Designer Anticancer Nanoprodrugs Featuring Self-toxification Activity Realized by Acid-triggered Biodegradation and in situ Fragments Complexation.
Designer Anticancer Nanoprodrugs Featuring Self-toxification Activity Realized by Acid-triggered Biodegradation and in situ Fragments Complexation.
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DOI：
10.1002/anie.202102704
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发表时间：
2021-03
影响因子：
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通讯作者：
Yannan Yang;M. Zhang;Yang Yang-Yang;Dan Cheng;Chengzhong Yu
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文献类型：
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作者：
Yannan Yang;M. Zhang;Yang Yang-Yang;Dan Cheng;Chengzhong Yu
允许响应于某些刺激将毒性较小的前体原位化学转化为活性药物的前药是有希望的抗癌候选物。在此，我们提出了一种新的设计纳米前药与“降解介导的自组装”的策略，实现细胞内合成的抗癌药物使用纳米粒子的自身降解片段作为前体。为了实现这一概念，从各种配体中仔细筛选出金属络合二环己基膦（DCP）有机硅烷以缀合到Pd（OH）2纳米点限定的中空二氧化硅纳米球（PD-HSN）上。这种构建的纳米前药在溶酶体中显示出酸触发的降解，并中和质子以诱导溶酶体破裂，产生预先设计的毒性较小的片段（Pd 2+和DCP-硅酸盐），其原位复合成DCP/Pd复合物以诱导DNA损伤，导致对各种癌细胞系以及异种移植肿瘤模型的增强的抗癌活性。
Prodrugs that allow in situ chemical conversion of less toxic precursors into active drugs in response to certain stimuli are promising anticancer candidates. Herein, we present a novel design of nanoprodrugs with a "degradation-mediated self-toxification" strategy, which realizes intracellular synthesis of anticancer agents using nanoparticles' own degradation fragments as the precursors. To fulfill this concept, a metal complexing dicyclohexylphosphine (DCP) organosilane is carefully screened out from various ligands to conjugate onto Pd(OH) 2 nanodots confined hollow silica nanospheres (PD-HSN). This constructed nanoprodrug shows acid-triggered degradation in lysosomes and neutralize protons to induce lysosomes rupturing, generating predesigned less toxic fragments (Pd 2+ and DCP-silicates) that complex into DCP/Pd complex in situ for inducing DNA damage, leading to enhanced anticancer activity against various cancer cell lines as well as in a xenograft tumour model.