Micellar Daunorubicin for the Treatment of Bone Cancer

描述(申请人提供)：根据美国癌症协会的数据，美国一半的男性和三分之一的女性在他们的一生中都会患上癌症。虽然化疗极大地提高了癌症患者的存活率，但它是以严重毒性为代价的，在某些情况下，应答率很低。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，有必要进行药物输送创新，以提高这些治疗的成功率，并改善这些患者的生活质量。药物输送载体需要稳定的给药后稀释，能够避免生物屏障(例如，网状内皮系统(RES)摄取)，并且能够响应在固体肿瘤环境中遇到的生理刺激(即，pH水平的变化)来输送药物。由两亲嵌段共聚物组装而成的聚合物胶束是一种特殊类型的纳米载体，由于其能够通过将疏水药物包裹在胶束核心内来赋予疏水药物水溶性而具有吸引力。为了克服传统胶束固有的不稳定性，开发了一种基于聚合物胶束的药物释放系统，该系统采用了新的稳定技术。这种稳定技术利用可逆的、依赖于pH的交联化学，将胶束稳定在生理pH，但在较低的pH环境下释放药物，如肿瘤周围或内吞体内。柔红霉素是一种被广泛处方的化疗药物家族的一部分，即蒽环类药物。不幸的是，这类药物的药代动力学和生物分布很差，心脏毒性很严重。虽然文献中有许多基于蒽环类药物的纳米载体的报道，但这些纳米载体在血液中通常不稳定，很快就会恢复到游离药物的药代动力学和毒性曲线。因此，非常希望有一种用于癌症治疗的稳定的、基于蒽环类药物的纳米颗粒，该纳米颗粒在心脏毒性方面表现出更好的安全性。在这项第一阶段的SBIR建议中，将评估稳定的柔红霉素胶束(称为IT-143)在骨癌异种移植模型中的抗肿瘤活性和对兔的心脏毒性。具体目的1将研究IT-143在包括尤文肉瘤和骨肉瘤模型在内的四种不同骨癌模型中的抗肿瘤效果。特定目的2将评价IT-143在兔体内的心脏毒性，并伴有支持的药代动力学。这些第一阶段目标的成功完成将为IT-143的进一步发展提供必要的临床前数据。第二阶段SBIR提案将侧重于IND-Enabling、GLP毒理学研究和IT-143的GMP制造。

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.