Mitigating Long-term Cardiotoxicity with Nanoparticle Encapsulated Anthracyclines

儿童癌症的幸存者不成比例地经历了随后的心血管疾病。儿科 癌症幸存者死于心血管疾病的可能性是普通癌症患者的7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下(低于100 mg/m2)，30%的 患者的心脏在确诊后6到20年内显示出结构性异常的迹象。减少污染的战略 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给药 右旋氮杂环己烷尚未被批准用于儿科，在这类患者中也没有被广泛采用。 该项目旨在推进获得专利的Apo-A1模拟肽/脂肪酸结合物的开发 这种自组装形成胶束结构，称为Myr5A纳米颗粒(Myr5A NPs)。Myr5A NPs可以 将治疗有效载荷封装并输送到癌细胞。人工合成Apo-A1模拟多肽 与生理性高密度脂蛋白中发现的Apo-A1一样，成分在功能上与清道夫受体B型1结合 (SR-B1)细胞表面受体，导致Myr5A NP药物有效载荷通过 选择性摄取。选择性摄取过程不是由内体介导的，从而导致Myr5A NP的递送 有效载荷直接进入细胞质。此外，可以高效地运送高度疏水的有效载荷。 在动物研究中，Myr5A纳米粒子表现出较长的循环半衰期，并且生产成本低廉 商业规模。以前的研究已经证明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于斯坦实验室已经 证实SR-B1在尤文肉瘤和其他儿童肉瘤中的表达。 基于这些观察，我们假设包裹在Myr5A NPs中的药物将选择性地靶向 高表达SR-B1的尤文肉瘤细胞和低表达SR-B1的正常组织 心脏和肾脏。为了验证这一假设，奥纳实验室将与于斯坦实验室合作，地址为 德克萨斯儿童医院和卡纳治疗公司评估关键DNA损伤标记的表达 新型蒽环类药物(AD198和Valruicin)负载Myr5A纳米粒对EWS细胞株和心脏组织的诱导作用 体外培养的细胞。此外，我们还将同时评估其抗肿瘤效果和心脏毒性。 这些药物在体内，使用由奥纳实验室开发的独特模型来研究蒽环类药物诱导 心脏毒性。该项目将促进这个合作小组收集关键的临床前数据，该小组将 为学术界、产业界和倡导团体支持的协作性临床试验奠定基础。 进一步的临床开发可能产生一种新的治疗实体，改善结果和长期质量 尤因肉瘤患者和其他儿科癌症患者的生活。

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.