Polymeric modification of gemcitabine via cyclic acetal linkage for enhanced anticancer potency with negligible side effects
Polymeric modification of gemcitabine via cyclic acetal linkage for enhanced anticancer potency with negligible side effects
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DOI：
10.1016/j.biomaterials.2020.119804
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发表时间：
2020-03-01
期刊：
影响因子：
14
通讯作者：
Nishiyama, Nobuhiro
中科院分区：
文献类型：
--
作者：
Takemoto, Hiroyasu;Inaba, Takanori;Nishiyama, Nobuhiro
吉西他滨（GEM）是一种治疗多种癌症的强效抗癌药物。然而，有效的治疗方法应解决抗癌功效和副作用。为此，我们创建了一个GEM共轭聚合物（PGEM）的基础上环缩醛连接作为交付载体的GEM。所获得的P-GEM在生理pH（即，血流），但响应于酸性环境如内体/溶酶体释放GEM。P-GEM对荷瘤小鼠全身给药后，相对于游离GEM系统，其可延长血液循环并增强肿瘤蓄积。此外，P-GEM的聚合物-药物缀合物结构实现了在肿瘤组织中的有效分布，从而在肿瘤部位的大部分区域诱导凋亡。值得注意的是，P-GEM的分子设计实现了在正常组织中的最小积累，导致可忽略的GEM衍生的不良反应（例如，胃肠道毒性和血液毒性）。最终，与游离GEM系统相比，基于GEM的甚至四倍更小剂量的P-GEM对于两种不同的胰腺肿瘤模型实现了相当/更高的肿瘤生长抑制作用。所获得的结果表明，目前的设计的巨大潜力的GEM共轭聚合物的抗癌治疗。
Gemcitabine (GEM) is a powerful anticancer drug for various cancers. However, the anticancer efficacy and the side effects should be addressed for effective therapeutics. To this end, we created a GEM-conjugated polymer (PGEM) based on cyclic acetal linkage as a delivery carrier of GEM. The obtained P-GEM stably conjugated GEM at physiological pH (i.e., bloodstream), but released GEM in response to acidic environments such as endosome/lysosome. After systemic administration of P-GEM for mice bearing subcutaneous tumors, it achieved prolonged blood circulation and enhanced tumor accumulation relative to free GEM system. In addition, the polymer-drug conjugate structure of P-GEM realized effective distribution in the tumor tissues toward the induction of apoptosis in most areas of the tumor sites. Of note, the molecular design of P-GEM achieved minimal accumulation in normal tissues, resulting in negligible GEM-derived adverse effects (e.g., gastrointestinal toxicity and hematotoxicity). Ultimately, even four times smaller dose of P-GEM on a GEM basis realized comparable/higher tumor growth suppression effect for two distinct pancreatic tumor models, compared to free GEM system. The obtained results suggest the huge potential of the present design of GEM-conjugated polymer for anticancer therapeutics.