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

• 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
• 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

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.

摘要 内皮细胞表面的小窝可以选择性地、快速地和主动地将靶向抗体泵出内皮细胞。 血液和进入体内的下层组织，即使当它们与高分子量 货物.基于这一令人兴奋的最新发现，我们还发现小窝泵送系统使 前所未有的肿瘤特异性靶向和渗透。综合来看，我们的证据有力地支持了这一点， 靶向肿瘤小窝是一种新的策略， 内皮细胞屏障并直接进入肿瘤。Caveolae可以快速泵送靶向抗体， 货物通过内皮细胞，达到实体瘤内的浓度，大大超过最大 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- 靶向肿瘤内皮小窝中截短型膜联蛋白A1的顺铂-羧甲基葡聚糖免疫偶联物 并有效地穿透实体肿瘤。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，并通过评估小窝 免疫靶向和泵入肿瘤可以增强化疗的治疗效果。我们会设计， 顺铂-羧甲基葡聚糖（CMDextran）-AnnA 1抗体的合成和体内疗效评估 偶联物，以产生新的肿瘤小窝靶向治疗剂，用于增强肺癌中的递送和功效 使用我们先进的动物模型。我们假设通过注射带有顺铂的抗体- CMDextran进入肿瘤，小窝可以快速和特异性地集中肿瘤内的治疗剂， 增强肿瘤破坏并显著降低毒性。该项目的具体目标是：目标1 - 表征靶向肿瘤中EC小窝的顺铂免疫缀合物的体内递送，以及目的2 - 评估EC小窝靶向顺铂免疫缀合物的治疗功效。该项目将利用我们的 新的活体显微镜（IVM）肿瘤模型系统，除了自发性乳腺肿瘤， 基因工程小鼠IVM允许靶向和内皮加工的直接可视化，以及 基质和肿瘤细胞的反应，所有这些都可以量化，以帮助提供新的见解， 肿瘤机制。靶向小窝打开了一个穿过限制性血管内皮细胞的特异性通道， 屏障它可以提供更接近理想目标的增强交付手段，以实现更多的目标。 有效的治疗。我们已经证明AnnA 1在人的血管和小窝中表达， 原发性和转移性肺肿瘤。总的来说，我们提出的项目可以创造一个范式转变， 被动经血管输送，大大限制了药物在人体内的疗效，提供了第一个原型， caveolae靶向抗癌疗法的未来翻译到临床。