The complex and variable nature of traumatic spinal cord inju- ry （SCI） presents a unique challenge for translational research. SCI is not bound by any demographic nor is it limited to specific injury biomechanics.
Currently,architecting a ratio nal and efficient nanoplatform combing with multi-therapeutic modalities is highly obligatory for advanced cancer treatment.In order to remedy the self-limiting hypoxic dilemma of photod...Currently,architecting a ratio nal and efficient nanoplatform combing with multi-therapeutic modalities is highly obligatory for advanced cancer treatment.In order to remedy the self-limiting hypoxic dilemma of photodynamic therapy(PDT),herein,a facile photosensitizer(i.e.,chlorin e6,Ce6) and bioreductive prodrug(i.e.,tirapazamine,TPZ)-coloaded hyaluronic acid(HA) nanomicelles(denoted as TPZ@HA-Ce6)was developed for the cascading mode of photo-bioreductive cancer therapy.Taking the typical advantage of Ce6 coupled HA conjugate,TPZ was easily and successfully accommodated into the hydrophobic core of HA-Ce6 nanomicelles,yielding TPZ@HA-Ce6.It showed good dispersibility and stability with the hydrodynamic size of ca.170 nm.It targeted the CD44 overexpressed cancer cells by receptor-mediated endocytosis way and killed them effectively with singlet oxygen and the subsequent TPZ radicals resulting from the oxygen depletion of PDT.The later was further verified by the hypoxia probe in vivo.Using murine mammary carcinoma 4 T1 model,TPZ@HA-Ce6 nanomicelles exhibited cascading and synergistic anticancer effect of PDT and TPZ bioreductive therapy compared with each monotherapy.This work suggests the promising prospect of the hybrid hyaluronic nanomicelles for highly efficient cancer combination treatment.展开更多
Cisplatin(CDDP)-based chemotherapy is substantially limited in the clinic due to its high postoperative recurrence rate.Synergy therapy has been proven as a potent approach to minimize recurrence and achieve enhanced ...Cisplatin(CDDP)-based chemotherapy is substantially limited in the clinic due to its high postoperative recurrence rate.Synergy therapy has been proven as a potent approach to minimize recurrence and achieve enhanced treatment effects.Herein,chemotherapy drug CDDP is assembled with the photothermal-Fenton agent of bovine serum albumin(BSA)stabilized gallic acid-functionalized iron nanoparticles(GA-Fe NPs)to achieve chemo/chemodynamic synergistic cascade oncotherapy.The Pt-GA-Fe NPs can be utilized to generate H_(2)O_(2) via the activation of nicotinamide adenine dinucleotide phosphate(NADPH)oxidases(NOXs)in the tumor microenvironment(TME),which would then greatly boost H2O2-depending chemodynamic therapy(CDT).The generated cytotoxic reactive oxygen species(hydroxyl radicals,·OH)and the depletion of glutathione(GSH)would further promote CDDP-induced DNA damage.Moreover,benefiting from the absorption in the near-infrared(NIR)region,Pt-GA-Fe NPs exhibit excellent photothermal conversion efficiency(η=45.5%)and allow photoacoustic imaging(PAI)guided photothermal therapy(PTT).In vitro and in vivo experiments show that synergy therapy can effectively kill cancer cells and successfully cure cancer without systemic toxicity.The work highlights a new type of therapeutic agent based on CDDP with the ability of H_(2)O_(2) self-generation,thermal responsiveness,and enhanced CDT effects for applications in cancer therapy.展开更多
Nicotinamide adenine dinucleotide (NAD+/NADH) pools homeostasis is recognized as an Achilles’ Heel in tumor metabolism reprogramming. However, mitochondria can enable cancer cells to overcome NADH exhaustion by provi...Nicotinamide adenine dinucleotide (NAD+/NADH) pools homeostasis is recognized as an Achilles’ Heel in tumor metabolism reprogramming. However, mitochondria can enable cancer cells to overcome NADH exhaustion by providing NAD+ precursors and/or intermediates, thus promoting their survival rate and potentially driving uncontrollable proliferation. Here, a synergistic intervention NAD+/NADH homeostasis and mitochondrial metabolism strategy with magnetic resonance imaging (MRI)/photoacoustic imaging (PAI) are developed to address grand challenge of metabolic reprogramming for antitumor bioenergetic therapy. A mitochondrial-targeted cascade amplification nanoplatform ([β-MQ]TRL), triggered by NAD(P)H: quinone oxidoreductase-1 (NQO1), can enable a continuous depletion of cytosol NADH until cell death. The end-product, hydrogen peroxide (H_(2)O_(2)), can be further catalytically converted to higher toxic ·OH in proximity to mitochondria based on [β-MQ]TRL mediated Fenton-like reaction, hijacking tumorigenic energy sources and leading to mitochondrial dysfunction. Additionally, the mild thermal ablation enabled by [β-MQ]TRL further amplifies this cascade reaction to effectively prevent tumor metastasis and recurrence. This synchronous intervention strategy with MRI/PAI establishes unprecedented efficiency in antitumor bioenergetic therapy in vivo, which shows excellent promise for clinical application.展开更多
We demonstrate Fourier domain optical coherenc tomography （FDOCT） monitoring and guiding of quantum cascade laser （QCL） therapy. The laser therapy is performed with a 6.1-tim mid-IR QCL and it involves both tissue...We demonstrate Fourier domain optical coherenc tomography （FDOCT） monitoring and guiding of quantum cascade laser （QCL） therapy. The laser therapy is performed with a 6.1-tim mid-IR QCL and it involves both tissue coagulation or ablation. FDOCT allows real-time monitoring that minimize unnecessary damage to the surrounding tissues. We perform lipid phantom tissue ablation, chicken egg yolk coagulation, and tissue and blood vessel coagulation on chicken embryo to validate the FDOCT guiding quantum cascade laser therapy.展开更多
Companion diagnostics(CDx)plays a pivotal role in precision medicine for cancer treatment.However,con-ventional CDx are often limited by their inability to provide real-time monitoring of cancer progression and therap...Companion diagnostics(CDx)plays a pivotal role in precision medicine for cancer treatment.However,con-ventional CDx are often limited by their inability to provide real-time monitoring of cancer progression and therapeutic responses.Herein,we develop a dual-modality imaging-based companion theranostic(CTx)nano-platform(LET-Cl@GOx),which integrates activatable photoacoustic(PA)and fluorescence(FL)imaging to enable the enhanced diagnostic accuracy and real-time therapeutic feedback,while demonstrating cascade-amplified photothermal/starvation synergistic therapy.The LET-Cl@GOx is designed by the assembly of glucose oxidase(GOx)with a pH-activatable near-infrared(NIR)dye(LET-Cl),enabling the turn-on of PA/FL imaging within the acidic tumor microenvironment(TME).The dynamic alterations of PA/FL imaging signals provide real-time feedback on TME acidification,enabling accurate monitoring of GOx catalysis progression and precision timing of photothermal therapy(PTT)intervention.Furthermore,the GOx-mediated tumor starvation reduces adenosine triphosphate(ATP)levels,leading to the diminished heat shock protein expression and consequently enhanced the sensitivity to PTT.Concurrently,the photothermal effect reciprocally enhances the catalytic activity of GOx,establishing a triple closed-loop system with positive feedback amplification.This multiscale-augmented synergistic therapy triggers robust pyroptosis via the Caspase-3/gasdermin E signaling pathway,demonstrating remarkable therapeutic efficacy of tumors in vivo.展开更多
Photothermal therapy (PTT) circumvents theconstraints of conventional treatments and has manifestedsubstantial potential for clinical applications. Nevertheless,the up-regulation of heat shock proteins (HSP) and mitoc...Photothermal therapy (PTT) circumvents theconstraints of conventional treatments and has manifestedsubstantial potential for clinical applications. Nevertheless,the up-regulation of heat shock proteins (HSP) and mitochondria-encoded genes within tumor cells endows themwith a high level of heat resistance, thereby limiting the ultimateefficacy of PTT. Herein, PtRhMo/Rh multi-metal-basednanozymes were designed by a one-step method for PTT andcascade enzymatic therapy. The PtRhMo/Rh nanozymes arecapable of combining multiple enzymatic activities (catalase,oxidase, glutathione peroxidase, NADH oxidase and peroxidase)for reactive oxygen radical boosting. With the help ofthe near-infrared laser, PtRhMo/Rh nanozymes can not onlykill tumor cells directly, but also down-regulate HSP70 leveland destroy the mitochondrial to weaken the heat-resistantability of tumor cells, further enhancing the effect of PTT.Overall, our work highlights a synergistic strategy for enzymatictherapy and enhanced PTT.展开更多
文摘The complex and variable nature of traumatic spinal cord inju- ry （SCI） presents a unique challenge for translational research. SCI is not bound by any demographic nor is it limited to specific injury biomechanics.
基金supported,in part or in whole,by the National Natural Science Foundation of China (Nos.81471785,81671821,11772088,11802056,31800780,11972111,31900940,U19A2006,32071304)the Basic Research Program of Sichuan Science and Technology (Nos.2021YJ0130,2019YJ0183,2019YJ0184)+1 种基金China Postdoctoral Science Foundation (Nos.2018M640904,2019T120831)the Fundamental Research Funds for the Central Universities (No.ZYGX2019J117)。
文摘Currently,architecting a ratio nal and efficient nanoplatform combing with multi-therapeutic modalities is highly obligatory for advanced cancer treatment.In order to remedy the self-limiting hypoxic dilemma of photodynamic therapy(PDT),herein,a facile photosensitizer(i.e.,chlorin e6,Ce6) and bioreductive prodrug(i.e.,tirapazamine,TPZ)-coloaded hyaluronic acid(HA) nanomicelles(denoted as TPZ@HA-Ce6)was developed for the cascading mode of photo-bioreductive cancer therapy.Taking the typical advantage of Ce6 coupled HA conjugate,TPZ was easily and successfully accommodated into the hydrophobic core of HA-Ce6 nanomicelles,yielding TPZ@HA-Ce6.It showed good dispersibility and stability with the hydrodynamic size of ca.170 nm.It targeted the CD44 overexpressed cancer cells by receptor-mediated endocytosis way and killed them effectively with singlet oxygen and the subsequent TPZ radicals resulting from the oxygen depletion of PDT.The later was further verified by the hypoxia probe in vivo.Using murine mammary carcinoma 4 T1 model,TPZ@HA-Ce6 nanomicelles exhibited cascading and synergistic anticancer effect of PDT and TPZ bioreductive therapy compared with each monotherapy.This work suggests the promising prospect of the hybrid hyaluronic nanomicelles for highly efficient cancer combination treatment.
基金National Natural Science Foundation(NNSF)of China(Nos.61775095,61935004,and 51803091)Jiangsu Province Policy Guidance Plan(No.BZ2019014)+2 种基金Natural Science Foundation of Jiangsu Province(No.BK20200092)Natural Science Foundation of Shandong Province(No.ZR2020KB018)“Taishan scholars”construction special fund of Shandong Province.
文摘Cisplatin(CDDP)-based chemotherapy is substantially limited in the clinic due to its high postoperative recurrence rate.Synergy therapy has been proven as a potent approach to minimize recurrence and achieve enhanced treatment effects.Herein,chemotherapy drug CDDP is assembled with the photothermal-Fenton agent of bovine serum albumin(BSA)stabilized gallic acid-functionalized iron nanoparticles(GA-Fe NPs)to achieve chemo/chemodynamic synergistic cascade oncotherapy.The Pt-GA-Fe NPs can be utilized to generate H_(2)O_(2) via the activation of nicotinamide adenine dinucleotide phosphate(NADPH)oxidases(NOXs)in the tumor microenvironment(TME),which would then greatly boost H2O2-depending chemodynamic therapy(CDT).The generated cytotoxic reactive oxygen species(hydroxyl radicals,·OH)and the depletion of glutathione(GSH)would further promote CDDP-induced DNA damage.Moreover,benefiting from the absorption in the near-infrared(NIR)region,Pt-GA-Fe NPs exhibit excellent photothermal conversion efficiency(η=45.5%)and allow photoacoustic imaging(PAI)guided photothermal therapy(PTT).In vitro and in vivo experiments show that synergy therapy can effectively kill cancer cells and successfully cure cancer without systemic toxicity.The work highlights a new type of therapeutic agent based on CDDP with the ability of H_(2)O_(2) self-generation,thermal responsiveness,and enhanced CDT effects for applications in cancer therapy.
基金financially supported by the Shanghai 2020 “Science and Technology Innovation Action Plan” Social Development Science and Technology Research Project(No.20dz1203600)the Fundamental Research Funds for the Central Universities,and the Open Funds for Characterization of Tongji University.
文摘Nicotinamide adenine dinucleotide (NAD+/NADH) pools homeostasis is recognized as an Achilles’ Heel in tumor metabolism reprogramming. However, mitochondria can enable cancer cells to overcome NADH exhaustion by providing NAD+ precursors and/or intermediates, thus promoting their survival rate and potentially driving uncontrollable proliferation. Here, a synergistic intervention NAD+/NADH homeostasis and mitochondrial metabolism strategy with magnetic resonance imaging (MRI)/photoacoustic imaging (PAI) are developed to address grand challenge of metabolic reprogramming for antitumor bioenergetic therapy. A mitochondrial-targeted cascade amplification nanoplatform ([β-MQ]TRL), triggered by NAD(P)H: quinone oxidoreductase-1 (NQO1), can enable a continuous depletion of cytosol NADH until cell death. The end-product, hydrogen peroxide (H_(2)O_(2)), can be further catalytically converted to higher toxic ·OH in proximity to mitochondria based on [β-MQ]TRL mediated Fenton-like reaction, hijacking tumorigenic energy sources and leading to mitochondrial dysfunction. Additionally, the mild thermal ablation enabled by [β-MQ]TRL further amplifies this cascade reaction to effectively prevent tumor metastasis and recurrence. This synchronous intervention strategy with MRI/PAI establishes unprecedented efficiency in antitumor bioenergetic therapy in vivo, which shows excellent promise for clinical application.
基金supported by NSF ERC(MIRTHE)partially supported by China Scholarship Council(CSC)
文摘We demonstrate Fourier domain optical coherenc tomography （FDOCT） monitoring and guiding of quantum cascade laser （QCL） therapy. The laser therapy is performed with a 6.1-tim mid-IR QCL and it involves both tissue coagulation or ablation. FDOCT allows real-time monitoring that minimize unnecessary damage to the surrounding tissues. We perform lipid phantom tissue ablation, chicken egg yolk coagulation, and tissue and blood vessel coagulation on chicken embryo to validate the FDOCT guiding quantum cascade laser therapy.
基金financially supported by the National Natural Science Foundation of China(U23A2097,82020108017,and 81921002)the Guangdong Basic and Applied Basic Research Foundation(2025A1515011950)+3 种基金the Shenzhen Science and Technology Program(KQTD20190929172538530,JCYJ20210324093815040)the Standard Project of Shanghai Science and Technology Commission(21DZ2203200)the Research Team Cultivation Program of Shenzhen University(2023QNT017 and 2023QNT019)the Shenzhen Uni-versity 2035 Program for Excellent Research.
文摘Companion diagnostics(CDx)plays a pivotal role in precision medicine for cancer treatment.However,con-ventional CDx are often limited by their inability to provide real-time monitoring of cancer progression and therapeutic responses.Herein,we develop a dual-modality imaging-based companion theranostic(CTx)nano-platform(LET-Cl@GOx),which integrates activatable photoacoustic(PA)and fluorescence(FL)imaging to enable the enhanced diagnostic accuracy and real-time therapeutic feedback,while demonstrating cascade-amplified photothermal/starvation synergistic therapy.The LET-Cl@GOx is designed by the assembly of glucose oxidase(GOx)with a pH-activatable near-infrared(NIR)dye(LET-Cl),enabling the turn-on of PA/FL imaging within the acidic tumor microenvironment(TME).The dynamic alterations of PA/FL imaging signals provide real-time feedback on TME acidification,enabling accurate monitoring of GOx catalysis progression and precision timing of photothermal therapy(PTT)intervention.Furthermore,the GOx-mediated tumor starvation reduces adenosine triphosphate(ATP)levels,leading to the diminished heat shock protein expression and consequently enhanced the sensitivity to PTT.Concurrently,the photothermal effect reciprocally enhances the catalytic activity of GOx,establishing a triple closed-loop system with positive feedback amplification.This multiscale-augmented synergistic therapy triggers robust pyroptosis via the Caspase-3/gasdermin E signaling pathway,demonstrating remarkable therapeutic efficacy of tumors in vivo.
基金financially supported by the Shenzhen Medical Research Fund (B2402032)the National Key Research and Development Program of China (2023YFB4705900)+3 种基金the Natural Science Foundation of Top Talent of Shenzhen Technology University (GDRC202303)the National Natural Science Foundation of China (62373259)the Common University Innovation Team Project of Guangdong (2021KCXTD041)the Foundation of Education Department of Guangdong Province, China (2022ZDJS115)。
文摘Photothermal therapy (PTT) circumvents theconstraints of conventional treatments and has manifestedsubstantial potential for clinical applications. Nevertheless,the up-regulation of heat shock proteins (HSP) and mitochondria-encoded genes within tumor cells endows themwith a high level of heat resistance, thereby limiting the ultimateefficacy of PTT. Herein, PtRhMo/Rh multi-metal-basednanozymes were designed by a one-step method for PTT andcascade enzymatic therapy. The PtRhMo/Rh nanozymes arecapable of combining multiple enzymatic activities (catalase,oxidase, glutathione peroxidase, NADH oxidase and peroxidase)for reactive oxygen radical boosting. With the help ofthe near-infrared laser, PtRhMo/Rh nanozymes can not onlykill tumor cells directly, but also down-regulate HSP70 leveland destroy the mitochondrial to weaken the heat-resistantability of tumor cells, further enhancing the effect of PTT.Overall, our work highlights a synergistic strategy for enzymatictherapy and enhanced PTT.
