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.

小儿癌的幸存者不成比例地患有随后的心血管疾病。小儿与一般性相比人口。通常使用的邻苯二甲素化学治疗剂，尤其是阿霉素，已经是在癌症存活中的心血管晚期疾病中实施，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暴露（低于100mg/m2）下，也有30％诊断后6到20年，患者的心脏显示出结构异常的迹象。减少策略蒽环类诱导的心脏毒性，包括连续输注脂质体阿霉素或给药右旋唑烷尚未被批准用于小儿使用，并且在该患者人群中未被广泛采用。该项目旨在推动获得专利的APO-A1模拟肽 /脂肪酸结合物的开发这种自组合成胶束结构，称为MYR5A纳米颗粒（MYR5A NPS）。 myr5a nps可以将热有效载荷封装给癌细胞。合成Apo-A1模拟肽与生理HDL中发现的Apo-A1一样（SR-B1）细胞表面受体，导致Myr5a NP药物有效载荷通过选择性吸收。选择性摄取过程没有内体介导，导致Myr5a NP的递送有效载荷直接到细胞质。另外，可以有效地交付高度疏水的有效载荷。 MYR5A NP在动物研究中暴露了长期循环的半衰期，并且在商业规模。先前的研究表明，在一系列肿瘤细胞中的SR-B1表达，另外到肝细胞，类固醇组织和巨噬细胞。德克萨斯儿童医院的Yustein实验室有 SR-B1在尤因肉瘤和其他儿科肉瘤中的证实表达。基于这些观察结果，我们假设封装在Myr5a NP中的代理将有选择地针对 ewing肉瘤细胞具有高表达SR-B1和备用SR-B1表达低的正常组织，此类作为心脏和肾脏。为了检验这一假设，Aune Lab将与Yustein Lab合作德克萨斯儿童医院和QANA Therapeutics评估关键DNA损伤标记的表达由EWS细胞系和心脏的Myr5a NP诱导的Myr5a NP诱导的新蒽环类药物（AD198和valrubicin）细胞体外。此外，我们将简单地评估抗肿瘤效率和心脏毒性特征这些代理在体内使用Aune Lab开发的独特模型来研究蒽环类药物诱导的心脏毒性。该项目将促进该协作小组收集关键的临床前数据为学术界，行业和倡导小组支持的协作临床试验奠定了基础。进一步的临床发展可能会产生一个新的治疗实体，以改善结果和长期质量尤因的肉瘤患者和其他儿科癌症患者的生命。