Steacie Supplement

人们越来越乐观地认为，纳米技术将在癌症诊断和治疗领域带来重大进展。近年来，利用水溶性聚合物作为细胞毒性药物的纳米载体引起了广泛的关注。现在已经确定，长期循环的药物-聚合物偶联物在各种实体肿瘤中以比正常组织高得多的浓度积累。由于它们在健康组织中的分布有限，它们通常比对照药物溶液显示更安全的毒理学特征。然而，尽管有这些吸引人的特性，在相同剂量下，聚合物偶联物很少比游离药物具有更大的抗肿瘤活性。这通常可以合理地解释为，由于活性药物在肿瘤细胞中的释放速度缓慢，生物可利用药物的细胞内浓度不足。事实上，为了获得最佳的细胞抑制活性，药物应该在到达恶性细胞后迅速从载体中释放出来。为了实现这一目标，我们建议构建聚合物偶联物，通过将纳米机械装置（即分子镊子）的构象改变嫁接到聚合物骨架上，从而释放药物。分子镊子可以设计成在特定构象时对底物表达非常高的亲和力，然后在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。

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.