Steacie Supplement

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，利用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。现在公认的是，长时间循环的药物-聚合物结合物在各种实体肿瘤中积聚的浓度比在正常组织中高得多。由于它们在健康组织中的分布有限，它们往往比对照药物溶液显示出更安全的毒理学特征。然而，尽管有这些吸引人的特性，聚合物结合物很少与同等剂量的游离药物相比具有更强的抗肿瘤活性。这通常是合理的，因为由于活性物质在肿瘤细胞中的释放速度缓慢，细胞内生物可用药物浓度不足。事实上，为了达到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上释放。为了实现这一目标，我们建议构建聚合物偶联物，通过在聚合物主链上嫁接的纳米机械装置(即分子镊子)的构象变化来释放药物。分子钳可以被设计成在特定构象时对底物表现出非常高的亲和力，然后随着分子形状的变化而迅速失去结合性能。这种构象变化可以由外部介质的酸化触发，这种情况是大分子药物在被肿瘤细胞摄取后遇到的。

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.