Laboratory of Tumor Immunology, Institute of Microbiology of the Czech Academy of Sciences, Vídeňská 1083, 142 20 Prague, 4, Czech Republic.
Department of Biomedicinal Polymers, Institute of Macromolecular Chemistry of the Czech Academy of Sciences, Heyrovský Sq. 2, 162 06 Prague, 6, Czech Republic.
J Control Release. 2017 Jan 28;246:1-11. doi: 10.1016/j.jconrel.2016.12.004. Epub 2016 Dec 6.
The tumor-specific targeting of cancerostatics using polymer drug carriers represents a potential strategy to achieve an effective treatment with reduced side toxicity. Synthetic water-soluble copolymers based on N-(2-hydroxypropyl)methacrylamide (HPMA) are carriers with tunable architecture and drug loading, tumor-specific accumulation of the drug, and its controlled release. We describe a combination treatment of murine EL4 T cell lymphoma with HPMA-based star conjugates (M 250,000gmol) of doxorubicin (Dox) or docetaxel (Dtx) designed for enhanced tumor accumulation and combination therapy. Although the combination of linear conjugates (M=28,000gmol) containing Dox or Dtx resulted in an additive effect in the treatment of the lymphoma, the opposite was observed in the combination of two star conjugates with Dox or Dtx, as the star Dtx conjugate decreased the treatment efficacy of the star Dox conjugate. The Dtx conjugate alone was virtually ineffective in the reduction of tumor growth or survival time extension; thus, a curative effect could be solely attributed to the Dox-containing conjugate. When Dtx was delivered to the tumor on the same polymer carrier as Dox, the efficacy of the Dox-induced treatment was reduced to a lesser extent. No reduction was found when Dtx was delivered by a linear polymer or applied as a free drug. The phenomenon was strictly related to the enhanced permeability and retention (EPR) effect, as it was not observed in BCL1 leukemia, a model without EPR. The diminished treatment outcome in the combination therapy with the two star conjugates was underlined by the significantly decreased accumulation of Dox in the tumor. The use of the drug-free polymer carrier instead of the Dtx-containing star conjugate did not reduce the treatment efficacy of the Dox conjugate. Thus, the physicochemical characteristics of the polymer carrier designed for tumor-specific drug delivery systems control the activity of the respective drug, leading to changes within the tumor microenvironment that can determine ultimate efficacy of the combination therapy.
使用聚合物药物载体对癌症抑制剂进行肿瘤特异性靶向治疗，代表了一种实现有效治疗、降低副作用的潜在策略。基于 N-(2-羟丙基)甲基丙烯酰胺（HPMA）的合成水溶性共聚物是具有可调节结构和药物负载、药物在肿瘤中的特异性积累以及其控制释放的载体。我们描述了使用基于 HPMA 的星型缀合物（M 250,000gmol）对小鼠 EL4 T 细胞淋巴瘤进行的联合治疗，该缀合物设计用于增强肿瘤积累和联合治疗，包含阿霉素（Dox）或多西紫杉醇（Dtx）。尽管含有 Dox 或 Dtx 的线性缀合物（M=28,000gmol）的组合治疗导致淋巴瘤的治疗效果呈相加作用，但在含有 Dox 或 Dtx 的两种星型缀合物的组合中观察到相反的结果，因为星型 Dtx 缀合物降低了星型 Dox 缀合物的治疗效果。单独的 Dtx 缀合物在减少肿瘤生长或延长生存时间方面几乎没有效果；因此，仅归因于含 Dox 的缀合物。当 Dtx 与 Dox 一起递送至肿瘤上的相同聚合物载体时，Dox 诱导的治疗效果降低的程度较小。当 Dtx 通过线性聚合物递送至肿瘤或作为游离药物应用时，未发现降低。这种现象与增强的通透性和保留（EPR）效应密切相关，因为在没有 EPR 的 BCL1 白血病模型中没有观察到这种现象。在两种星型缀合物的联合治疗中，Dox 在肿瘤中的积累明显减少，突出了治疗效果的降低。使用无药物聚合物载体代替含 Dtx 的星型缀合物不会降低 Dox 缀合物的治疗效果。因此，设计用于肿瘤特异性药物传递系统的聚合物载体的物理化学特性控制了各自药物的活性，导致肿瘤微环境发生变化，从而决定了联合治疗的最终疗效。
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