Photodynamic therapy(PDT) has been widely investigated for cancer therapy. The intracellular accumulation of reactive oxygen species(ROS)-damaged protein facilitates tumor cell apoptosis. However, there is growing evi...Photodynamic therapy(PDT) has been widely investigated for cancer therapy. The intracellular accumulation of reactive oxygen species(ROS)-damaged protein facilitates tumor cell apoptosis. However, there is growing evidence that the ubiquitin-proteasome pathway(UPP) significantly impedes PDT by preventing the enrichment of ROS-damaged proteins in tumor cells. To tackle this challenge, we report a facile dual-drug nanoassembly based on the discovery of an interesting co-assembly of bortezomib(BTZ, a proteasome inhibitor) and pyropheophorbide a(PPa) for proteasome inhibition-mediated PDT sensitization.The precisely engineered nanoassembly with the optimal dose ratio of BTZ and PPa demonstrates multiple advantages, including simple fabrication, high drug co-loading efficiency, flexible dose adjustment,good colloidal stability, long systemic circulation, favorable tumor-specific accumulation, as well as significant enrichment of ROS-damaged proteins in tumor cells. As a result, the cooperative nanoassembly exhibits potent synergistic antitumor activity in vivo. This study provides a novel dual-drug engineering modality for multimodal cancer treatment.展开更多
One of the major barriers in utilizing prodrug nanocarriers for cancer therapy is the slow release of parent drug in tumors.Tumor cells generally display the higher oxidative level than normal cells,and also displayed...One of the major barriers in utilizing prodrug nanocarriers for cancer therapy is the slow release of parent drug in tumors.Tumor cells generally display the higher oxidative level than normal cells,and also displayed the heterogeneity in terms of redox homeostasis level.We previously found that the disulfide bond-linkage demonstrates surprising oxidationsensitivity to form the hydrophilic sulfoxide and sulphone groups.Herein,we develop oxidation-strengthened prodrug nanosystem loaded with pyropheophorbide a(PPa)to achieve light-activatable cascade drug release and enhance therapeutic efficacy.The disulfide bond-driven prodrug nanosystems not only respond to the redox-heterogeneity in tumor,but also respond to the exogenous oxidant(singlet oxygen)elicited by photosensitizers.Once the prodrug nanoparticles(NPs)are activated under irradiation,they would undergo an oxidative self-strengthened process,resulting in a facilitated drug cascade release.The IC50 value of the PPa@PTX-S-S NPs without irradiation was 2-fold higher than those of NPs plus irradiation.In vivo,the PPa@PTX prodrug NPs display prolonged systemic circulation and increased accumulation in tumor site.The PPa@PTXS-S NPs showed much higher efficiency than free PTX or the PPa@PTX-C-C NPs to suppress the growth of 4 T1 tumors.Therefore,this novel oxidation-strengthened disulfide-bridged prodrug-nanosystem has a great potential in the enhanced efficacy of cancer synergetic photochemotherapy.展开更多
Pure drug-assembled nanomedicines(PDANs)are currently under intensive investigation as promising nanoplatforms for cancer therapy.However,poor colloidal stability and less tumor-homing ability remain critical unresolv...Pure drug-assembled nanomedicines(PDANs)are currently under intensive investigation as promising nanoplatforms for cancer therapy.However,poor colloidal stability and less tumor-homing ability remain critical unresolved problems that impede their clinical translation.Herein,we report a core-matched nanoassembly of pyropheophorbide a(PPa)for photodynamic therapy(PDT).Pure PPa molecules are found to self-assemble into nanoparticles(NPs),and an amphiphilic PEG polymer(PPaPEG_(2K))is utilized to achieve core-matched PEGylating modification via the p-p stacking effect and hydrophobic interaction between the PPa core and the PPa-PEG_(2K) shell.Compared to PCL-PEG_(2K) with similar molecular weight,PPa-PEG_(2K) significantly increases the stability,prolongs the systemic circulation and improves the tumor-homing ability and ROS generation efficiency of PPa-nanoassembly.As a result,PPa/PPa-PEG_(2K) NPs exert potent antitumor activity in a 4T1 breast tumor-bearing BALB/c mouse xenograft model.Together,such a core-matched nanoassembly of pure photosensitizer provides a new strategy for the development of imaging-guided theragnostic nanomedicines.展开更多
Substantial progress in the use of chemo-photodynamic nano-drug delivery systems(nanoDDS) for the treatment of the malignant breast cancer has been achieved. The inability to customize precise nanostructures, however,...Substantial progress in the use of chemo-photodynamic nano-drug delivery systems(nanoDDS) for the treatment of the malignant breast cancer has been achieved. The inability to customize precise nanostructures, however, has limited the therapeutic efficacy of the prepared nano-DDS to date. Here,we report a structurally defined tandem-responsive chemo-photosensitive co-nanoassembly to eliminate primary breast tumor and prevent lung metastasis. This both-in-one co-nanoassembly is prepared by assembling a biocompatible photosensitive derivative(pheophorbide-diphenylalanine peptide, PPADA) with a hypoxia-activated camptothecin(CPT) prodrug [(4-nitrophenyl) formate camptothecin, NCPT]. According to computational simulations, the co-assembly nanostructure is not the classical core-shell type, but consists of many small microphase regions. Upon exposure to a 660 nm laser,PPA-DA induce high levels of ROS production to effectively achieve the apoptosis of normoxic cancer cells. Subsequently, the hypoxia-activated N-CPT and CPT spatially penetrate deep into the hypoxic region of the tumor and suppress hypoxia-induced tumor metastasis. Benefiting from the rational design of the chemo-photodynamic both-in-one nano-DDS, these nanomedicines exhibit a promising potential in the inhibition of difficult-to-treat breast tumor metastasis in patients with breast cancer.展开更多
基金financially supported by the Liaoning Revitalization Talents Program (No. XLYC1907129)the Excellent Youth Science Foundation of Liaoning Province (No. 2020-YQ-06)the China Postdoctoral Science Foundation (No. 2020M670794)。
文摘Photodynamic therapy(PDT) has been widely investigated for cancer therapy. The intracellular accumulation of reactive oxygen species(ROS)-damaged protein facilitates tumor cell apoptosis. However, there is growing evidence that the ubiquitin-proteasome pathway(UPP) significantly impedes PDT by preventing the enrichment of ROS-damaged proteins in tumor cells. To tackle this challenge, we report a facile dual-drug nanoassembly based on the discovery of an interesting co-assembly of bortezomib(BTZ, a proteasome inhibitor) and pyropheophorbide a(PPa) for proteasome inhibition-mediated PDT sensitization.The precisely engineered nanoassembly with the optimal dose ratio of BTZ and PPa demonstrates multiple advantages, including simple fabrication, high drug co-loading efficiency, flexible dose adjustment,good colloidal stability, long systemic circulation, favorable tumor-specific accumulation, as well as significant enrichment of ROS-damaged proteins in tumor cells. As a result, the cooperative nanoassembly exhibits potent synergistic antitumor activity in vivo. This study provides a novel dual-drug engineering modality for multimodal cancer treatment.
基金financially supported by National Nature Science Foundation of China(No.81872816,81703451)Liaoning Revitalization Talents Program,No XLYC1808017+2 种基金Key projects of Technology bureau in Shenyang,No18400408Key projects of Liaoning Province Department of Education,No.2017LZD03supported by Heilongjiang Provincial Key Laboratory of Plant Genetic Engineering and Biological Fermentation Engineering for Cold Region。
文摘One of the major barriers in utilizing prodrug nanocarriers for cancer therapy is the slow release of parent drug in tumors.Tumor cells generally display the higher oxidative level than normal cells,and also displayed the heterogeneity in terms of redox homeostasis level.We previously found that the disulfide bond-linkage demonstrates surprising oxidationsensitivity to form the hydrophilic sulfoxide and sulphone groups.Herein,we develop oxidation-strengthened prodrug nanosystem loaded with pyropheophorbide a(PPa)to achieve light-activatable cascade drug release and enhance therapeutic efficacy.The disulfide bond-driven prodrug nanosystems not only respond to the redox-heterogeneity in tumor,but also respond to the exogenous oxidant(singlet oxygen)elicited by photosensitizers.Once the prodrug nanoparticles(NPs)are activated under irradiation,they would undergo an oxidative self-strengthened process,resulting in a facilitated drug cascade release.The IC50 value of the PPa@PTX-S-S NPs without irradiation was 2-fold higher than those of NPs plus irradiation.In vivo,the PPa@PTX prodrug NPs display prolonged systemic circulation and increased accumulation in tumor site.The PPa@PTXS-S NPs showed much higher efficiency than free PTX or the PPa@PTX-C-C NPs to suppress the growth of 4 T1 tumors.Therefore,this novel oxidation-strengthened disulfide-bridged prodrug-nanosystem has a great potential in the enhanced efficacy of cancer synergetic photochemotherapy.
基金supported by Science and Technology Major Project of Liaoning(No.2019JH1/10300004,China)the National Natural Science Foundation of China(No.81773656 and 81703451)+2 种基金the Excellent Youth Science Foundation of Liaoning Province(No.2020-YQ-06,China)the China Postdoctoral Science Foundation(No.2020M670794)the Liaoning Revitalization Talents Program(No.XLYC1907129 and XLYC1808017,China)。
文摘Pure drug-assembled nanomedicines(PDANs)are currently under intensive investigation as promising nanoplatforms for cancer therapy.However,poor colloidal stability and less tumor-homing ability remain critical unresolved problems that impede their clinical translation.Herein,we report a core-matched nanoassembly of pyropheophorbide a(PPa)for photodynamic therapy(PDT).Pure PPa molecules are found to self-assemble into nanoparticles(NPs),and an amphiphilic PEG polymer(PPaPEG_(2K))is utilized to achieve core-matched PEGylating modification via the p-p stacking effect and hydrophobic interaction between the PPa core and the PPa-PEG_(2K) shell.Compared to PCL-PEG_(2K) with similar molecular weight,PPa-PEG_(2K) significantly increases the stability,prolongs the systemic circulation and improves the tumor-homing ability and ROS generation efficiency of PPa-nanoassembly.As a result,PPa/PPa-PEG_(2K) NPs exert potent antitumor activity in a 4T1 breast tumor-bearing BALB/c mouse xenograft model.Together,such a core-matched nanoassembly of pure photosensitizer provides a new strategy for the development of imaging-guided theragnostic nanomedicines.
基金supported by National Natural Science Foundation of China,Nos.81773656 and U1608283Liaoning Revitalization Talents Program,No.XLYC1808017+2 种基金Key Projects of Technology Bureau in Shenyang,No.18400408Key projects of Liaoning Province Department of Education,No.2017LZD03China Postdoctoral Science Foundation(No.2020M680986)。
文摘Substantial progress in the use of chemo-photodynamic nano-drug delivery systems(nanoDDS) for the treatment of the malignant breast cancer has been achieved. The inability to customize precise nanostructures, however, has limited the therapeutic efficacy of the prepared nano-DDS to date. Here,we report a structurally defined tandem-responsive chemo-photosensitive co-nanoassembly to eliminate primary breast tumor and prevent lung metastasis. This both-in-one co-nanoassembly is prepared by assembling a biocompatible photosensitive derivative(pheophorbide-diphenylalanine peptide, PPADA) with a hypoxia-activated camptothecin(CPT) prodrug [(4-nitrophenyl) formate camptothecin, NCPT]. According to computational simulations, the co-assembly nanostructure is not the classical core-shell type, but consists of many small microphase regions. Upon exposure to a 660 nm laser,PPA-DA induce high levels of ROS production to effectively achieve the apoptosis of normoxic cancer cells. Subsequently, the hypoxia-activated N-CPT and CPT spatially penetrate deep into the hypoxic region of the tumor and suppress hypoxia-induced tumor metastasis. Benefiting from the rational design of the chemo-photodynamic both-in-one nano-DDS, these nanomedicines exhibit a promising potential in the inhibition of difficult-to-treat breast tumor metastasis in patients with breast cancer.
