Journal
CHEMICAL ENGINEERING JOURNAL
Volume 402, Issue -, Pages -Publisher
ELSEVIER SCIENCE SA
DOI: 10.1016/j.cej.2020.126125
Keywords
Polyprodrug; Cisplatin resistance; Nitric oxide; Superoxide; Peroxynitrite
Categories
Funding
- National Natural Scientific Foundation of China [51973071, 21674040]
- Natural Science Foundation for Distinguished Young Scholars of Guangdong Province [2016A030306013]
- Pearl River Young Talents Program of Science and Technology in Guangzhou [201906010047]
- National Key Research and Development Program of China [2018YFA0209800]
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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.
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