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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

基本信息

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
项目类别：
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

项目摘要

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。