Redox-responsive self-assembled polymeric nanoprodrug for delivery of gemcitabine in B-cell lymphoma therapy
Redox-responsive self-assembled polymeric nanoprodrug for delivery of gemcitabine in B-cell lymphoma therapy
复制标题
用于 B 细胞淋巴瘤治疗中吉西他滨递送的氧化还原响应自组装聚合物纳米前药
DOI：
10.1016/j.actbio.2022.03.035
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发表时间：
2022
影响因子：
9.7
通讯作者：
Jun Wu
中科院分区：
文献类型：
--
作者：
Wenhao Zhong;Xinyu Zhang;Xiao Duan;Hengyu Liu;Yifen Fang;Moucheng Luo;Zhengwen Fang;Congxiu Miao;Dongjun Lin;Jun Wu
吉西他滨作为临床治疗B细胞淋巴瘤的标准和经典策略，其药效学较差。虽然刺激响应性聚合物纳米递送系统在过去十年中已被广泛研究，但诸如复杂的程序、低负载能力和不可控的释放动力学等问题仍然阻碍其临床转化。基于上述考虑，我们尝试通过简单的方法构建具有相当载药量的超支化聚前药胶束，并利用肿瘤微环境的特殊性，确保胶束在正常组织中“失活”而在肿瘤微环境中“活化”。因此，在这项工作中，氧化还原响应性聚合物吉西他滨-前药（GEM-S-S-PEG）是通过简单的酯化和酰化一锅合成。自组装的亚尺寸（< 100 nm）GEM-S-S-PEG（GSP NPs）具有相当大的负载量（约24.6%），在模拟肿瘤微环境下表现出按需和精确的控制吉西他滨的释放，从而在体外显著诱导B细胞淋巴瘤的凋亡。此外，在A20肿瘤异种移植鼠模型中，GSP NPs有效地降低了肿瘤组织的扩张，具有最小的全身毒性。总的来说，这些具有氧化还原响应性和自组装的GSP纳米颗粒与一个简单的一锅合成程序可能在临床翻译中具有很大的潜力，用于增强B细胞淋巴瘤的化疗。通过酯化和酰化反应，一锅法合成了GEM-S-S-PEG。（< 100 nm）GEM-S-S-PEG（GSP NPs）在体外和体内均表现出显著的肿瘤治疗效果，本研究制备的聚前药GEM-S-S-PEG显示了氧化还原响应性纳米药物的巨大潜力，为功能性聚前药的优化设计提供了参考价值。
Gemcitabine, as a standard and classic strategy for B-cell lymphoma in the clinic, is limited by its poor pharmacodynamics. Although stimuli-responsive polymeric nanodelivery systems have been widely investigated in the past decade, issues such as complicated procedures, low loading capacity, and uncontrollable release kinetics still hinder their clinical translation. In view of the above considerations, we attempt to construct hyperbranched polyprodrug micelles with considerable drug loading via simple procedures and make use of the particularity of the tumor microenvironment to ensure that the micelles are “inactivated” in normal tissues and “activated” in the tumor microenvironment. Hence, in this work, a redox-responsive polymeric gemcitabine-prodrug (GEM-S-S-PEG) was one-pot synthesized via facile esterification and acylation. The self-assembled subsize (< 100 nm) GEM-S-S-PEG (GSP NPs) with considerable loading capacity (≈ 24.6%) exhibited on-demand and accurate control of gemcitabine release under a simulated tumor microenvironment and thus significantly induced the apoptosis of B-cell lymphomain vitro. Moreover, in the A20 tumor xenograft murine model, GSP NPs efficiently decreased the expansion of tumor tissues with minimal systemic toxicity. In summary, these redox-responsive and self-assembling GSP NPs with a facile one-pot synthesis procedure may hold great potency in clinical translation for enhanced chemotherapy of B-cell lymphoma.Statement of significanceA redox-responsive polymeric gemcitabine-prodrug (GEM-S-S-PEG) was one-pot synthesizedviafacile esterification and acylation.The self-assembled subsize (< 100 nm) GEM-S-S-PEG (GSP NPs) exhibited significant tumor therapeutic effectsin vitroandin vivo.The polyprodrug GEM-S-S-PEG prepared in this study shows the great potential of redox-responsive nanodrugs for antitumor activity, which provides a reference value for the optimization of the design of functional polyprodrugs.