Postpolymerization modification of highly defined “scaffold” polymers is a promising approach for overcoming the existing limitations of controlled radical polymerization such as batch-to-batch inconsistencies, accessibility to different monomers, and compatibility with harsh synthesis conditions. Using multiple physicochemical characterization techniques, we demonstrate that poly(2-vinyl-4,4-dimethyl azlactone) (PVDMA) scaffolds can be efficiently modified with a coumarin derivative, doxorubicin, and camptothecin small molecule drugs. Subsequently, we show that coumarin-modified PVDMA has a high cellular biocompatibility and that coumarin derivatives are liberated from the polymer in the intracellular environment for cytosolic accumulation. In addition, we report the pharmacokinetics, biodistribution, and antitumor efficacy of a PVDMA-based polymer for the first time, demonstrating unique accumulation patterns based on the administration route (i.e., intravenous vs oral), efficient tumor uptake, and tumor growth inhibition in 4T1 orthotopic triple negative breast cancer (TNBC) xenografts. This work establishes the utility of PVDMA as a versatile chemical platform for producing polymer-drug conjugates with a tunable, stimuli-responsive delivery.

中文翻译：

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聚（2-乙烯基-4,4-二甲基吖内酯）的后聚合修饰作为药物缀合和刺激响应释放的多功能策略

高度明确的“支架”聚合物的后聚合改性是克服受控自由基聚合现有局限性的一种有前途的方法，例如批次间的不一致、不同单体的可访问性以及与恶劣合成条件的兼容性。使用多种物理化学表征技术，我们证明聚（2-乙烯基-4,4-二甲基吖内酯）（PVDMA）支架可以用香豆素衍生物、阿霉素和喜树碱小分子药物进行有效修饰。随后，我们证明香豆素修饰的PVDMA具有高细胞生物相容性，并且香豆素衍生物在细胞内环境中从聚合物中释放出来并在细胞质中积累。此外，我们首次报告了基于 PVDMA 的聚合物的药代动力学、生物分布和抗肿瘤功效，证明了基于给药途径（即静脉注射与口服）的独特积累模式、有效的肿瘤摄取和肿瘤生长抑制。 4T1 原位三阴性乳腺癌 (TNBC) 异种移植物。这项工作确立了 PVDMA 作为多功能化学平台的实用性，用于生产具有可调节、刺激响应性递送的聚合物-药物缀合物。