Cocktail polyprodrug nanoparticles concurrently release cisplatin and peroxynitrite-generating nitric oxide in cisplatin-resistant cancers
Cocktail polyprodrug nanoparticles concurrently release cisplatin and peroxynitrite-generating nitric oxide in cisplatin-resistant cancers
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DOI：
10.1016/j.cej.2020.126125
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发表时间：
2020-12-15
影响因子：
15.1
通讯作者：
Hu, Xianglong
中科院分区：
文献类型：
--
作者：
Chu, Chengyan;Lyu, Xiaoming;Hu, Xianglong
严重的多药耐药经常影响一线化疗药物顺铂的疗效。在这里，我们报告了鸡尾酒聚前药纳米颗粒（CPNs），可以同时泵出一氧化氮（NO）和过氧亚硝酸盐（ONOO-），以应对还原性细胞溶质环境，以克服顺铂耐药的癌症。顺铂和一氧化氮（NO）的支化聚前药两亲物P（DMA-co-PtMA-co-StNO）由顺铂前药交联剂单体（PtMA）、NO前药单体（StNO）和亲水性单体N，N-二甲基丙烯酰胺（DMA）的一锅共聚容易地制备。含有双前药的支化聚前药可以在水中自组装成球形CPN。在被癌细胞摄取后，CPN被还原性胞质环境降解，以在局部位点同时释放NO和顺铂双重母体药物。释放的顺铂可以激活烟酰胺腺嘌呤二核苷酸磷酸氧化酶（NOX）以催化O-2成为超氧化物（O-2（中心点-）），其进一步与原位释放的NO反应以产生高活性的ONOO-，其比O-2（中心点-）或仅NO更致命。体外和体内分析表明，CPNs可以有效地克服顺铂耐药，目前的合作模式。合理设计的鸡尾酒式聚前药为高效泵出NO和ONOO-提供了一个有限的空间，在逆转顺铂耐药性，实现肿瘤的精确临床治疗方面具有诱人的前景。
Severe multidrug resistance has frequently compromised the therapeutic efficacy of one first-line chemotherapeutic drug cisplatin. Here, we report cocktail polyprodrug nanoparticles (CPNs) that can concurrently pump out nitric oxide (NO) and peroxynitrite (ONOO-) in response to reductive cytosolic milieu to overcome cisplatin-resistant cancers. Branched polyprodrug amphiphiles of cisplatin and nitric oxide (NO), P(DMA-co-PtMA-co-StNO), are facilely fabricated from one-pot co-polymerization of cisplatin prodrug crosslinker monomer (PtMA), NO prodrug monomer (StNO), and hydrophilic monomer, N, N-dimethylacrylamide (DMA). The branched polyprodrug containing dual prodrugs can self-assemble into spherical CPNs in water. Upon cellular uptake by cancer cells, CPNs are degraded by reductive cytosolic milieu to concurrently release NO and cisplatin dual parent drugs at local sites. The released cisplatin can activate nicotinamide adenine dinucleotide phosphate oxidase (NOXs) to catalyze O-2 into superoxide (O-2(center dot-)), which further reacts with in-situ released NO to produce highly reactive ONOO- that is more lethal than O-2(center dot-) or NO only. In vitro and in vivo analyses demonstrate that CPNs can efficiently overcome cisplatin resistance by current collaborative modalities. The rational design of cocktail polyprodrug provides a confined space to pump out NO and ONOO- efficiently, which has alluring prospect to reverse the cisplatin resistance for precision clinical cancer therapy.