Drug efficiency delivery and release to target site play an important role in the treatment of cancer. To achieve these goals, developing drug delivery systems is the key step. The common materials used for drug deliv...Drug efficiency delivery and release to target site play an important role in the treatment of cancer. To achieve these goals, developing drug delivery systems is the key step. The common materials used for drug delivery like liposomes, micelles, dendrimers cannot control the delivery and releasing by spatial and temporal. In this paper, we design a photoresponsive drug delivery system to reduce the side effects of traditional chemotherapy on normal cells and improve therapeutic efficacy in treating cancers. We synthesized two kinds of photo-responsive polymers using two different monomers containing two photoresponsive groups. The two monomers were crosslinked by poly （ethylene glycol） dimethacrylate to form polymers and then encapsulated β-lapachone into the nanoparticles, after UV irradiation, the particle will degrade and release the drug. This method may provide new strategies for the photoresponsive nanomaterials.展开更多
In non-small cell lung cancer(NSCLC),poly(ADP-ribose)polymerase 1(PARP1)induces genomic instability and promotes tumor progression by impairing DNA repair pathways.Although PARP1-targeting proteolysis-targeting chimer...In non-small cell lung cancer(NSCLC),poly(ADP-ribose)polymerase 1(PARP1)induces genomic instability and promotes tumor progression by impairing DNA repair pathways.Although PARP1-targeting proteolysis-targeting chimeras(PROTACs)offer a promising strategy for selective protein degradation,their clinical application remains limited by poor water solubility and insufficient tumor selectivity.Here,we report a pHresponsive magnetic nanoparticle system co-delivering β-lapachone(β-lap)and a PARP1-targeted PROTAC(PRO)for synergistic and tumor-targeting therapy.Designed with a hydrophobic self-assembled core and a magnetic coating,the nanoparticle(NP_(β-lap+PRO))enables pHresponsive drug release and magnetic resonance imaging(MRI)monitoring.β-Lap is a bioactivated drug that relies on NAD(P)H:quinone oxidoreductase 1(NQO1),which is overexpressed in NSCLC cells.It has the potential to deliver tumor-selective DNA damage and induce cell death.The NP_(β-lap+PRO) exploits elevated NQO1 levels in NSCLC to initiate β-lap-driven oxidative stress and DNA damage,while simultaneously enhancing PROTAC-mediated PARP1 degradation within the acidic tumor microenvironment synergistically induces apoptosis.In A549 NSCLC tumor models,this system effectively induces PARP1 degradation,blocks DNA repair,and preserves NAD(P)H pools,thereby amplifying β-lapinduced reactive oxygen species production,leading to enhanced DNA double-strand breaks and apoptosis.This study presents a biomarker-driven nanotherapeutic strategy that integrates PROTAC technology with redox-targeted combination therapy,offering a promising approach for precision treatment of NSCLC.展开更多
β-Lapachone (β-Lap) is a promising orthonaphthoquinone drug for cancer treatment and has been inclinical trials. Its application is constrained by the low aqueoussolubility, and severe side effects. Even prodrug des...β-Lapachone (β-Lap) is a promising orthonaphthoquinone drug for cancer treatment and has been inclinical trials. Its application is constrained by the low aqueoussolubility, and severe side effects. Even prodrug designation isan effective approach to render it with tumor selectivity, it islimited by the lack of modifiable groups on β-Lap. Herein, anovel azo bond primary cleavage and carbon–carbon (C–C)bond secondary cleavage-based polymeric β-Lap prodrug(Azo-Lap NP) is designed, in which the self-immolated paraaminobenzyl linker is connected to poly(L-glutamic acid)(PGlu) via azo linkage and the responsive drug release of β-Lapagainst tumors can be achieved under high NAD(P)H:quinoneoxidoreductase 1 (NQO1) expression and low pH environmentin tumors. The effective covalent loading of β-Lap by Azo-LapNPs permitted a high administration dose of β-Lap and enabled significant tumor retention time. Moreover, Azo-LapNPs markedly reduced the side effects of β-Lap by avoidinghemolysis and the production of methemoglobin. The safety ofAzo-Lap NPs administration is validated in the antitumorexperiment of mice. In the 4T1 model, Azo-Lap NPs exhibiteda markedly higher tumor suppression rate than β-Lap. Thiswork provides an effective and safe polymeric prodrug fortumor selective delivery of β-Lap.展开更多
文摘Drug efficiency delivery and release to target site play an important role in the treatment of cancer. To achieve these goals, developing drug delivery systems is the key step. The common materials used for drug delivery like liposomes, micelles, dendrimers cannot control the delivery and releasing by spatial and temporal. In this paper, we design a photoresponsive drug delivery system to reduce the side effects of traditional chemotherapy on normal cells and improve therapeutic efficacy in treating cancers. We synthesized two kinds of photo-responsive polymers using two different monomers containing two photoresponsive groups. The two monomers were crosslinked by poly （ethylene glycol） dimethacrylate to form polymers and then encapsulated β-lapachone into the nanoparticles, after UV irradiation, the particle will degrade and release the drug. This method may provide new strategies for the photoresponsive nanomaterials.
基金supported by the Key Laboratory of Advanced Interdisciplinary Studies,The First Affiliated Hospital of Guangzhou Medical University of China(No.2023A03J0355)OpenProject of State Key Laboratory of Respiratory Disease of China(No.SKIRD OP-202311)Guangdong Provincial Zhong Nanshan Medical Foundation of China(No.ZNS-XS-ZZ-202409-007).
文摘In non-small cell lung cancer(NSCLC),poly(ADP-ribose)polymerase 1(PARP1)induces genomic instability and promotes tumor progression by impairing DNA repair pathways.Although PARP1-targeting proteolysis-targeting chimeras(PROTACs)offer a promising strategy for selective protein degradation,their clinical application remains limited by poor water solubility and insufficient tumor selectivity.Here,we report a pHresponsive magnetic nanoparticle system co-delivering β-lapachone(β-lap)and a PARP1-targeted PROTAC(PRO)for synergistic and tumor-targeting therapy.Designed with a hydrophobic self-assembled core and a magnetic coating,the nanoparticle(NP_(β-lap+PRO))enables pHresponsive drug release and magnetic resonance imaging(MRI)monitoring.β-Lap is a bioactivated drug that relies on NAD(P)H:quinone oxidoreductase 1(NQO1),which is overexpressed in NSCLC cells.It has the potential to deliver tumor-selective DNA damage and induce cell death.The NP_(β-lap+PRO) exploits elevated NQO1 levels in NSCLC to initiate β-lap-driven oxidative stress and DNA damage,while simultaneously enhancing PROTAC-mediated PARP1 degradation within the acidic tumor microenvironment synergistically induces apoptosis.In A549 NSCLC tumor models,this system effectively induces PARP1 degradation,blocks DNA repair,and preserves NAD(P)H pools,thereby amplifying β-lapinduced reactive oxygen species production,leading to enhanced DNA double-strand breaks and apoptosis.This study presents a biomarker-driven nanotherapeutic strategy that integrates PROTAC technology with redox-targeted combination therapy,offering a promising approach for precision treatment of NSCLC.
基金financially supported by the Ministry of Science and Technology of the People’s Republic of China (2022YFE0110200)the National Natural Science Foundation of China (52025035, 52273157, and 52073279)+1 种基金the Department of Science and Technology of Jilin Province (20240305041YY and 20230508102RC)the Youth Innovation Promotion Association of the Chinese Academy of Sciences (2022224)。
文摘β-Lapachone (β-Lap) is a promising orthonaphthoquinone drug for cancer treatment and has been inclinical trials. Its application is constrained by the low aqueoussolubility, and severe side effects. Even prodrug designation isan effective approach to render it with tumor selectivity, it islimited by the lack of modifiable groups on β-Lap. Herein, anovel azo bond primary cleavage and carbon–carbon (C–C)bond secondary cleavage-based polymeric β-Lap prodrug(Azo-Lap NP) is designed, in which the self-immolated paraaminobenzyl linker is connected to poly(L-glutamic acid)(PGlu) via azo linkage and the responsive drug release of β-Lapagainst tumors can be achieved under high NAD(P)H:quinoneoxidoreductase 1 (NQO1) expression and low pH environmentin tumors. The effective covalent loading of β-Lap by Azo-LapNPs permitted a high administration dose of β-Lap and enabled significant tumor retention time. Moreover, Azo-LapNPs markedly reduced the side effects of β-Lap by avoidinghemolysis and the production of methemoglobin. The safety ofAzo-Lap NPs administration is validated in the antitumorexperiment of mice. In the 4T1 model, Azo-Lap NPs exhibiteda markedly higher tumor suppression rate than β-Lap. Thiswork provides an effective and safe polymeric prodrug fortumor selective delivery of β-Lap.
