The aim in this study is to examine the effect of tirapazamine (TPZ) and mild temperature hyperthermia (MTH) on the repair of radiation-induced damage in pimonidazole-unlabeled quiescent (Q) tumor cells. Labeling of p...The aim in this study is to examine the effect of tirapazamine (TPZ) and mild temperature hyperthermia (MTH) on the repair of radiation-induced damage in pimonidazole-unlabeled quiescent (Q) tumor cells. Labeling of proliferating (P) cells in C57BL/6J mice bearing EL4 tumors was achieved by continuous administration of 5-bromo-2-deoxyuridine (BrdU). Tumors were irradiated with γ-rays at 1 h after the administration of pimonidazole followed by TPZ treatment or MTH. Twenty-four hours later, assessment of the responses of Q and total (= P + Q) cells were based on the frequencies of micronucleation and apoptosis using immunofluorescence staining for BrdU. The response of the pimonidazole-unlabeled tumor cell fractions was assessed by means of apoptosis frequency using immunofluorescence staining for pimonidazole. With γ-rays only, the pimonidazole-unlabeled cell fraction showed significantly enhanced radio-sensitivity compared with the whole cell fraction more remarkably in Q cells than total cells. However, a significantly greater decrease in radio-sensitivity in the pimonidazole-unlabeled than the whole cell fraction, evaluated using a delayed assay, was more clearly observed in Q cells than total cells. Post-irradiation MTH more remarkably repressed the decrease in radio-sensitivity in the Q cell than the total cells. Post-irradiation TPZ administration produced a large radio-sensitizing effect on both total and Q cells, especially on Q cells. On the other hand, in pimonidazole-unlabeled cell fractions in both total and Q cells, TPZ suppressed the reduction in sensitivity due to delayed assay much more efficiently than MTH, whereas no radio-sensitizing effect was produced. Not only through suppressing the recovery from radiation-induced damage but also through radio-sensitizing effect, post-irradiation TPZ administration is very useful for repressing the increase in the difference in radio-sensitivity due to the delayed assay not only between total and Q tumor cells but also between the pimonidazole-unlabeled and the whole cell fractions within the total and Q tumor cells.展开更多
Vulnerable atherosclerotic plaque(VASPs)is the major pathological cause of acute cardiovascular event.Early detection and precise intervention of VASP hold great clinical significance,yet remain a major challenge.Phot...Vulnerable atherosclerotic plaque(VASPs)is the major pathological cause of acute cardiovascular event.Early detection and precise intervention of VASP hold great clinical significance,yet remain a major challenge.Photodynamic therapy(PDT)realizes potent ablation efficacy under precise manipulation of laser irradiation.In this study,we constructed theranostic nanoprobes(NPs),which could precisely regress VASPs through a cascade of synergistic events triggered by local irradiation of lasers under the guidance of fluorescence/MR imaging.The NPs were formulated from human serum albumin(HSA)conjugated with a high affinity-peptide targeting osteopontin(OPN)and encapsulated with photosensitizer IR780 and hypoxia-activatable tirapazamine(TPZ).After intravenous injection into atherosclerotic mice,the OPN-targeted NPs demonstrated high specific accumulation in VASPs due to the overexpression of OPN in activated foamy macrophages in the carotid artery.Under the visible guidance of fluorescence and MR dual-model imaging,the precise near-infrared(NIR)laser irradiation generated massive reactive oxygen species(ROS),which resulted in efficient plaque ablation and amplified hypoxia within VASPs.In response to the elevated hypoxia,the initially inactive TPZ was successively boosted to present potent biological suppression of foamy macrophages.After therapeutic administration of the NPs for 2 weeks,the plaque area and the degree of carotid artery stenosis were markedly reduced.Furthermore,the formulated NPs displayed excellent biocompatibility.In conclusion,the developed HSA-based NPs demonstrated appreciable specific identification ability of VASPs and realized precise synergistic regression of atherosclerosis.展开更多
Vadimezan,one of the typical vascular disrupting agents(VDAs) currently in clinical trials,has been extensively implemented for cancer research,whereas its clinical efficacy is adversely affected by the inevitable sid...Vadimezan,one of the typical vascular disrupting agents(VDAs) currently in clinical trials,has been extensively implemented for cancer research,whereas its clinical efficacy is adversely affected by the inevitable side effects.Inspired by Vadimezaninduced intratumoral coagulation activation and hypoxia aggravation,we report a strategy by utilizing these biological effects to achieve targeted delivery and activation of hypoxia-activated prodrug(HAP) thus to maximize the therapeutic effect of Vadimezan.By encapsulating HAP tirapazamine into poly(lactic-co-glycolic acid)(PLGA) nanocarriers along with the modification of clot-binding peptide,the obtained nanoplatform could target tumors under the coagulation activation effect of Vadimezan.Meanwhile,the aggravated hypoxia tumor microenvironment induced by Vadimezan can also boost hypoxia-activated chemotherapy.In the murine tumor model,this strategy showed 80.0% suppression of tumor growth,indicating its great potential in tumor treatment.This study offers an ingenious tactic for the combination of vascular disrupting therapy and hypoxia-activated chemotherapy,which may open up a window of the VDAs-based combination therapy.展开更多
文摘The aim in this study is to examine the effect of tirapazamine (TPZ) and mild temperature hyperthermia (MTH) on the repair of radiation-induced damage in pimonidazole-unlabeled quiescent (Q) tumor cells. Labeling of proliferating (P) cells in C57BL/6J mice bearing EL4 tumors was achieved by continuous administration of 5-bromo-2-deoxyuridine (BrdU). Tumors were irradiated with γ-rays at 1 h after the administration of pimonidazole followed by TPZ treatment or MTH. Twenty-four hours later, assessment of the responses of Q and total (= P + Q) cells were based on the frequencies of micronucleation and apoptosis using immunofluorescence staining for BrdU. The response of the pimonidazole-unlabeled tumor cell fractions was assessed by means of apoptosis frequency using immunofluorescence staining for pimonidazole. With γ-rays only, the pimonidazole-unlabeled cell fraction showed significantly enhanced radio-sensitivity compared with the whole cell fraction more remarkably in Q cells than total cells. However, a significantly greater decrease in radio-sensitivity in the pimonidazole-unlabeled than the whole cell fraction, evaluated using a delayed assay, was more clearly observed in Q cells than total cells. Post-irradiation MTH more remarkably repressed the decrease in radio-sensitivity in the Q cell than the total cells. Post-irradiation TPZ administration produced a large radio-sensitizing effect on both total and Q cells, especially on Q cells. On the other hand, in pimonidazole-unlabeled cell fractions in both total and Q cells, TPZ suppressed the reduction in sensitivity due to delayed assay much more efficiently than MTH, whereas no radio-sensitizing effect was produced. Not only through suppressing the recovery from radiation-induced damage but also through radio-sensitizing effect, post-irradiation TPZ administration is very useful for repressing the increase in the difference in radio-sensitivity due to the delayed assay not only between total and Q tumor cells but also between the pimonidazole-unlabeled and the whole cell fractions within the total and Q tumor cells.
基金This work was supported by the National Nature Science Foundation of China(Nos.81820108019,91939303 and 31971302)the National Key Research and Development Program of China(2018YFC0116305)the Science Foundation of PLA General Hospital(2018XXFC-9,CX19028,China).
文摘Vulnerable atherosclerotic plaque(VASPs)is the major pathological cause of acute cardiovascular event.Early detection and precise intervention of VASP hold great clinical significance,yet remain a major challenge.Photodynamic therapy(PDT)realizes potent ablation efficacy under precise manipulation of laser irradiation.In this study,we constructed theranostic nanoprobes(NPs),which could precisely regress VASPs through a cascade of synergistic events triggered by local irradiation of lasers under the guidance of fluorescence/MR imaging.The NPs were formulated from human serum albumin(HSA)conjugated with a high affinity-peptide targeting osteopontin(OPN)and encapsulated with photosensitizer IR780 and hypoxia-activatable tirapazamine(TPZ).After intravenous injection into atherosclerotic mice,the OPN-targeted NPs demonstrated high specific accumulation in VASPs due to the overexpression of OPN in activated foamy macrophages in the carotid artery.Under the visible guidance of fluorescence and MR dual-model imaging,the precise near-infrared(NIR)laser irradiation generated massive reactive oxygen species(ROS),which resulted in efficient plaque ablation and amplified hypoxia within VASPs.In response to the elevated hypoxia,the initially inactive TPZ was successively boosted to present potent biological suppression of foamy macrophages.After therapeutic administration of the NPs for 2 weeks,the plaque area and the degree of carotid artery stenosis were markedly reduced.Furthermore,the formulated NPs displayed excellent biocompatibility.In conclusion,the developed HSA-based NPs demonstrated appreciable specific identification ability of VASPs and realized precise synergistic regression of atherosclerosis.
基金supported by the National Natural Science Foundation of China (51988102,51833007,22135005,52173136 and 21721005)
文摘Vadimezan,one of the typical vascular disrupting agents(VDAs) currently in clinical trials,has been extensively implemented for cancer research,whereas its clinical efficacy is adversely affected by the inevitable side effects.Inspired by Vadimezaninduced intratumoral coagulation activation and hypoxia aggravation,we report a strategy by utilizing these biological effects to achieve targeted delivery and activation of hypoxia-activated prodrug(HAP) thus to maximize the therapeutic effect of Vadimezan.By encapsulating HAP tirapazamine into poly(lactic-co-glycolic acid)(PLGA) nanocarriers along with the modification of clot-binding peptide,the obtained nanoplatform could target tumors under the coagulation activation effect of Vadimezan.Meanwhile,the aggravated hypoxia tumor microenvironment induced by Vadimezan can also boost hypoxia-activated chemotherapy.In the murine tumor model,this strategy showed 80.0% suppression of tumor growth,indicating its great potential in tumor treatment.This study offers an ingenious tactic for the combination of vascular disrupting therapy and hypoxia-activated chemotherapy,which may open up a window of the VDAs-based combination therapy.
