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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.

儿童癌症幸存者不成比例地经历随后的心血管疾病。儿科