Chemotherapy remains one of the irreplaceable treatments for cancer therapy.The use of immunogenic cell death(ICD)-inducing chemotherapeutic drugs offers a practical strategy for killing cancer cells,simultaneously el...Chemotherapy remains one of the irreplaceable treatments for cancer therapy.The use of immunogenic cell death(ICD)-inducing chemotherapeutic drugs offers a practical strategy for killing cancer cells,simultaneously eliciting an antitumor immune response by promoting the recruitment of cytotoxic immune cells and production of granzyme B(GrB).However,numerous malignant cancers adaptively acquired the capacity of secreting serpinb9(Sb9),a physiological inhibitor of GrB,which can reversibly inhibit the biological activity of GrB.To circumvent this dilemma,in this study,an integrated tailor-made nanomedicine composed of tumor-targeting peptide(Arg-Gly-Asp,RGD)decorated liposome,doxorubicin(DOX,an effective ICD inducer),and the compound 3034(an inhibitor of Sb9),is developed(termed as D3RL)for breast cancer chemo-immunotherapy.In vitro and in vivo studies show that D3RL can directly kill tumor cells and trigger the host immune response by inducing ICD.Meanwhile,D3RL can competitively relieve the inhibition of Sb9 to GrB.The restored GrB can not only effectively induce tumor immunotherapy,but also degrade matrix components in the tumor microenvironment,consequently improving the infiltration of immune cells and the penetration of nanomedicines,which in return enhance the combined antitumor effect.Taken together,this work develops an integrated therapeutic solution for targeted production and restoration of GrB to achieve a combined chemo-immunotherapy for breast cancer.展开更多
Traditional surgical treatment is difficult to thoroughly remove esophageal squamous cell carcinomas(ESCC),postoperative recurrence caused by residual tumor cells is a critical factor in the poor prognosis.Since surgi...Traditional surgical treatment is difficult to thoroughly remove esophageal squamous cell carcinomas(ESCC),postoperative recurrence caused by residual tumor cells is a critical factor in the poor prognosis.Since surgical resection promotes the local angiogenesis at the tumor site,further exacerbating the proliferation and invasion of residual tumor cells,it is urgent to inhibit angiogenesis after surgery.Here,a functional peptide-based nanomedicine was obtained from peptide–drug conjugates,which are composed of a hydrophilic targeting motif(vascular endothelial growth factor family and their receptors(VEGFR)targeting peptide for anti-angiogenesis),an ester-linked hydrophobic oridonin(ORI).The nanomedicine exhibits esterase-catalyzed disassembly and drug release,significantly enhanced the anti-tumor efficacy of chemotherapeutics in a postoperative tumor recurrence model through synergistic anti-angiogenic strategies.This study provides an integrated solution for anti-angiogenesisaugmented chemotherapy and demonstrates the encouraging potential for postoperative treatment.展开更多
Multiple organ dysfunction syndrome(MODS)is a clinical syndrome characterized by the dysfunction of two or more systems or organs.This internal environment disorder occurs simultaneously 24 h after severe trauma,shock...Multiple organ dysfunction syndrome(MODS)is a clinical syndrome characterized by the dysfunction of two or more systems or organs.This internal environment disorder occurs simultaneously 24 h after severe trauma,shock,or infection.MODS has a high fatality rate ranging from 20%to 100%.[1]In the development of MODS following severe trauma or infection,multiple organ system fail sequentially,involving the lungs,kidneys,liver,cardiovascular,central nervous system,gastrointestinal,immune,and the blood coagulation system.MODS has complex pathogenic factors,and there are four main pathogenesis hypotheses:(1)uncontrolled inflammation hypothesis,(2)ischemia–reperfusion injury,(3)the gastrointestinal hypothesis,and(4)the biphasic preexcitation theory.Although the current clinical treatment methods of MODS,such as inflammatory factor antibodies,highly effective anti-coagulants,renal function replacement therapy,and other treatment methods,have been improved continuously,their effectiveness in MODS treatment is not ideal.Therefore,clinical MODS treatment is faced with great challenges[Figure 1].展开更多
Breast cancer remains a leading cause of morbidity and mortality among women worldwide,emphasizing the urgent need for enhanced diagnostic and therapeutic approaches.Leucine-rich-alpha-2-glycoprotein 1(LRG1)has emerge...Breast cancer remains a leading cause of morbidity and mortality among women worldwide,emphasizing the urgent need for enhanced diagnostic and therapeutic approaches.Leucine-rich-alpha-2-glycoprotein 1(LRG1)has emerged as a notable target due to its markedly elevated expression in breast tumors,suggesting the viability of LRG1 as a theranostic target.In our study,we employed phage display technology to identify a peptide,termed ET,that binds to LRG1 with a dissociation constant of 48.4μM.After modified with fluorescent cyanine dye,the ET peptide showcased effective tumor-targeting imaging across three different primary breast tumor models and a metastatic breast tumor model.We also undertook a comprehensive safety evaluation,which verified the good biosafety credentials of ET peptide.In summary,the ET peptide identified in this study shows effective LRG1-targeting ability both in vitro and in vivo,thus exhibiting immense potential for clinical translation.展开更多
基金supported by grants from the National Natural Science Foundation of China(Nos.32000998,and 32201240)The Young Elite Scientists Sponsorship Program by Henan Association for Science and Technology(No.2022HYTP046)+2 种基金the China Postdoctoral Science Foundation(Nos.2019TQ0285,2019M662513,and 2021TQ0298)Henan provincial Medical Science and Technology Research Project(No.LHGJ20210210)Science and Technology Development Project of Henan Province(Nos.212102310138 and 222102310525).
文摘Chemotherapy remains one of the irreplaceable treatments for cancer therapy.The use of immunogenic cell death(ICD)-inducing chemotherapeutic drugs offers a practical strategy for killing cancer cells,simultaneously eliciting an antitumor immune response by promoting the recruitment of cytotoxic immune cells and production of granzyme B(GrB).However,numerous malignant cancers adaptively acquired the capacity of secreting serpinb9(Sb9),a physiological inhibitor of GrB,which can reversibly inhibit the biological activity of GrB.To circumvent this dilemma,in this study,an integrated tailor-made nanomedicine composed of tumor-targeting peptide(Arg-Gly-Asp,RGD)decorated liposome,doxorubicin(DOX,an effective ICD inducer),and the compound 3034(an inhibitor of Sb9),is developed(termed as D3RL)for breast cancer chemo-immunotherapy.In vitro and in vivo studies show that D3RL can directly kill tumor cells and trigger the host immune response by inducing ICD.Meanwhile,D3RL can competitively relieve the inhibition of Sb9 to GrB.The restored GrB can not only effectively induce tumor immunotherapy,but also degrade matrix components in the tumor microenvironment,consequently improving the infiltration of immune cells and the penetration of nanomedicines,which in return enhance the combined antitumor effect.Taken together,this work develops an integrated therapeutic solution for targeted production and restoration of GrB to achieve a combined chemo-immunotherapy for breast cancer.
基金the National Natural Science Foundation of China(Nos.32000998 and U2004123)the Young Elite Scientists Sponsorship Program by Henan Association for Science and Technology(No.2022HYTP046)the China Postdoctoral Science Foundation(Nos.2019TQ0285,2019M662513,2021TQ0298,and 2022TQ0296).
文摘Traditional surgical treatment is difficult to thoroughly remove esophageal squamous cell carcinomas(ESCC),postoperative recurrence caused by residual tumor cells is a critical factor in the poor prognosis.Since surgical resection promotes the local angiogenesis at the tumor site,further exacerbating the proliferation and invasion of residual tumor cells,it is urgent to inhibit angiogenesis after surgery.Here,a functional peptide-based nanomedicine was obtained from peptide–drug conjugates,which are composed of a hydrophilic targeting motif(vascular endothelial growth factor family and their receptors(VEGFR)targeting peptide for anti-angiogenesis),an ester-linked hydrophobic oridonin(ORI).The nanomedicine exhibits esterase-catalyzed disassembly and drug release,significantly enhanced the anti-tumor efficacy of chemotherapeutics in a postoperative tumor recurrence model through synergistic anti-angiogenic strategies.This study provides an integrated solution for anti-angiogenesisaugmented chemotherapy and demonstrates the encouraging potential for postoperative treatment.
基金the all-army laboratory animal project(No.SYDW[2020]19)the General Project of Yunnan Applied Basic Research Program(No.202101AT070212)the 920th Hospital of the PLA Joint Logistics Support Force In-Hospital Technology Plan(No.2020YGD05).
文摘Multiple organ dysfunction syndrome(MODS)is a clinical syndrome characterized by the dysfunction of two or more systems or organs.This internal environment disorder occurs simultaneously 24 h after severe trauma,shock,or infection.MODS has a high fatality rate ranging from 20%to 100%.[1]In the development of MODS following severe trauma or infection,multiple organ system fail sequentially,involving the lungs,kidneys,liver,cardiovascular,central nervous system,gastrointestinal,immune,and the blood coagulation system.MODS has complex pathogenic factors,and there are four main pathogenesis hypotheses:(1)uncontrolled inflammation hypothesis,(2)ischemia–reperfusion injury,(3)the gastrointestinal hypothesis,and(4)the biphasic preexcitation theory.Although the current clinical treatment methods of MODS,such as inflammatory factor antibodies,highly effective anti-coagulants,renal function replacement therapy,and other treatment methods,have been improved continuously,their effectiveness in MODS treatment is not ideal.Therefore,clinical MODS treatment is faced with great challenges[Figure 1].
基金supported by grants from the National Natural Science Foundation of China(Nos.32000998 and 32201240)The Young Elite Scientists Sponsorship Program by Henan Association for Science and Technology(No.2022HYTP046)+2 种基金the China Postdoctoral Science Foundation(No.2021TQ0298)Science and Technology Development Project of Henan Province(Nos.222102310525,232102310351)National College Students’innovation and entrepreneurship training program(No.202310459197).
文摘Breast cancer remains a leading cause of morbidity and mortality among women worldwide,emphasizing the urgent need for enhanced diagnostic and therapeutic approaches.Leucine-rich-alpha-2-glycoprotein 1(LRG1)has emerged as a notable target due to its markedly elevated expression in breast tumors,suggesting the viability of LRG1 as a theranostic target.In our study,we employed phage display technology to identify a peptide,termed ET,that binds to LRG1 with a dissociation constant of 48.4μM.After modified with fluorescent cyanine dye,the ET peptide showcased effective tumor-targeting imaging across three different primary breast tumor models and a metastatic breast tumor model.We also undertook a comprehensive safety evaluation,which verified the good biosafety credentials of ET peptide.In summary,the ET peptide identified in this study shows effective LRG1-targeting ability both in vitro and in vivo,thus exhibiting immense potential for clinical translation.
