Micellar Daunorubicin for the Treatment of Bone Cancer

描述（由申请人提供）：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，但它的代价是严重的毒性，在某些情况下反应率很低。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，药物输送创新是必要的，以提高这些治疗的成功率和改善这些患者的生活质量。药物递送载体需要在给药后稀释时稳定，能够避免生物屏障（例如网状内皮系统（RES）摄取），并且能够响应实体肿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，由于其通过将疏水药物包裹在胶束核心内而赋予其水溶性的能力而具有吸引力。为了克服传统胶束固有的不稳定性，开发了一种利用新型稳定技术的聚合物胶束给药系统。这种稳定技术利用可逆的、pH依赖的交联化学，在生理pH下稳定胶束，但在较低pH环境下释放药物，如肿瘤周围区域或核内体内。柔红霉素是一种广泛使用的化疗药物——蒽环类药物的一部分。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。虽然文献中有许多关于蒽环类药物纳米载体的报道，但这些纳米载体在血液中通常不稳定，会迅速恢复到游离药物的药代动力学和毒性特征。因此，非常需要一种稳定的、基于蒽环类药物的纳米颗粒来治疗癌症，这种纳米颗粒在心脏毒性方面表现出更高的安全性。在这项I期SBIR提案中，将评估稳定的柔红霉素负载胶束（称为IT-143）在骨癌异种移植模型中的抗肿瘤活性和兔心脏毒性。特异性目的1将研究IT-143在尤文氏肉瘤和骨肉瘤四种不同骨癌模型中的抗肿瘤效果。特异性目的2将评估IT-143对家兔的心脏毒性，并伴有相应的药代动力学。这些I期目标的成功完成将为IT-143的进一步发展提供必要的临床前数据。II期SBIR提案将重点关注IT-143的ind启用、GLP毒理学研究和GMP生产。

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.