Design of a pH-sensitive polymeric carrier for drug release and its application in cancer therapy
Design of a pH-sensitive polymeric carrier for drug release and its application in cancer therapy
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DOI：
10.1158/1078-0432.ccr-03-0544
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发表时间：
2004-04-01
影响因子：
11.5
通讯作者：
Mayumi, T
中科院分区：
文献类型：
--
作者：
Kamada, H;Tsutsumi, Y;Mayumi, T
目的：在本研究中，为了优化用于癌症化疗的聚合物药物递送系统，我们开发了一种新的ph敏感聚合物载体，聚（乙烯基吡咯烷酮-共二甲基马来酸酐）[PVD]，它可以随着ph的变化从缀合物中逐渐释放具有充分活性的天然形式的药物。我们检验了PVD作为聚合物药物载体的有效性。实验设计：以乙烯基吡咯烷酮和已知的ph可逆氨基保护试剂2,3-二甲基马来酸酐为原料，从根本上合成PVD。在微碱性条件下（pH 8.5）制备了PVD与阿霉素（ADR）等药物的偶联物。研究了PVD的药物释放模式和抗肿瘤活性。结果：在pH 8.5时，未观察到药物从缀合物中释放。相比之下，PVD可以在pH接近中性的情况下以天然形式释放完全活性药物，并在中性pH（7.0）和微酸性pH（6.0）下逐渐释放药物。药物在血清中的释放模式与在这些生理条件下观察到的几乎相似。pvd偶联ADR对小鼠肉瘤-180实体瘤具有较强的抗肿瘤活性，毒副作用小于游离ADR。这种抗肿瘤治疗窗口期的增强可能不仅是由于ADR的血浆半衰期和肿瘤积累的改善，而且是由于其在体内偶联物的控制和持续释放。结论：PVD是优化肿瘤治疗的有效载体。
Purpose: In this study, to optimize the polymeric drug delivery system for cancer chemotherapy, we developed a new pH-sensitive polymeric carrier, poly(vinylpyrrolidone-co-dimethylmaleic anhydride) [PVD], that could gradually release native form of drugs with full activity, from the conjugates in response to changes in pH. We examined the usefulness of PVD as a polymeric drug carrier.Experimental Design: PVD was radically synthesized with vinylpyrrolidone and 2,3-dimethylmaleic anhydride, which is known to be a pH-reversible amino-protecting reagent. Conjugates between PVD and other drugs, such as Adriamycin (ADR), were prepared under the slightly basic conditions (pH 8.5). The drug-release pattern and the antitumor activity of PVD were examined.Results: At pH 8.5, the release of the drugs from the conjugate was not observed. In contrast, PVD could release fully active drugs in the native form in response to the change in pH near neutrality, and gradually released drugs at neutral pH (7.0) and slightly acidic pH (6.0). The drug-release pattern in serum was almost similar to that observed during these physiological conditions. The PVD-conjugated ADR showed superior antitumor activity against sarcoma-180 solid tumor in mice, and it had less toxic side effects than free ADR. This enhancement in the antitumor therapeutic window may be due to not only the improvement of plasma half-lives and tumor accumulation of ADR, but also its controlled and sustained release from the conjugates in vivo.Conclusions: These results indicate that PVD is an effective polymeric carrier for optimizing cancer therapy.