast cancer. Systemic chemotherapy is one of the common forms of breast cancer treatments, however clinical efficacy of Pt(II) antitumor drugs is limited by the significant in vivo barriers inhibit delivery of these drugs into solid tumors, requiring the use of high doses, producing serious side effects and facilitating development of drug resistance. In order to address these problems and significantly improve treatment of breast cancer we propose two novel paradigms: 1) our newly discovered endothelial cell (EC) caveolae targeting system to sidestep passive delivery and dramatically enhance speed and efficiency of tumor penetration, and 2) to design and develop novel platinum(II) supramolecular coordination complexes (Pt(II)-SCCs), the nanoparticles (NPs) that have shown remarkable efficacy in tumor destruction in preclinical breast cancer models while being monodisperse, stable and well-characterized. Our main hypothesis is that immunoconjugates that fully utilize the advantages of caveolae-targeting antibodies will increase Pt(II)-SCCs delivery into tumors for enhanced efficacy and reduced toxicity, potentially resulting in a fundamentally new class of anticancer therapeutics. This hypothesis will be tested by the following specific aims: In Aim 1, we plan to design and synthesize Pt(II)-SCC immunoconjugates. In this Aim will also design, synthesize and characterize the chemical identity, purity and physicochemical properties of our Pt(II)-SCCs immunoconjugates. We will use caveolae-targeted antibody which we have shown can move the attached cargo from the blood across the EC barrier into solid tumor with unprecedented speed and specificity. In Aim 2 we will characterize in vivo delivery of Pt(II)-SCC immunoconjugates targeting the EC caveolae in tumors. We will perform dynamic monitoring of antibody-Pt(II)-SCC targeting in real time in live mice with intravital microscopy (IVM) using fluorescence emission of the assembled SCCs. In Aim 3 we will assess the therapeutic efficacy of the EC-targeting Pt(II)-SCC immunoconjugates. The efficacy of our targeted delivery system will be examined in IVM models using fluorescence microscopy and in non-IVM Her2/Neu tumor models with whole-body animal imaging. The long-term goal of this project is to translate our key basic discoveries into an innovative drug delivery platform in order to improve therapeutic efficacy and reduce toxicity in the breast cancer treatment.

这项拟议研究的总体目标是利用新发现的主动跨内皮细胞转运 途径，小窝抽吸系统，以提供有效的解决方案的输送和毒性 铂(II)类化疗药物在乳腺癌中的应用问题。全身化疗是一种常见的 乳腺癌的治疗形式，然而铂(II)抗肿瘤药物的临床疗效受到显著限制 体内的屏障抑制了这些药物向实体肿瘤的传递，需要使用高剂量，产生 严重的副作用和促进耐药性的发展。为了解决这些问题， 显著改善乳腺癌的治疗我们提出了两个新的范例：1)我们新发现的 内皮细胞(EC)小凹靶向系统绕过被动投放并显著提高速度 和肿瘤穿透效率，以及2)设计和开发新型铂(II)超分子 铂(II)-SCCs，纳米粒子(NPs)，已显示出显著的肿瘤疗效 在临床前乳腺癌模型中的破坏，同时是单分散的，稳定的和良好的特征。我们的 主要假设是，充分利用小窝靶向抗体优势的免疫结合物将 增加铂(II)-SCCs对肿瘤的转运，以增强疗效和降低毒性，潜在地导致 全新的抗癌疗法。这一假设将通过以下具体情况进行检验 目的：在目标1中，我们计划设计和合成铂(II)-SCC免疫结合物。在这个目标上也将设计， 铂(II)-SCCs的合成与表征 免疫结合物。我们将使用小凹靶向抗体，我们已经证明它可以移动附着的 货物从血液中穿过EC屏障，以前所未有的速度和特异性进入实体肿瘤。在AIM 2 我们将表征针对肿瘤中EC小窝的铂(II)-SCC免疫结合物的体内递送。我们 将在活体小鼠体内实时动态监测抗体-铂(II)-SCC靶向 使用组装的SCCs的荧光发射的显微镜(IVM)。在目标3，我们将评估 EC靶向铂(II)-SCC免疫结合物的治疗效果我们的定向递送的有效性 系统将在使用荧光显微镜的IVM模型和非IVM Her2/Neu肿瘤中进行检查 拥有全身动物影像的模特。该项目的长期目标是将我们的关键基础 发现创新的药物输送平台，以提高治疗效果和降低毒性 在乳腺癌的治疗中。