Steacie Supplement

斯泰西补充品

• 批准号: 364039-2008
• 负责人: Leroux, JeanChristophe
• 金额: $ 9.62万
• 依托单位: Université de Montréal
• 依托单位国家: 加拿大
• 项目类别: EWR Steacie Fellowships - Supplement
• 财政年份: 2009
• 资助国家: 加拿大
• 起止时间: 2009-01-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=434118
• 关键词: Steacie; Supplement

There is increasing optimism with respect to nanotechnology giving rise to significant advances in the fields of cancer diagnosis and treatment. In recent years, the use of water-soluble polymers as nanocarriers of cytotoxic drugs has attracted wide interest. It is now well-established that long-circulating drug-polymer conjugates accumulate in a variety of solid tumors at much higher concentrations than in normal tissues. Due to their limited distribution in healthy tissues, they often display safer toxicological profiles than control drug solutions. However, despite these attractive characteristics, polymeric conjugates are seldom associated with a greater antitumoral activity than the free drug at equivalent doses. This can often be rationalized in terms of insufficient intracellular concentrations of bioavailable drug due to a slow release rate of the active agent in the tumor cells. Indeed, for optimal cytostatic activity, the drug should be rapidly released from the carrier upon reaching the malignant cells. To achieve this objective, we propose to construct polymer conjugates whereby the drug is released as a result of the conformational change of a nanomechanical device (i.e. molecular tweezer) grafted to the polymeric backbone. Molecular tweezers can be designed to express very high affinity for a substrate when in a specific conformation, and then rapidly lose their binding properties following a change in their molecular shape. This conformational change can be triggered by acidification of the external medium, a condition that is encountered by macromolecular drugs following their uptake by the tumor cells.

人们对纳米技术在癌症诊断和治疗领域取得重大进展越来越乐观。近年来，水溶性聚合物作为细胞毒药物的纳米载体引起了人们的广泛兴趣。现在已经确定，长循环药物-聚合物缀合物在各种实体瘤中以比正常组织中高得多的浓度积累。由于它们在健康组织中的分布有限，它们通常表现出比对照药物溶液更安全的毒理学特征。然而，尽管这些有吸引力的特性，聚合物缀合物很少与更大的抗肿瘤活性比游离药物在同等剂量。这通常可以根据由于活性剂在肿瘤细胞中的缓慢释放速率导致的生物可利用药物的细胞内浓度不足来合理化。实际上，为了获得最佳的细胞抑制活性，药物应该在到达恶性细胞时从载体中快速释放。为了实现这一目标，我们建议构建聚合物缀合物，由此药物被释放作为接枝到聚合物骨架的纳米机械装置（即分子镊子）的构象变化的结果。分子钳可以被设计成当处于特定构象时对底物表达非常高的亲和力，然后在其分子形状改变后迅速失去其结合特性。这种构象变化可以由外部介质的酸化触发，这是大分子药物在被肿瘤细胞摄取后遇到的一种情况。