Vascular disrupting agents(VDAs)can destroy tumor vasculature and lead to tumor ischemia and hypoxia,resulting in tumor necrosis.However,VDAs are easy to induce the upregulation of genes that are associated with cance...Vascular disrupting agents(VDAs)can destroy tumor vasculature and lead to tumor ischemia and hypoxia,resulting in tumor necrosis.However,VDAs are easy to induce the upregulation of genes that are associated with cancer cell drug resistance and angiogenesis in tumor cells.Hypoxia-activated chemotherapy will be an ideal supplement to VDAs therapy since it can help to fully utilize the ischemia and hypoxia induced by VDAs to realize a synergistic antitumor therapeutic outcome.Here,we design a liposome whose surface is modified with a tumor-homing peptide Cys-Arg-Glu-Lys-Ala(CREKA,which can specifically target tumor vessels and stroma)and whose aqueous cavity and lipid bilayer are loaded by a hypoxia-activatable drug banoxantrone dihydrochloride(AQ4N)and a VDA combretastatin A4(CA4),respectively.CA4 can selectively target vascular endothelial cells and destroy the tumor blood vessels,which will cause the rapid inhibition of blood flow in tumor and enhance the hypoxia in the tumor region.As a consequence,AQ4N can exert its boosted cytotoxicity under the enhanced hypoxic environment.The as-prepared liposome with a uniform particle size exhibits good stability and high cancer cell killing efficacy in vitro.In addition,in vivo experiments confirm the excellent tumortargeting/accumulation,tumor vasculature-damaging,and tumor inhibition effects of the liposome.This work develops a liposomal which can achieve safe and effective tumor suppression without external stimulus excitation by only single injection,and is expected to benefit the future development of effective antitumor liposomal drugs.展开更多
Developing intrinsically mitochondria-targetable nanosystems for subcellular structure-oriented precise cancer therapy is highly desirable.Here,we conjugate the cluster determinant 44(CD44)-targetable hyaluronic acid(...Developing intrinsically mitochondria-targetable nanosystems for subcellular structure-oriented precise cancer therapy is highly desirable.Here,we conjugate the cluster determinant 44(CD44)-targetable hyaluronic acid(HA)with cholesterol-poly(ethylene glycol)2 k-NH2 and mitochondria-acting IR825-NH2(a cyanine dye)to construct a self-assembled nanostructure(abbreviated as HA-IR825-Chol)for photothermal therapy.The HA-IR825-Chol exhibits improved photostability and desirable photothermal properties,and can rapidly and substantially enter CD44-overexpressed cancer cells and selectively accumulate in the mitochondria of the cells.Upon near-infrared laser irradiation,it can induce severe mitochondrial damage,which causes cytochrome c release and triggers cell apoptosis.Furthermore,we demonstrate the feasibility of loading the chemotherapeutics 10-hydroxycamptothecin(HCPT)into the hydrophobic cores of HA-IR825-Chol NPs for combined chemophotothermal therapy.HCPT encapsulated within HA-IR825-Chol achieves significantly increased cellular uptake and simultaneous mitochondrial and nuclear localization,leading to the release of cytochrome c from mitochondria and upregulation of cleaved caspase-3,both of which contribute to the cell apoptosis/death.In vivo experiments reveal the excellent tumor-targeting ability of HA-IR825-Chol/HCPT,ensuring the efficient tumor eradication by the chemo-photothermal therapy.This work exemplifies the development of an intrinsically mitochondria-targetable nanocarrier for precise subcellular structure-localized drug delivery,and the Chol-mediated rapid and massive endocytosis of the nanoagents may represent a robust strategy for enhancing the efficacies of nanomedicines.展开更多
基金supported by the Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor(Guangxi Medical University),Ministry of Education(No.GKE-KF202305)the Guangxi Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor,and the Natural Science Foundation of Jiangsu Province(No.BK20211510)。
文摘Vascular disrupting agents(VDAs)can destroy tumor vasculature and lead to tumor ischemia and hypoxia,resulting in tumor necrosis.However,VDAs are easy to induce the upregulation of genes that are associated with cancer cell drug resistance and angiogenesis in tumor cells.Hypoxia-activated chemotherapy will be an ideal supplement to VDAs therapy since it can help to fully utilize the ischemia and hypoxia induced by VDAs to realize a synergistic antitumor therapeutic outcome.Here,we design a liposome whose surface is modified with a tumor-homing peptide Cys-Arg-Glu-Lys-Ala(CREKA,which can specifically target tumor vessels and stroma)and whose aqueous cavity and lipid bilayer are loaded by a hypoxia-activatable drug banoxantrone dihydrochloride(AQ4N)and a VDA combretastatin A4(CA4),respectively.CA4 can selectively target vascular endothelial cells and destroy the tumor blood vessels,which will cause the rapid inhibition of blood flow in tumor and enhance the hypoxia in the tumor region.As a consequence,AQ4N can exert its boosted cytotoxicity under the enhanced hypoxic environment.The as-prepared liposome with a uniform particle size exhibits good stability and high cancer cell killing efficacy in vitro.In addition,in vivo experiments confirm the excellent tumortargeting/accumulation,tumor vasculature-damaging,and tumor inhibition effects of the liposome.This work develops a liposomal which can achieve safe and effective tumor suppression without external stimulus excitation by only single injection,and is expected to benefit the future development of effective antitumor liposomal drugs.
基金supported by the National Natural Science Foundation of China(21673037).
文摘Developing intrinsically mitochondria-targetable nanosystems for subcellular structure-oriented precise cancer therapy is highly desirable.Here,we conjugate the cluster determinant 44(CD44)-targetable hyaluronic acid(HA)with cholesterol-poly(ethylene glycol)2 k-NH2 and mitochondria-acting IR825-NH2(a cyanine dye)to construct a self-assembled nanostructure(abbreviated as HA-IR825-Chol)for photothermal therapy.The HA-IR825-Chol exhibits improved photostability and desirable photothermal properties,and can rapidly and substantially enter CD44-overexpressed cancer cells and selectively accumulate in the mitochondria of the cells.Upon near-infrared laser irradiation,it can induce severe mitochondrial damage,which causes cytochrome c release and triggers cell apoptosis.Furthermore,we demonstrate the feasibility of loading the chemotherapeutics 10-hydroxycamptothecin(HCPT)into the hydrophobic cores of HA-IR825-Chol NPs for combined chemophotothermal therapy.HCPT encapsulated within HA-IR825-Chol achieves significantly increased cellular uptake and simultaneous mitochondrial and nuclear localization,leading to the release of cytochrome c from mitochondria and upregulation of cleaved caspase-3,both of which contribute to the cell apoptosis/death.In vivo experiments reveal the excellent tumor-targeting ability of HA-IR825-Chol/HCPT,ensuring the efficient tumor eradication by the chemo-photothermal therapy.This work exemplifies the development of an intrinsically mitochondria-targetable nanocarrier for precise subcellular structure-localized drug delivery,and the Chol-mediated rapid and massive endocytosis of the nanoagents may represent a robust strategy for enhancing the efficacies of nanomedicines.
