Mitigating Long-term Cardiotoxicity with Nanoparticle Encapsulated Anthracyclines

用纳米颗粒封装的蒽环类药物减轻长期心脏毒性

• 批准号: 10378678
• 负责人: GREGORY J. AUNE
• 金额: $ 19.77万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10378678
• 关键词: Academia; Acute; Adopted; Adrenal Cortex; Adult; Advanced Development; Advocacy; Aftercare; Age; Animal Model; Animals; Anthracycline; Antitumor Response; Apolipoprotein A-I; Biological Assay; Cancer Patient; Cancer Survivor; Cardiac; Cardiac Myocytes; Cardiotoxicity; Cardiovascular Diseases; Cardiovascular system; Cell Line; Cell Surface Receptors; Cells; Childhood; Clinical; Clinical Trials; Collection; Continuous Infusion; Cytoplasm; DNA Damage; Data; Development; Dexrazoxane; Diagnosis; Dose; Doxorubicin; Drug Delivery Systems; Encapsulated; Ewings sarcoma; Exhibits; Exposure to; Fatty Acids; Fibroblasts; Flow Cytometry; Foundations; Funding; General Population; Half-Life; Health; Heart; Heart Diseases; Hepatocyte; High Density Lipoproteins; Hydrophobicity; In Vitro; Industry; Kidney; Laboratories; Lead; Legal patent; Link; Lipids; Liposomal Doxorubicin; Long-Term Survivors; Longitudinal Studies; Malignant Childhood Neoplasm; Measures; Mediating; Modeling; Mononuclear; Mus; Nature; Normal Cell; Normal tissue morphology; Organ; Outcome; Patients; Pediatric Hospitals; Pediatric Oncology; Phagocytes; Pharmacodynamics; Pharmacologic Substance; Phase I Clinical Trials; Physiological; Plasma; Population; Process; Property; Quality of life; Recording of previous events; Research; Risk; Risk Factors; SR-B proteins; Solid Neoplasm; Structural defect; Structure; Subgroup; Survival Rate; Survivors; System; TP53 gene; Testing; Texas; Therapeutic; Time; Tissues; Translating; Treatment-Related Cancer; Treatment-related toxicity; Work; Xenograft procedure; anti-cancer; base; cancer cell; cell cortex; cell type; chemotherapeutic agent; chemotherapy; childhood cancer survivor; childhood sarcoma; clinical development; cohort; cost effective; cytotoxic; cytotoxicity; effective therapy; experience; experimental study; improved; improved outcome; in vivo; induced pluripotent stem cell; innovation; kidney cell; macrophage; mimetics; mortality; nanoparticle; nanoparticle drug; neoplastic cell; novel; novel therapeutics; patient advocacy group; patient population; peptidomimetics; pre-clinical; response; sarcoma; side effect; targeted delivery; treatment group; treatment strategy; tumor; uptake

Survivors of pediatric cancers disproportionately experience subsequent cardiovascular disease. Pediatric cancer survivors are seven times more likely to die of cardiovascular disease compared to the general population. Commonly used anthracycline chemotherapeutic agents, particularly doxorubicin, have been implicated in late cardiovascular disease in cancer survivors, with cumulative dose being the most important risk factor. Studies have shown that even at lower doses of anthracycline exposure (under 100mg/m2), 30% of patients’ hearts show signs of structural abnormalities 6 to 20 years after diagnosis. Strategies to reduce anthracycline-induced cardiotoxicity, including continuous infusion of liposomal doxorubicin or administration of dexrazoxane have not been approved for pediatric use and are not widely adopted in this patient population. This project seeks to advance the development of a patented Apo-A1 mimetic peptide / fatty acid conjugate that self-assembles into micellar structures termed Myr5A-nanoparticles (Myr5A NPs). Myr5A NPs can encapsulate and deliver therapeutic payloads to cancer cells. The synthetic Apo-A1 mimetic peptide component, like Apo-A1 found in physiologic HDL, functionally engages the scavenger receptor class B type 1 (SR-B1) cell surface receptor, resulting in the transfer Myr5A NP drug payloads into the target cell through selective uptake. The selective uptake process is not endosomally-mediated, resulting in delivery of Myr5A NP payloads directly to the cytoplasm. In addition, highly hydrophobic payloads may be efficiently delivered. Myr5A NPs have exhibited long circulating half-lives in animal studies and would be inexpensive to produce at commercial scale. Previous studies have demonstrated SR-B1 expression in a range of tumor cells, in addition to hepatocytes, steroidogenic tissues, and macrophages. The Yustein Lab at Texas Children’s Hospital has confirmed expression of SR-B1 in Ewing sarcoma and other pediatric sarcomas. Based on these observations, we hypothesize that agents encapsulated in Myr5A NPs will selectively target Ewing sarcoma cells with high expression of SR-B1 and spare normal tissues with low SR-B1 expression, such as the heart and kidneys. To test this hypothesis, the Aune Lab will work collaboratively with the Yustein Lab at Texas Children’s Hospital and Qana Therapeutics to evaluate the expression of key DNA damage markers induced by Myr5A NPs loaded with novel anthracyclines (AD198 and valrubicin) in EWS cell lines and cardiac cells in vitro. In addition, we will simultaneously evaluate the antitumor efficacy and cardiac toxicity profile of these agents in vivo, using a unique model developed by the Aune lab to study anthracycline-induced cardiotoxicity. This project will facilitate collection of critical preclinical data by this collaborative group that will lay the foundation for a collaborative clinical trial supported by academia, industry and advocacy groups. Further clinical development could yield a new therapeutic entity that improves outcomes and long-term quality of life for Ewing’s sarcoma patients and other pediatric cancer patients.

儿童癌症的幸存者不成比例地经历随后的心血管疾病。儿科 癌症幸存者死于心血管疾病的可能性是普通人的七倍 人口。常用的蒽环类化疗药物，特别是阿霉素，已被 与癌症幸存者的晚期心血管疾病有关，其中累积剂量是最重要的 风险因素。研究表明，即使在较低剂量的蒽环类药物暴露（低于 100mg/m2）下，30% 的 患者的心脏在诊断后 6 至 20 年内出现结构异常的迹象。减少策略 蒽环类药物引起的心脏毒性，包括持续输注脂质体阿霉素或施用 右雷佐生尚未被批准用于儿科，也没有在该患者群体中广泛采用。 该项目旨在推进专利 Apo-A1 模拟肽/脂肪酸缀合物的开发 自组装成胶束结构，称为 Myr5A 纳米颗粒（Myr5A NP）。 Myr5A NP 可以 封装治疗有效负载并将其递送至癌细胞。合成的 Apo-A1 模拟肽 成分，如生理 HDL 中发现的 Apo-A1，在功能上与 B 类清道夫受体 1 型结合 (SR-B1) 细胞表面受体，导致 Myr5A NP 药物有效负载通过 选择性吸收。选择性摄取过程不是内体介导的，导致 Myr5A NP 的递送 有效负载直接进入细胞质。此外，可以有效地递送高度疏水性的有效负载。 Myr5A NP 在动物研究中表现出较长的循环半衰期，并且生产成本低廉 商业规模。先前的研究已经证明 SR-B1 在一系列肿瘤细胞中表达，此外 肝细胞、类固醇生成组织和巨噬细胞。德克萨斯儿童医院的尤斯坦实验室 证实 SR-B1 在尤文肉瘤和其他儿童肉瘤中表达。 基于这些观察，我们假设封装在 Myr5A NP 中的药物将选择性地靶向 SR-B1高表达的尤因肉瘤细胞，而保留SR-B1低表达的正常组织，例如 如心脏和肾脏。为了验证这一假设，Aune 实验室将与 Yustein 实验室合作 德克萨斯儿童医院和 Qana Therapeutics 评估关键 DNA 损伤标记物的表达 由负载新型蒽环类药物（AD198 和戊柔比星）的 Myr5A NP 在 EWS 细胞系和心脏中诱导 体外细胞。此外，我们将同时评估其抗肿瘤功效和心脏毒性特征 这些药物在体内，使用 Aune 实验室开发的独特模型来研究蒽环类药物诱导的 心脏毒性。该项目将促进该合作小组收集关键的临床前数据，这将 为学术界、工业界和倡导团体支持的协作临床试验奠定基础。 进一步的临床开发可能会产生一种新的治疗实体，从而改善结果和长期质量 尤文氏肉瘤患者和其他儿童癌症患者的生命。