Caveolae-Targeted Cisplatin Immunoconjugates for Effective Lung Cancer Therapy

小窝靶向顺铂免疫缀合物可有效治疗肺癌

基本信息

批准号：
9408697
负责人：
Michael David Levin
金额：
$ 30万
依托单位：
CAVATAR, LLC
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9408697
关键词：
Adverse effects Animal Model Annexin A1 Antibodies Applications Grants Asses Biodistribution Biological Models Blood Blood Circulation Blood Vessels Breast Cancer therapy Cancer Model Cancer Patient Carboplatin Case Study Caveolae Cell surface Chemicals Cisplatin Clinic Complex Data Dextrans Disease Dose Drug Delivery Systems Drug Targeting Endothelial Cells Future Genetically Engineered Mouse Human Imagery Immunoconjugates Incidence Injection of therapeutic agent Intravenous Label Lewis Lung Carcinoma Lung Lung Neoplasms Malignant neoplasm of lung Mammary Neoplasms Maximum Tolerated Dose Measures Medicine Modeling Molecular Weight Monitor Mus Neoplasm Metastasis Non-Small-Cell Lung Carcinoma Organ Pathway interactions Patients Penetration Pharmaceutical Preparations Platinum Platinum Compounds Publishing Pump Quality of life Research Institute Rodent Safety Site Solid Solid Neoplasm Specificity Speed Surface System Therapeutic Therapeutic Agents Therapeutic Effect Tissues Toxic effect Translations Treatment Efficacy Treatment Protocols Tumor Tissue United States Vascular Endothelial Cell Vascular Permeabilities X-Ray Computed Tomography Xenograft Model anti-cancer therapeutic antibody conjugate base body system cancer therapy chemotherapy clinical translation design drug candidate drug efficacy effective therapy efficacy study improved in vivo innovation insight intravital microscopy microscopic imaging mortality neoplastic cell novel oxaliplatin proteogenomics prototype public health relevance response single photon emission computed tomography systemic toxicity targeted treatment therapeutic effectiveness therapeutic evaluation tool treatment response tumor tumor microenvironment uptake

项目摘要

Abstract Caveolae at the endothelial cells surface can selectively, rapidly, and actively pump targeted antibodies out of the bloodstream and into underlying tissue in vivo, even when they are conjugated to high-molecular weight cargo. Based on this exciting recent discovery, we also found that caveolae pumping system enables unprecedented tumor-specific targeting and penetration. Taken together, our evidence strongly supports that targeting tumor caveolae is a new strategy providing a portal to deliver therapeutic agents across the vascular endothelial cell barrier and directly into tumors. Caveolae can rapidly pump a targeted antibody with the attached cargo across the endothelial cells to reach concentrations inside solid tumors that greatly exceed maximum concentrations in the blood. In this project we will focus on testing of the therapeutic utility of the antibody- cisplatin-CMdextran immunoconjugates to target truncated form of Annexin A1 in tumor endothelial caveolae and to effectively penetrate solid tumors. The data will provide proof-of-principle of our innovative delivery strategy for therapy of lung cancer and moves toward clinical translation by assessing how well caveolae immunotargeting and pumping into tumors can enhance the therapeutic impact of chemotherapy. We will design, synthesize and asses in vivo the efficacy of cisplatin-carboxymethyl dextran (CMdextran)- AnnA1 antibody conjugate to create new tumor caveolae-targeted therapeutics for enhanced delivery and efficacy in lung cancer models using our advanced animal models. We hypothesize that by pumping antibodies armed with cisplatin- CMdextran into tumors, caveolae can rapidly and specifically concentrate therapeutic agents inside tumors and enhance tumor destruction with significantly reduced toxicity. The Specific Aims of this project are: Aim 1 - to characterize in vivo delivery of cisplatin immunoconjugates targeting EC caveolae in tumors, and Aim 2 - to assess therapeutic efficacy of the EC caveolae-targeting cisplatin immunoconjugates. This project will utilize our new intravital microscopy (IVM) tumor model system in addition to spontaneous mammary tumors from genetically engineered mice. IVM permits direct visualization of targeting and endothelial processing as well as stroma and tumor cell responses, all of which can be quantified to help provide new insights into therapeutic mechanisms in tumors. Targeting caveolae opens a specific gateway across the restrictive vascular endothelial barrier. It can provide means for enhanced delivery much closer to ideal targeting in order to achieve more effective therapies. We have demonstrated that AnnA1 is expressed in the vasculature and caveolae of human primary and metastatic lung tumors. Overall, our proposed project could create a paradigm shift away from the passive transvascular delivery that greatly limits drug efficacy in humans, affording the first prototype of caveolae-targeted anticancer therapeutics for future translation into the clinic.

抽象的内皮细胞表面的小凹可以选择性、快速、主动地将靶向抗体泵出即使它们与高分子量缀合，也能进入血液并进入体内的底层组织货物。基于这一令人兴奋的最新发现，我们还发现小凹泵送系统能够前所未有的肿瘤特异性靶向和渗透。总而言之，我们的证据有力地支持了这一点靶向肿瘤小窝是一种新策略，提供了跨血管输送治疗药物的门户突破内皮细胞屏障，直接进入肿瘤。 Caveolae 可以快速泵送带有附着物的靶向抗体货物穿过内皮细胞，在实体瘤内达到大大超过最大浓度的浓度血液中的浓度。在这个项目中，我们将重点测试抗体的治疗效用- 顺铂-CM葡聚糖免疫偶联物靶向肿瘤内皮细胞小窝中膜联蛋白 A1 的截短形式并有效穿透实体瘤。这些数据将为我们的创新交付提供原理证明肺癌治疗策略，并通过评估小凹效果走向临床转化免疫靶向和泵入肿瘤可以增强化疗的治疗效果。我们将设计、合成顺铂-羧甲基葡聚糖 (CMdextran)-AnnA1 抗体并在体内评估其功效结合物创建新的肿瘤小窝靶向疗法，以增强肺癌的递送和疗效使用我们先进的动物模型进行模型制作。我们假设通过泵送带有顺铂的抗体将CMdextran注入肿瘤内，小窝可以快速、特异性地将治疗药物集中在肿瘤内部，增强肿瘤破坏并显着降低毒性。该项目的具体目标是：目标 1 - 表征靶向肿瘤 EC 细胞膜陷的顺铂免疫缀合物的体内递送，目标 2 - 评估 EC Caveolae 靶向顺铂免疫偶联物的治疗效果。该项目将利用我们的除了自发性乳腺肿瘤之外，新的活体显微镜 (IVM) 肿瘤模型系统基因工程小鼠。 IVM 允许直接可视化靶向和内皮处理以及基质和肿瘤细胞反应，所有这些都可以量化，以帮助提供治疗的新见解肿瘤中的机制。靶向小窝打开了穿过限制性血管内皮的特定门户障碍。它可以提供更接近理想目标的增强交付方式，以实现更多目标有效的疗法。我们已经证明 AnnA1 在人类的脉管系统和小窝中表达原发性和转移性肺部肿瘤。总的来说，我们提出的项目可以创造一种范式转变，远离被动经血管输送极大地限制了药物在人体中的功效，提供了第一个原型小窝靶向抗癌疗法未来将转化为临床。