Exosomes as carriers of cancer therapeutics

外泌体作为癌症治疗的载体

• 批准号: 10312645
• 负责人: Rajagopal Ramesh
• 金额: $ 57.62万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-14 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10312645
• 关键词: Adjuvant; Animal Model; Antibodies; Antineoplastic Agents; Area; Binding; Biological; Blood Circulation; Cancer Biology; Cancer Control; Cancer Patient; Cells; Cessation of life; Cisplatin; Clinical; Data; Development; Disease; Distant; Dose-Limiting; Doxorubicin; Drug Carriers; Drug Delivery Systems; Drug Kinetics; Drug resistance; Endosomes; Exhibits; Exocytosis; Fibroblasts; Formulation; Future; Gene Delivery; Growth; Human; Image; Immune checkpoint inhibitor; Immune response; Immunology; In Situ; In Vitro; Incidence; Laboratories; Ligands; Lipids; Lung; Lung Neoplasms; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of lung; Measurement; Membrane; Modeling; Molecular; Monitor; Mononuclear; Mus; Neoplasm Metastasis; Normal Cell; Oncologist; Organoids; Pathologic; Pathology; Patients; Phagocytes; Pharmaceutical Preparations; Pharmacy (field); Pilot Projects; Polyethylene Glycols; Polysialic Acid; Property; Proteins; Recurrent disease; Reporting; Role; Signal Transduction; Site; Study models; Surface; Survival Rate; System; TFRC gene; Testing; Therapeutic; Toxic effect; Treatment Efficacy; Treatment outcome; Vesicle; anti-cancer; anticancer activity; base; cancer cell; cancer therapy; contrast imaging; cytotoxicity; drug release kinetics; effective therapy; exosome; imaging agent; improved; in vivo; innovation; iron oxide nanoparticle; lung cancer cell; molecular targeted therapies; mortality; multidisciplinary; nanoparticle; neoplastic cell; novel therapeutics; overexpression; particle; pharmacokinetics and pharmacodynamics; preclinical study; research clinical testing; statistics; superparamagnetism; treatment response; tumor; tumor growth; tumor xenograft; uptake

Effective treatment of lung cancer remains a formidable clinical challenge. The advent of molecularly- targeted therapies and immune checkpoint inhibitors has shown promise in lung cancer treatment. However, only a subset of lung cancer patients benefit from these therapies. Further, inefficient delivery and accumulation of anticancer drugs in tumor depots combined with dose-limiting toxicity contributes to disease relapse, drug resistance, and metastasis culminating in patient death. As a result, the overall survival rate of lung cancer patients is <16%. Thus, testing of new therapeutics and novel drug delivery systems that can efficiently transport anticancer drugs to tumor depots and kill cancer cells are necessary for improving treatment outcomes. In the present application, we propose testing “exosomes” as drug carriers for cancer therapy. The exosomes derived from normal human lung fibroblast and murine fibroblast cell-derived exosomes (Exo) are loaded with iron-oxide nanoparticles (IONP) carrying an anticancer drug [Doxorubicin (Dox), Cisplatin (CDDP)]. The release of the chemodrug from the IONP is controlled by a pH responsive linker thereby minimizing drug- related toxicity to normal cells. Further, the drug-IONP loaded exosome is decorated with a tumor-targeted ligand for enhancing tumor-specific drug delivery and reducing cytotoxicity to normal cells. Finally, inclusion of IONP enables monitoring tumor growth and treatment response by magnetic resonance imaging (MRI). Pilot studies demonstrated exosomes could be successfully loaded with Dox-, and CDDP-conjugated IONP. Further, excellent drug loading efficiency and drug release kinetics was demonstrated from the exosomes. In vitro studies showed chemodrug-loaded exosomes exerted significant cytotoxicity towards cancer cells but not normal cells. MRI and SQUID studies showed drug-loaded exosomes provided good contrast image without losing the superparamagnetic properties of IONP. Furthermore, tumor-targeted (tt) exosomes directed towards transferrin receptor (TfR) overexpressing lung cancer cells exhibited greater cytotoxicity compared to non- targeted exosomes and accumulated in the tumor xenograft resulting in in vivo efficacy. Based on our compelling preliminary data, we hypothesize that tt-exosomes will efficiently deliver chemotherapeutics to tumor cells and concurrently enable measurement of treatment response by MRI with minimal toxicity to normal cell when tested both, in vitro and in vivo. We will conduct the proposed studies under the following two specific aims. Aim 1a. Physico-biological characterization of tt-exosome as drug carriers for use in in vitro and in vivo studies. Aim 1b. Determine the efficacy of tt-exosome against human and mouse lung cancer and normal cells, spheroids and organoids in vitro. Aim 2. Investigate the in vivo antitumor activity of tt-exosome against lung tumor models.

肺癌的有效治疗仍然是一项艰巨的临床挑战。 靶向治疗和免疫检查点抑制剂在肺癌治疗中显示出了希望。 只有一小部分肺癌患者从这些疗法中受益，此外，治疗效率低下。 抗癌药物在肿瘤库中的积累与剂量限制性毒性相结合导致疾病 复发、耐药性和转移最终导致患者死亡。 肺癌患者<16% 因此，测试新的疗法和新的药物输送系统可以。 有效地将抗癌药物运送到肿瘤库并杀死癌细胞是改善癌症的必要条件 治疗结果。 在本申请中，我们建议测试“外泌体”作为癌症治疗的药物载体。 正常人肺成纤维细胞来源的外泌体和鼠成纤维细胞来源的外泌体（Exo）是 负载有氧化铁纳米粒子（IONP），携带抗癌药物[阿霉素（Dox）、顺铂（CDDP）]。 IONP 中化学药物的释放由 pH 响应连接体控制，从而最大限度地减少药物释放 此外，负载 IONP 的外泌体还修饰有肿瘤靶向药物。 用于增强肿瘤特异性药物输送并减少对正常细胞的细胞毒性的配体。 IONP 能够通过磁共振成像 (MRI) 监测肿瘤生长和治疗反应。 初步研究表明，外泌体可以成功负载 Dox 和 CDDP 缀合的 IONP。 此外，外泌体还表现出优异的药物装载效率和药物释放动力学。 体外研究表明，装载化学药物的外泌体对癌细胞具有显着的细胞毒性，但没有 MRI 和 SQUID 研究表明，载药外泌体无需提供良好的对比图像。 失去 IONP 的超顺磁特性此外，肿瘤靶向（tt）外泌体针对 与非转铁蛋白受体（TfR）过表达的肺癌细胞相比，转铁蛋白受体（TfR）过表达的肺癌细胞表现出更大的细胞毒性。 靶向外泌体并在肿瘤异种移植物中积累，从而产生体内功效。 通过令人信服的初步数据，我们追求 tt-外泌体将有效地将化疗药物传递给 肿瘤细胞，同时能够通过 MRI 测量治疗反应，对肿瘤细胞的毒性最小 在体外和体内测试时的正常细胞我们将在以下两项下进行拟议的研究。 具体目标。 目标 1a. tt-外泌体作为药物载体用于体外和体内研究的物理生物学特征。 目标 1b. 确定 tt-外泌体对人类和小鼠肺癌以及正常细胞的功效， 体外球体和类器官。 目标 2. 研究 tt-exosome 对肺肿瘤模型的体内抗肿瘤活性。