Micellar Daunorubicin for the Treatment of Bone Cancer

胶束柔红霉素用于治疗骨癌

• 批准号: 8578848
• 负责人: Kevin N Sill
• 金额: $ 15.69万
• 依托单位: INTEZYNE TECHNOLOGIES, LLC
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8578848
• 关键词: Address; Adolescent; Adverse effects; American Cancer Society; Amputation; Anthracyclines; Area; Back; Biochemical; Biodistribution; Biological; Blood; Blood Circulation; Cancer Model; Cancer Patient; Cancer cell line; Cardiac; Cardiotoxicity; Cell Line; Cells; Chemistry; Chemotherapy-Oncologic Procedure; Chondrosarcoma; Chronic; Data; Daunorubicin; Development; Diagnosis; Disease; Dose; Doxorubicin; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Effectiveness; Encapsulated; Endosomes; Environment; Europe; Ewings sarcoma; Family; Goals; Grant; Growth; Hour; In Vitro; Inhibitory Concentration 50; Intellectual Property; Left Ventricular Ejection Fraction; Legal patent; Limb structure; Literature; Lung; Malignant Bone Neoplasm; Malignant Neoplasms; Malignant neoplasm of lung; Metastatic Neoplasm to the Bone; Methotrexate; Micelles; Modeling; Monitor; Mus; Neoplasm Metastasis; Oryctolagus cuniculus; Patients; Pharmaceutical Preparations; Phase; Physiological; Polymers; Positioning Attribute; Process; Production; Quality of life; Rare Diseases; Reporting; Reticuloendothelial System; Safety; Saline; Small Business Innovation Research Grant; Solid Neoplasm; Stable Disease; Stimulus; Survival Rate; Technology; Time; Toxic effect; Toxicology; Troponin T; United States; Woman; Xenograft Model; Xenograft procedure; base; cancer therapy; chemotherapeutic agent; chemotherapy; commercial application; commercialization; copolymer; cost; crosslink; design; fibrosarcoma; improved; in vitro activity; in vivo; innovation; men; nanocarrier; nanoparticle; novel; osteosarcoma; pre-clinical; public health relevance; research study; response; screening; success; technological innovation; tumor; uptake; water solubility

DESCRIPTION (provided by applicant): According to the American Cancer Society, half of all men and one-third of all women in the United States will develop cancer in their lifetime. While chemotherapy has dramatically improved the survival rate of cancer patients, it comes at the cost of severe toxicities and in some cases poor response rates. In certain cases, such as bone cancer, chemotherapy has very limited effectiveness. In order to address these shortcomings, drug delivery innovations are necessary to improve the success rate of these treatments and improve the quality of life for these patients. Drug delivery vehicles are needed that are stable t post-administration dilution, can avoid biological barriers (e.g. reticuloendothelial system (RES) uptake), and deliver drugs in response to a physiological stimuli encountered in solid tumor environment (i.e. change in the pH level). Polymer micelles formed by the assembly of amphiphilic block copolymers are a particular type of nanocarrier that are attractive due to their ability to confer water solubility to hydrophobic drugs by encapsulating them within the core of the micelle. In an effort to overcome the inherent instability of traditional micelles, a polymer micelle-based drug delivery system was developed that utilizes novel stabilizing technology. This stabilizing technology utilizes reversible, pH-dependent crosslinking chemistry that stabilizes the micelle at physiological pH, but releases the drug in response to lower pH environments, such as areas surrounding a tumor or within endosomes. Daunorubicin is part of a widely prescribed family of chemotherapeutic drugs, anthracyclines. Unfortunately, this class of drugs suffers from poor pharmacokinetic and biodistribution profiles and severe cardiotoxicity. While there are many reports of anthracycline-based nanocarriers in the literature, these nanocarriers are typically unstable in the bloodstream, which quickly revert back to the pharmacokinetic and toxicity profiles of the free drug. Accordingly, it would be highly desirable t have a stable, anthracycline-based nanoparticle for the treatment of cancer that demonstrates an improved safety profile with respect to cardiotoxicity. In this Phase I SBIR proposal, stabilized, daunorubicin-loaded micelles (termed IT-143) will be evaluated for antitumor activity in bone cancer xenograft models and cardiotoxicity in rabbits. Specific Aim 1 will investigate the anti-tumor efficacy of IT-143 in four separate bone cancer models including Ewing Sarcoma and osteosarcoma models. Specific Aim 2 will evaluate the cardiac toxicity of IT-143 in rabbits accompanied by supporting pharmacokinetics. Successful completion of these Phase I aims will provide essential preclinical data for the further advancement of IT-143. The Phase II SBIR proposal will focus on IND-enabling, GLP toxicology studies and GMP manufacture of IT-143.

描述（由申请人提供）：根据美国癌症协会，美国一半的男性和三分之一的女性在一生中会患上癌症。虽然化疗大大提高了癌症患者的生存率，但它是以严重的毒性和在某些情况下的低反应率为代价的。在某些情况下，如骨癌，化疗的效果非常有限。为了解决这些缺点，药物递送创新是必要的，以提高这些治疗的成功率，并改善这些患者的生活质量。需要药物递送载体，其在施用后稀释时稳定，可以避免生物屏障（例如网状内皮系统（RES）摄取），并且响应于实体瘤环境中遇到的生理刺激（即pH水平的变化）递送药物。由两亲性嵌段共聚物组装形成的聚合物胶束是一种特殊类型的纳米载体，由于其通过将疏水性药物包封在胶束的核心内而赋予疏水性药物水溶性的能力，其是有吸引力的。为了克服传统胶束固有的不稳定性，开发了一种利用新型稳定技术的聚合物胶束药物递送系统。这种稳定化技术利用可逆的pH依赖性交联化学，其在生理pH下稳定胶束，但响应于较低pH环境（例如肿瘤周围或内体内的区域）释放药物。柔红霉素是一种广泛使用的化疗药物蒽环类药物家族的一部分。不幸的是，这类药物具有不良的药代动力学和生物分布特征以及严重的心脏毒性。虽然在文献中有许多关于蒽环类纳米载体的报道，但这些纳米载体通常在血流中不稳定，其很快恢复到游离药物的药代动力学和毒性特征。因此，非常需要具有稳定的基于蒽环类的纳米颗粒用于治疗癌症，其在心脏毒性方面表现出改善的安全性。在该I期SBIR提案中，将评价稳定的载柔红霉素胶束（称为IT-143）在骨癌异种移植模型中的抗肿瘤活性和在兔中的心脏毒性。具体目标1将研究IT-143在四个单独的骨癌模型中的抗肿瘤功效，包括尤文肉瘤和骨肉瘤模型。具体目标2将评价IT-143在家兔中的心脏毒性以及支持性药代动力学。这些I期目标的成功完成将为IT-143的进一步发展提供重要的临床前数据。II期SBIR提案将侧重于IT-143的IND启用、GLP毒理学研究和GMP生产。