Mitigating Long-term Cardiotoxicity with Nanoparticle Encapsulated Anthracyclines

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剂，特别是多柔比星，已经被广泛应用于临床。 与癌症幸存者的晚期心血管疾病有关，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100 mg/m2）， 病人的心脏在确诊后6至20年内出现结构异常的迹象。战略以减少 蒽环类药物诱导的心脏毒性，包括脂质体阿霉素的连续输注或 右雷佐生尚未被批准用于儿科用途，并且未在该患者人群中广泛采用。 该项目旨在推进专利Apo-A1模拟肽/脂肪酸缀合物的开发 其自组装成称为Myr 5A-纳米颗粒（Myr 5A NP）的胶束结构。Myr 5A NP可以 封装并将治疗有效载荷递送至癌细胞。合成的Apo-A1模拟肽 与生理HDL中发现的Apo-A1类似，一种组分在功能上与清道夫受体B类1型结合 （SR-B1）细胞表面受体，导致Myr 5A NP药物有效载荷通过 选择性摄取选择性摄取过程不是内体介导的，导致Myr 5A NP的递送 直接进入细胞质。此外，可以有效地递送高度疏水的有效载荷。 Myr 5A纳米颗粒在动物研究中表现出长的循环半衰期，并且在2000年生产将是廉价的。 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。德克萨斯州儿童医院的Yustein实验室 证实SR-B1在尤文肉瘤和其他小儿肉瘤中表达。 基于这些观察，我们假设包封在Myr 5A纳米颗粒中的试剂将选择性靶向 SR-B1高表达的尤文肉瘤细胞和SR-B1低表达的正常组织，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 在EWS细胞系和心脏中由负载新型蒽环类药物（AD 198和戊柔比星）的Myr 5A NPs诱导 体外细胞此外，我们还将同时评估 这些药物在体内，使用一个独特的模型开发的Aune实验室研究蒽环类药物诱导 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， 为学术界、工业界和倡导团体支持的合作临床试验奠定基础。 进一步的临床开发可以产生一种新的治疗实体，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。

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.