Human cancers typically express a high level of tumor-promoting mutant p53 protein(Mutp53)with a minimal level of tumor-suppressing wild-type p53 protein(WTp53).In this regard,inducing Mutp53 degradation while activat...Human cancers typically express a high level of tumor-promoting mutant p53 protein(Mutp53)with a minimal level of tumor-suppressing wild-type p53 protein(WTp53).In this regard,inducing Mutp53 degradation while activating WTp53 is a viable strategy for precise anti-tumor therapy.Herein,a new carrier-free nanoprodrug(i.e.,Mn-ZnO_(2)nanoparticles)was developed for concurrent delivery of dual Zn-Mn ions and reactive oxygen species(ROS)within tumor to regulate the p53 protein for high anti-tumor efficacy.In response to the mild tumor acidic environment,the released Zn^(2+)and H_(2)O_(2)from Mn-ZnO_(2)NPs induced ubiquitination-mediated proteasomal degradation of Mutp53,while the liberative Mn^(2+)and increased ROS level activated the ATM-p53-Bax pathway to elevate WTp53 level.Both in vitro and in vivo results demonstrated that pH-responsive decomposition of Mn-ZnO2 NPs could effectively elevate the intracellular dual Zn-Mn ions and ROS level and subsequently generate the cytotoxic hydroxyl radical(·OH)through the Fenton-like reaction.With the integration of multiple functions(i.e.,carrier-free ion and ROS delivery,tumor accumulation,p53 protein modulation,toxic·OH generation,and pH-activated MRI contrast)in a single nanosystem,Mn-ZnO_(2)NPs demonstrate its superiority as a promising nanotherapeutics for p53-mutated tumor therapy.展开更多
Near-infrared(NIR)-light-triggered nanomedicine, including photodynamic therapy(PDT)and photothermal therapy(PTT), is growing an attractive approach for cancer therapy due to its high spatiotemporal controllability an...Near-infrared(NIR)-light-triggered nanomedicine, including photodynamic therapy(PDT)and photothermal therapy(PTT), is growing an attractive approach for cancer therapy due to its high spatiotemporal controllability and minimal invasion, but the tumor eradication is limited by the intrinsic anti-stress response of tumor cells. Herein, we fabricate a tumor-microenvironment responsive CRISPR nanoplatform based on oxygen-deficient titania(TiO_(2-x)) for mild NIR-phototherapy. In tumor microenvironment, the overexpressed hyaluronidase(HAase) and glutathione(GSH) can readily destroy hyaluronic acid(HA) and disulfide bond and releases the Cas9/sgRNA from TiO_(2-x) to target the stress alleviating regulators, i.e., nuclear factor E2-related factor 2(NRF2) and heat shock protein 90a(HSP90a), thereby reducing the stress tolerance of tumor cells. Under subsequent NIR light illumination, the TiO_(2-x) demonstrates a higher anticancer effect both in vitro and in vivo. This strategy not only provides a promising modality to kills cancer cells in a minimal side-effects manner by interrupting anti-stress pathways but also proposes a general approach to achieve controllable gene editing in tumor region without unwanted genetic mutation in normal environments.展开更多
Nanoprodrugs that are directly assembled by prodrugs attract considerable attention with high anticancer potentials.However,their stability and efficiency of tumor-targeted delivery remain a major challenge in practic...Nanoprodrugs that are directly assembled by prodrugs attract considerable attention with high anticancer potentials.However,their stability and efficiency of tumor-targeted delivery remain a major challenge in practical biomedical applications.Here,we report a new deep tumor-penetrating nano-delivery strategy to achieve enhanced anti-cancer performance by systematic optimization of a porphyrin-doxorubicin-based nanoprodrug using various PEGylations/crosslinks and co-administration of targeting peptide iRGD.Polyethylene glycols(PEGs)with different molecular weights and grafts are employed to crosslink the nanoprodrug and optimize size,charge,tumor accumulation and penetration,and anti-cancer efficiency,etc.The tumor penetration was validated in syngeneic oral cancer mouse models,patient-derived xenograft(PDX)models,and oral cancer tissue from patients.The optimized nanoprodrug co-administrated with iRGD remarkably enhances the accumulation and penetration both in tumor vascular and PDX tumor tissue.It is effective and safe to improve in vivo therapeutic efficacy via the passive tumor targeting dependent and independent mode.Our tumor-penetrating nano-delivery strategy is promising to strengthen the nanoprodrugs in clinical implementation.展开更多
基金supported by the NIAMS award number 1R01AR067859National Natural Science Foundation of China(82102208,81830061)+2 种基金Program for Excellent Innovative Talents in Universities of Hebei Province(BJ2021019)Natural Science Foundation of Hebei Province(H2021202002,H2020202005)the Natural Science Foundation of Tianjin(19JCYBJC28300).
文摘Human cancers typically express a high level of tumor-promoting mutant p53 protein(Mutp53)with a minimal level of tumor-suppressing wild-type p53 protein(WTp53).In this regard,inducing Mutp53 degradation while activating WTp53 is a viable strategy for precise anti-tumor therapy.Herein,a new carrier-free nanoprodrug(i.e.,Mn-ZnO_(2)nanoparticles)was developed for concurrent delivery of dual Zn-Mn ions and reactive oxygen species(ROS)within tumor to regulate the p53 protein for high anti-tumor efficacy.In response to the mild tumor acidic environment,the released Zn^(2+)and H_(2)O_(2)from Mn-ZnO_(2)NPs induced ubiquitination-mediated proteasomal degradation of Mutp53,while the liberative Mn^(2+)and increased ROS level activated the ATM-p53-Bax pathway to elevate WTp53 level.Both in vitro and in vivo results demonstrated that pH-responsive decomposition of Mn-ZnO2 NPs could effectively elevate the intracellular dual Zn-Mn ions and ROS level and subsequently generate the cytotoxic hydroxyl radical(·OH)through the Fenton-like reaction.With the integration of multiple functions(i.e.,carrier-free ion and ROS delivery,tumor accumulation,p53 protein modulation,toxic·OH generation,and pH-activated MRI contrast)in a single nanosystem,Mn-ZnO_(2)NPs demonstrate its superiority as a promising nanotherapeutics for p53-mutated tumor therapy.
基金supported by the National Key R&D Program of China (2019YFA0709200)the financial support from the National Natural Science Foundation of China (21874066, 81601632, and 31901010)+5 种基金the Natural Science Foundation of Jiangsu Province(BK20160616, China)the Fundamental Research Funds for Central Universitiesthe Priority Academic Program Development of Jiangsu Higher Education Institutions (Integration of Chinese and Western Medicine, China)the Key International Cooperation of the National Natural Science Foundation of China (No.81920108029)the Key Foundation for Social Development Project of the Jiangsu Province,China (BE2021741)Jiangsu Specially Appointed Professorship Foundation (China)
文摘Near-infrared(NIR)-light-triggered nanomedicine, including photodynamic therapy(PDT)and photothermal therapy(PTT), is growing an attractive approach for cancer therapy due to its high spatiotemporal controllability and minimal invasion, but the tumor eradication is limited by the intrinsic anti-stress response of tumor cells. Herein, we fabricate a tumor-microenvironment responsive CRISPR nanoplatform based on oxygen-deficient titania(TiO_(2-x)) for mild NIR-phototherapy. In tumor microenvironment, the overexpressed hyaluronidase(HAase) and glutathione(GSH) can readily destroy hyaluronic acid(HA) and disulfide bond and releases the Cas9/sgRNA from TiO_(2-x) to target the stress alleviating regulators, i.e., nuclear factor E2-related factor 2(NRF2) and heat shock protein 90a(HSP90a), thereby reducing the stress tolerance of tumor cells. Under subsequent NIR light illumination, the TiO_(2-x) demonstrates a higher anticancer effect both in vitro and in vivo. This strategy not only provides a promising modality to kills cancer cells in a minimal side-effects manner by interrupting anti-stress pathways but also proposes a general approach to achieve controllable gene editing in tumor region without unwanted genetic mutation in normal environments.
基金supported by National Institutes of Health/National Cancer Institute(Nos.R01CA199668 and R01CA232845)National Institutes of Health/National Institute of Dental and Craniofacial Research(No.1R01DE029237)+1 种基金National Institutes of Health/National Institute of Biomedical Imaging and Bioengineering(No.9R01EB033677-06A1)UC Davis Comprehensive Cancer Center Support Grant(CCSG)awarded by the National Cancer Institute(No.NCI P30CA093373).
文摘Nanoprodrugs that are directly assembled by prodrugs attract considerable attention with high anticancer potentials.However,their stability and efficiency of tumor-targeted delivery remain a major challenge in practical biomedical applications.Here,we report a new deep tumor-penetrating nano-delivery strategy to achieve enhanced anti-cancer performance by systematic optimization of a porphyrin-doxorubicin-based nanoprodrug using various PEGylations/crosslinks and co-administration of targeting peptide iRGD.Polyethylene glycols(PEGs)with different molecular weights and grafts are employed to crosslink the nanoprodrug and optimize size,charge,tumor accumulation and penetration,and anti-cancer efficiency,etc.The tumor penetration was validated in syngeneic oral cancer mouse models,patient-derived xenograft(PDX)models,and oral cancer tissue from patients.The optimized nanoprodrug co-administrated with iRGD remarkably enhances the accumulation and penetration both in tumor vascular and PDX tumor tissue.It is effective and safe to improve in vivo therapeutic efficacy via the passive tumor targeting dependent and independent mode.Our tumor-penetrating nano-delivery strategy is promising to strengthen the nanoprodrugs in clinical implementation.
