An essential concept of cancer immunotherapy is that immunogenic cell death(ICD),characterized by the release of tumor-associated antigens(TAAs)and tumor-specific antigens(TSAs)like neoantigens,danger-associated molec...An essential concept of cancer immunotherapy is that immunogenic cell death(ICD),characterized by the release of tumor-associated antigens(TAAs)and tumor-specific antigens(TSAs)like neoantigens,danger-associated molecular patterns(DAMPs),and pro-inflammatory cytokines,facilitates the presentation of TAAs and TSAs to adaptive immune cells,eliciting an emerging or reinstating a pre-existing anti-cancer immune response.展开更多
Tumor lymph node(LN)metastasis seriously affects the treatment prognosis.Studies have shown that nanoparticles with size of sub-50 nm can directly penetrate into LN metastases after intravenous administration.Here,we ...Tumor lymph node(LN)metastasis seriously affects the treatment prognosis.Studies have shown that nanoparticles with size of sub-50 nm can directly penetrate into LN metastases after intravenous administration.Here,we speculate through introducing targeting capacity,the nanoparticle accumulation in LN metastases would be further enhanced for improved local treatment such as photothermal therapy.Trastuzumabtargeted micelles(<50 nm)were formulated using a unique surfactantstripping approach that yielded concentrated phthalocyanines with strong near-infrared absorption.Targeted micellar phthalocyanine(T-MP)was an effective photothermal transducer and ablated HT-29 cells in vitro.A HER2-expressing colorectal cancer cell line(HT-29)was used to establish an orthotopic mouse model that developed metastatic disease in mesenteric sentinel LN.T-MP accumulated more in the LN metastases compared to the micelles conjugated with control IgG.Following surgical resection of the primary tumor,minimally invasive photothermal treatment of the metastatic LN with T-MP,but not the control micelles,extended mouse survival.Our findings demonstrate for the first time that targeted small-sized nanoparticles have potential to enable superior paradigms for dealing with LN metastases.展开更多
Photodynamic therapy(PDT)is a non-invasive tumor ablation modality that can be enhanced in combination with concurrent chemotherapy.Previously,we demonstrated that liposomes containing a bilayer-anchored photosensitiz...Photodynamic therapy(PDT)is a non-invasive tumor ablation modality that can be enhanced in combination with concurrent chemotherapy.Previously,we demonstrated that liposomes containing a bilayer-anchored photosensitizer(porphyrin-phospholipid;PoP)can be loaded with drugs in their aqueous core to improve drug delivery and tumor ablation upon target tissue irradiation with red-light.In the present work,we demonstrate that this concept can be extended to drugs loaded within the hydrophobic bilayer of liposomes.Cabazitaxel(CTX)is a potent second generation taxane anti-cancer drug that was loaded in the bilayer of liposomes also containing 0.1 molar%PoP,generating CTX-loaded PoP liposomes(CTX-PoP-Lip).CTX-PoP-Lip showed unilamellar vesicle morphology,and exhibited integrity in storage and serum,while maintaining drug stability under laser irradiation.In vitro cell killing evaluation showed that red-light laser irradiation induced cytotoxicity in cells incubated with CTX-PoP-Lip,compared to control treatments.In vivo pharmacokinetic analysis revealed that following intravenous administration to mice,CTX and PoP exhibited somewhat altered circulation profiles,suggesting that the CTX may have exchanged with serum factors in blood.Nevertheless,when a single treatment of CTX-PoP-Lip with laser irradiation was administered to mice bearing human MIA Paca-2 tumors,tumors were effectively ablated whereas the equivalent chemotherapy and PDT monotherapies were ineffective.These results demonstrate the versatility of liposome delivery systems for achieving tumor ablation with chemophototherapy.展开更多
Autologous tumor cells and cell-derived secretions(CDS)can induce antitumor immune responses.The conditions in which cells are cultured and treated impact CDS,and cellular insults alter their composition and function....Autologous tumor cells and cell-derived secretions(CDS)can induce antitumor immune responses.The conditions in which cells are cultured and treated impact CDS,and cellular insults alter their composition and function.In this study,we generated CDS from tumor cells exposed to normal culture conditions,hypoxia,cisplatin,radiotherapy,photodynamic therapy,or hypochlorous acid(HOCl).In vitro HOCl-CDS showed the strongest stimulatory effects on dendritic cells and macrophages compared to CDS generated by hypoxia,cisplatin,radiotherapy or photodynamic therapy.To improve HOCl-CDS activity at the tumor site,we loaded HOCl-CDS into a melittin-encapsulated hydrogel scaffold.When injected intratumorally,the HOCl-CDS hydrogel promoted tumor cell death,cytotoxic T lymphocyte infiltration,and tumor-associated macrophage reprogramming towards an M1 phenotype.The hydrogel inhibited tumor growth and prolonged the survival of mice bearing B16-F10 melanoma.Furthermore,hydrogel-delivered HOCl-CDS augmented the antitumor effects of immune checkpoint blockade.These results underscore the importance of the CDS generation method and delivery approach for improving cancer immunotherapy.展开更多
基金The work was financially supported by the National Natural Science Foundation of China(Nos.81874233 and 51873207)the Natural Science Foundation of Hubei Province(No.2019CFB465).
文摘An essential concept of cancer immunotherapy is that immunogenic cell death(ICD),characterized by the release of tumor-associated antigens(TAAs)and tumor-specific antigens(TSAs)like neoantigens,danger-associated molecular patterns(DAMPs),and pro-inflammatory cytokines,facilitates the presentation of TAAs and TSAs to adaptive immune cells,eliciting an emerging or reinstating a pre-existing anti-cancer immune response.
基金Hai-Yi Feng and Yihang Yuan contributed equally to this work.We thank Prof.Gang Zheng(University of Toronto)for valuable discussion.We also thank the Core Facility of Basic Medical Sciences(SJTU-SM)for frozen section making and scanningThis work was supported by National Natural Science Foundation of China(81572998,81773274,82073379)+1 种基金Shanghai Municipal Science and Technology Commission(20ZR1451700,16520710700)Shanghai Collaborative Innovation Center for Translational Medicine(TM201731).
文摘Tumor lymph node(LN)metastasis seriously affects the treatment prognosis.Studies have shown that nanoparticles with size of sub-50 nm can directly penetrate into LN metastases after intravenous administration.Here,we speculate through introducing targeting capacity,the nanoparticle accumulation in LN metastases would be further enhanced for improved local treatment such as photothermal therapy.Trastuzumabtargeted micelles(<50 nm)were formulated using a unique surfactantstripping approach that yielded concentrated phthalocyanines with strong near-infrared absorption.Targeted micellar phthalocyanine(T-MP)was an effective photothermal transducer and ablated HT-29 cells in vitro.A HER2-expressing colorectal cancer cell line(HT-29)was used to establish an orthotopic mouse model that developed metastatic disease in mesenteric sentinel LN.T-MP accumulated more in the LN metastases compared to the micelles conjugated with control IgG.Following surgical resection of the primary tumor,minimally invasive photothermal treatment of the metastatic LN with T-MP,but not the control micelles,extended mouse survival.Our findings demonstrate for the first time that targeted small-sized nanoparticles have potential to enable superior paradigms for dealing with LN metastases.
基金supported by the National Institutes of Health of the US(DP5OD017898 and R01EB017270)the National Science Foundation of the US(1555220)+1 种基金the National Natural Science Foundation of China(32071384)the National Key Research and Development Program of China(2021YFC2102300)。
基金This study was supported by the National Institutes of Health(No.R01EB017270)The National Natural Science Foundation of China(No.82001752)。
文摘Photodynamic therapy(PDT)is a non-invasive tumor ablation modality that can be enhanced in combination with concurrent chemotherapy.Previously,we demonstrated that liposomes containing a bilayer-anchored photosensitizer(porphyrin-phospholipid;PoP)can be loaded with drugs in their aqueous core to improve drug delivery and tumor ablation upon target tissue irradiation with red-light.In the present work,we demonstrate that this concept can be extended to drugs loaded within the hydrophobic bilayer of liposomes.Cabazitaxel(CTX)is a potent second generation taxane anti-cancer drug that was loaded in the bilayer of liposomes also containing 0.1 molar%PoP,generating CTX-loaded PoP liposomes(CTX-PoP-Lip).CTX-PoP-Lip showed unilamellar vesicle morphology,and exhibited integrity in storage and serum,while maintaining drug stability under laser irradiation.In vitro cell killing evaluation showed that red-light laser irradiation induced cytotoxicity in cells incubated with CTX-PoP-Lip,compared to control treatments.In vivo pharmacokinetic analysis revealed that following intravenous administration to mice,CTX and PoP exhibited somewhat altered circulation profiles,suggesting that the CTX may have exchanged with serum factors in blood.Nevertheless,when a single treatment of CTX-PoP-Lip with laser irradiation was administered to mice bearing human MIA Paca-2 tumors,tumors were effectively ablated whereas the equivalent chemotherapy and PDT monotherapies were ineffective.These results demonstrate the versatility of liposome delivery systems for achieving tumor ablation with chemophototherapy.
基金This work was supported by the National Natural Science Foundation of China(No.81773285,81874233 and 82022040)Health Commission of Hubei Province scientific research project(WJ2021Z004)Scientific Research Project of Hubei Provincial Health and Family Planning Commission,China(WJ2015MB017 to J.C.).
文摘Autologous tumor cells and cell-derived secretions(CDS)can induce antitumor immune responses.The conditions in which cells are cultured and treated impact CDS,and cellular insults alter their composition and function.In this study,we generated CDS from tumor cells exposed to normal culture conditions,hypoxia,cisplatin,radiotherapy,photodynamic therapy,or hypochlorous acid(HOCl).In vitro HOCl-CDS showed the strongest stimulatory effects on dendritic cells and macrophages compared to CDS generated by hypoxia,cisplatin,radiotherapy or photodynamic therapy.To improve HOCl-CDS activity at the tumor site,we loaded HOCl-CDS into a melittin-encapsulated hydrogel scaffold.When injected intratumorally,the HOCl-CDS hydrogel promoted tumor cell death,cytotoxic T lymphocyte infiltration,and tumor-associated macrophage reprogramming towards an M1 phenotype.The hydrogel inhibited tumor growth and prolonged the survival of mice bearing B16-F10 melanoma.Furthermore,hydrogel-delivered HOCl-CDS augmented the antitumor effects of immune checkpoint blockade.These results underscore the importance of the CDS generation method and delivery approach for improving cancer immunotherapy.
