Esophageal cancer(ESC)is a malignant tumor that originates from the mucosal epithelium of the esophagus and is part of the digestive tract.Although the exact pathogenesis of ESC has not been fully elucidated,excessive...Esophageal cancer(ESC)is a malignant tumor that originates from the mucosal epithelium of the esophagus and is part of the digestive tract.Although the exact pathogenesis of ESC has not been fully elucidated,excessive oxidative stress is an important characteristic that leads to the development of many cancers.Abnormal expression of several proteins and transcription factors contributes to oxidative stress in ESCs,which alters the growth and proliferation of ESCs and promotes their metastasis.Natural compounds,including alkaloids,terpenes,polyphenols,and xanthine compounds,can inhibit reactive oxygen species production in ESCs.These compounds reduce oxidative stress levels and subsequently inhibit the oc-currence and progression of ESC through the regulation of targets and pathways such as the cytokine interleukins 6 and 10,superoxide dismutase,the NF-+ACY-kappa+ADs-B/MAPK pathway,and the mammalian Nrf2/ARE target pathway.Thus,targeting tumor oxidative stress has become a key focus in anti-ESC therapy.This review discusses the potential of Natural products(NPs)for treating ESCs and summarizes the application prospects of oxidative stress as a new target for ESC treatment.The findings of this review provide a reference for drug development targeting ESCs.Nonetheless,further high-quality studies will be necessary to determine the clinical efficacy of these various NPs.展开更多
Nano drug delivery systems have made significant progress in delivering anticancer drugs camptothecin(CPT).However,many challenges for CPT delivery remain,including low drug loading efficiency,premature drug leakage,a...Nano drug delivery systems have made significant progress in delivering anticancer drugs camptothecin(CPT).However,many challenges for CPT delivery remain,including low drug loading efficiency,premature drug leakage,and poor cellular internalization.Herein,we report a novel dual-sensitive polypeptide-based micelle with remarkably high drug loading of CPT for cancer therapy.This self-assembled micelle possesses the following essential components for CPT:(1)pH-sensitive PEG(OHC-PEG-CHO)for prolonging blood circulation and allowing biocompatibility by shielding the cationic micelles,which can be detached under the tumor acidic microenvironment and facilitates the cellular uptake;(2)polypeptide polylysine-polyphenylalanine(PKF)synthesized via ring-opening polymerization for micelle formation and CPT analogue loading;(3)dimeric CPT(DCPT)with redox-sensitive linker for increasing CPT loading and ensuring drug release at tumor sites.Interestingly,the linear-like morphology of PEG-PKF/DCPT micelles was able to enhance their cellular internalization when compared with the spherical blank PKF micelles.Also,the anticancer efficacy of DCPT against lung cancer cells was significantly improved by the micelle formation.In conclusion,this work provides a promising strategy facilitating the safety and effective application of CPT in cancer therapy.展开更多
Pancreatic cancer is characterized by inter-tumoral and intra-tumoral heterogeneity,especially in genetic alteration and microenvironment.Conventional therapeutic strategies for pancreatic cancer usually suffer resist...Pancreatic cancer is characterized by inter-tumoral and intra-tumoral heterogeneity,especially in genetic alteration and microenvironment.Conventional therapeutic strategies for pancreatic cancer usually suffer resistance,highlighting the necessity for personalized precise treatment.Cancer vaccines have become promising alternatives for pancreatic cancer treatment because of their multifaceted advantages including multiple targeting,minimal nonspecific effects,broad therapeutic window,low toxicity,and induction of persistent immunological memory.Multiple conventional vaccines based on the cells,microorganisms,exosomes,proteins,peptides,or DNA against pancreatic cancer have been developed;however,their overall efficacy remains unsatisfactory.Compared with these vaccine modalities,messager RNA(mRNA)-based vaccines offer technical and conceptional advances in personalized precise treatment,and thus represent a potentially cutting-edge option in novel therapeutic approaches for pancreatic cancer.This review summarizes the current progress on pancreatic cancer vaccines,highlights the superiority of mRNA vaccines over other conventional vaccines,and proposes the viable tactic for designing and applying personalized mRNA vaccines for the precise treatment of pancreatic cancer.展开更多
Gene therapy provides a promising approach in treating cancers with high efficacy and selectivity and few adverse effects.Currently,the development of functional vectors with safety and effectiveness is the intense fo...Gene therapy provides a promising approach in treating cancers with high efficacy and selectivity and few adverse effects.Currently,the development of functional vectors with safety and effectiveness is the intense focus for improving the delivery of nucleic acid drugs for gene therapy.For this purpose,stimuli-responsive nanocarriers displayed strong potential in improving the overall efficiencies of gene therapy and reducing adverse effects via effective protection,prolonged blood circulation,specific tumor accumulation,and controlled release profile of nucleic acid drugs.Besides,synergistic therapy could be achieved when combined with other therapeutic regimens.This review summarizes recent advances in various stimuliresponsive nanocarriers for gene delivery.Particularly,the nanocarriers responding to endogenous stimuli including pH,reactive oxygen species,glutathione,and enzyme,etc.,and exogenous stimuli including light,thermo,ultrasound,magnetic field,etc.,are introduced.Finally,the future challenges and prospects of stimuli-responsive gene delivery nanocarriers toward potential clinical translation are well discussed.The major objective of this review is to present the biomedical potential of stimuli-responsive gene delivery nanocarriers for cancer therapy and provide guidance for developing novel nanoplatforms that are clinically applicable.展开更多
The endoplasmic reticulum(ER),an organelle present in various eukaryotic cells,is responsible for intracellular protein synthesis,post-translational modification,and folding and transport,as well as the regulation of ...The endoplasmic reticulum(ER),an organelle present in various eukaryotic cells,is responsible for intracellular protein synthesis,post-translational modification,and folding and transport,as well as the regulation of lipid and steroid metabolism and Ca2+homeostasis.Hypoxia,nutrient deficiency,and a low pH tumor microenvironment lead to the accumulation of misfolded or unfolded proteins in the ER,thus activating ER stress(ERS)and the unfolded protein response,and resulting in either restoration of cellular homeostasis or cell death.ERS plays a crucial role in cancer oncogenesis,progression,and response to therapies.This article reviews current studies relating ERS to ovarian cancer,the most lethal gynecologic malignancy among women globally,and discusses pharmacological agents and possible targets for therapeutic intervention.展开更多
Developing novel cancer therapies that exploit programmed cell death pathways holds promise for advancing cancer treatment.According to a recently published study in Science,copper death(cuproptosis)occurs when intrac...Developing novel cancer therapies that exploit programmed cell death pathways holds promise for advancing cancer treatment.According to a recently published study in Science,copper death(cuproptosis)occurs when intracellular copper is overloaded,triggering aggregation of lipidated mitochondrial proteins and Fe–S cluster proteins.This intriguing phenomenon is triggered by the instability of copper ions.Understanding the molecular mechanisms behind cuproptosis and its associated genes,as identified by Tsvetkov,including ferredoxin 1,lipoic acid synthase,lipoyltransferase 1,dihydrolipid amide dehydrogenase,dihydrolipoamide transacetylase,pyruvate dehydrogenaseα1,pyruvate dehydrogenaseβ,metallothionein,glutaminase,and cyclin-dependent kinase inhibitor 2A,may open new avenues for cancer therapy.Here,we provide a new understanding of the role of copper death and related genes in cancer.展开更多
A recent study published in Gut(doi:10.1136/gutjnl-2022-326928)reveals a novel potential strategy for cancer immunotherapy:a methioninerestricted diet(MRD).A research team,led by Dr.JU Huaiqiang and Dr.XU Ruihua from ...A recent study published in Gut(doi:10.1136/gutjnl-2022-326928)reveals a novel potential strategy for cancer immunotherapy:a methioninerestricted diet(MRD).A research team,led by Dr.JU Huaiqiang and Dr.XU Ruihua from the Sun Yat-sen University Cancer Center,and Dr.PIAO Hailong from the CAS Dalian Institute of Chemical Physics(DICP),discovered that a diet deficient in methionine,an essential amino acid,can reduce tumor growth and boost antitumor immunity.This is achieved by increasing the number and cytotoxicity of tumor-infiltrating CD8+T cells,a type of immune cell that plays a crucial role in fighting cancer.展开更多
Against tumor-dependent metabolic vulnerability is an attractive strategy for tumor-targeted therapy.However,metabolic inhibitors are limited by the drug resistance of cancerous cells due to their metabolic plasticity...Against tumor-dependent metabolic vulnerability is an attractive strategy for tumor-targeted therapy.However,metabolic inhibitors are limited by the drug resistance of cancerous cells due to their metabolic plasticity and heterogeneity.Herein,choline metabolism was discovered by spatially resolved metabolomics analysis as metabolic vulnerability which is highly active in different cancer types,and a choline-modified strategy for small molecule-drug conjugates(SMDCs)design was developed to fool tumor cells into indiscriminately taking in choline-modified chemotherapy drugs for targeted cancer therapy,instead of directly inhibiting choline metabolism.As a proof-of-concept,choline-modified SMDCs were designed,screened,and investigated for their druggability in vitro and in vivo.This strategy improved tumor targeting,preserved tumor inhibition and reduced toxicity of paclitaxel,through targeted drug delivery to tumor by highly expressed choline transporters,and site-specific release by carboxylesterase.This study expands the strategy of targeting metabolic vulnerability and provides new ideas of developing SMDCs for precise cancer therapy.展开更多
The reversible and precise temporal and spatial regulation of histone lysine methyltransferases(KMTs)is essential for epigenome homeostasis.The dysregulation of KMTs is associated with tumor initiation,metastasis,chem...The reversible and precise temporal and spatial regulation of histone lysine methyltransferases(KMTs)is essential for epigenome homeostasis.The dysregulation of KMTs is associated with tumor initiation,metastasis,chemoresistance,invasiveness,and the immune microenvironment.Therapeutically,their promising effects are being evaluated in diversified preclinical and clinical trials,demonstrating encouraging outcomes in multiple malignancies.In this review,we have updated recent understandings of KMTs'functions and the development of their targeted inhibitors.First,we provide an updated overview of the regulatory roles of several KMT activities in oncogenesis,tumor suppression,and immune regulation.In addition,we summarize the current targeting strategies in different cancer types and multiple ongoing clinical trials of combination therapies with KMT inhibitors.In summary,we endeavor to depict the regulation of KMT-mediated epigenetic landscape and provide potential epigenetic targets in the treatment of cancers.展开更多
The development of cancer nanotherapeutics has attracted great interest in the recent decade. Cancer nanotherapeutics have overcome several limitations of conventional therapies, such as nonspecific biodistribution, p...The development of cancer nanotherapeutics has attracted great interest in the recent decade. Cancer nanotherapeutics have overcome several limitations of conventional therapies, such as nonspecific biodistribution, poor water solubility, and limited bioavailability. Nanoparticles with tuned size and surface characteristics are the key components of nanotherapeutics, and are designed to passively or actively deliver anti-cancer drugs to tumor cells. We provide an overview of nanoparticle-based drug delivery methods and cancer therapies based on tumor-targeting delivery strategies that have been developed in recent years.展开更多
Since the discovery of the Nobel prize-winning mechanism of RNA interference(RNAi)ten years ago,it has become a promising drug target for the treatment of multiple diseases,including cancer.There have already been som...Since the discovery of the Nobel prize-winning mechanism of RNA interference(RNAi)ten years ago,it has become a promising drug target for the treatment of multiple diseases,including cancer.There have already been some successful applications of siRNA drugs in the treatment of age-related macular degeneration and respiratory syncytial virus infection.However,significant barriers still exist on the road to clinical applications of siRNA drugs,including poor cellular uptake,instability under physiological conditions,off-target effects and possible immunogenicity.The successful application of siRNA for cancer therapy requires the development of clinically suitable,safe and effective drug delivery systems.Herein,we review the design criteria for siRNA delivery systems and potential siRNA drug delivery systems for cancer therapy,including chemical modifications,lipidbased nanovectors,polymer-mediated delivery systems,conjugate delivery systems,and others.展开更多
The use of bacteria to specifically migrate to cancerous tissue and elicit an antitumor immune response provides a promising platform against cancer with significantly high potency.With dozens of clinical trials under...The use of bacteria to specifically migrate to cancerous tissue and elicit an antitumor immune response provides a promising platform against cancer with significantly high potency.With dozens of clinical trials underway,some researchers hold the following views:“humans are nearing the first commercial live bacteria therapeutic.”However,the facultative anaerobe Salmonella typhimurium VNP20009,which is particularly safe and shows anticancer effects in preclinical studies,had failed in a phase I clinical trial due to low tumor regression and undesired dose-dependent side effects.This is almost certain to disappoint people’s inflated expectations,but it is noted that recent stateof-the-art research has turned attention to bacteria-mediated synergistic cancer therapy(BMSCT).In this review,the foundation of bacteria-mediated bio-therapy is outlined.Then,we summarize the potential benefits and challenges of bacterial bio-therapy in combination with different traditional anticancer therapeutic modalities(chemotherapy,photothermal therapy,reactive oxygen and nitrogen species therapy,immunotherapy,or prodrug-activating therapy)in the past 5 years.Next,we discuss multiple administration routes of BMSCT,highlighting potentiated antitumor responses and avoidance of potential side effects.Finally,we envision the opportunities and challenges for BMSCT development,with the purpose of inspiring medicinal scientists to widely utilize the microbiome approach in patient populations.展开更多
Gemcitabine has been extensively applied in treating various solid tumors. Nonetheless,the clinical performance of gemcitabine is severely restricted by its unsatisfactory pharmacokinetic parameters and easy deactivat...Gemcitabine has been extensively applied in treating various solid tumors. Nonetheless,the clinical performance of gemcitabine is severely restricted by its unsatisfactory pharmacokinetic parameters and easy deactivation mainly because of its rapid deamination, deficiencies in deoxycytidine kinase (DCK), and alterations in nucleoside transporter. On this account, repeated injections with a high concentration of gemcitabine are adopted, leading to severe systemic toxicity to healthy cells. Accordingly, it is highly crucial to fabricate efficient gemcitabine delivery systems to obtain improved therapeutic efficacy of gemcitabine. A large number of gemcitabine pro-drugs were synthesized by chemical modification of gemcitabine to improve its biostability and bioavailability. Besides,gemcitabine-loaded nano-drugs were prepared to improve the delivery efficiency. In this review article, we introduced different strategies for improving the therapeutic performance of gemcitabine by the fabrication of pro-drugs and nano-drugs. We hope this review will provide new insight into the rational design of gemcitabine-based delivery strategies for enhanced cancer therapy.展开更多
Natural products,with remarkable chemical diversity,have been extensively investigated for their anticancer potential for more than a half-century.The collective efforts of the community have achieved the tremendous a...Natural products,with remarkable chemical diversity,have been extensively investigated for their anticancer potential for more than a half-century.The collective efforts of the community have achieved the tremendous advancements,bringing natural products to clinical use and discovering new therapeutic opportunities,yet the challenges remain ahead.With remarkable changes in the landscape of cancer therapy and growing role of cutting-edge technologies,we may have come to a crossroads to revisit the strategies to understand nature products and to explore their therapeutic utility.This review summarizes the key advancements in nature product-centered cancer research and calls for the implementation of systematic approaches,new pharmacological models,and exploration of emerging directions to revitalize natural products search in cancer therapy.展开更多
The therapeutic strategy that gives consideration to the combination of photodynamic therapy and chemotherapy,has emerged as a potential development of effective anti-cancer medicine.Nevertheless,co-delivery of photos...The therapeutic strategy that gives consideration to the combination of photodynamic therapy and chemotherapy,has emerged as a potential development of effective anti-cancer medicine.Nevertheless,co-delivery of photosensitizers(PSs)and chemotherapeutic drugs in traditional carriers still remains great limitations due to low drug loadings and poor biocompatibility.Herein,we have utilized a computer-aided strategy to achieve a desired carrier-free self-delivery of pyropheophorbide a(PPa,a common PS)and podophyllotoxin(PPT,a classical chemotherapeutic drug)for synergistic cancer therapy.First,the computational simulation method identified the similar molecular sizes and rigid molecular structures between two drugs molecules.Based on the molecular docking,the intermolecular interactions were found to includeπ-πstackings,hydrophobic interactions and hydrogen bonds.Next,both drugs could co-assemble into nanoparticles(NPs)via one-step nanoprecipitation method.The various spectral experiments(UV,IR and FL)were conducted to evaluate the formation mechanism of spherical NPs.Moreover,in vitro and in vivo experiments systematically demonstrated that PPT/PPa NPs not only showed better cellular uptake efficiency,stronger cytotoxicity and higher accumulation in tumor sites,but also exhibited synergistic antitumor effect in female BALB/C bearing-4T1 tumor mice.Such a computer-aided design strategy of chem-photodynamic drugs self-delivery systems pave the way for efficient synergistic cancer therapy.展开更多
The transforming growth factor(TGF)-βsignaling pathway controls many cellular processes,including proliferation,differentiation,and apoptosis.Abnormalities in the TGF-βsignaling pathway and its components are closel...The transforming growth factor(TGF)-βsignaling pathway controls many cellular processes,including proliferation,differentiation,and apoptosis.Abnormalities in the TGF-βsignaling pathway and its components are closely related to the occurrence of many human diseases,including cancer.Mothers against decapentaplegic homolog 4(Smad4),also known as deleted in pancreatic cancer locus 4,is a typical tumor suppressor candidate gene locating at q21.1 of human chromosome 18 and the common mediator of the TGF-β/Smad and bone morphogenetic protein/Smad signaling pathways.It is believed that Smad4 inactivation correlates with the development of tumors and stem cell fate decisions.Smad4 also interacts with cytokines,miRNAs,and other signaling pathways,jointly regulating cell behavior.However,the regulatory function of Smad4 in tumorigenesis,stem cells,and drug resistance is currently controversial.In addition,Smad4 represents an attractive therapeutic target for cancer.Elucidating the specific role of Smad4 is important for understanding the mechanism of tumorigenesis and cancer treatment.Here,we review the identification and characterization of Smad4,the canonical TGF-β/Smad pathway,as well as the multiple roles of Smad4 in tumorigenesis,stem cells,and drug resistance.Furthermore,we provide novel insights into the prospects of Smad4-targeted cancer therapy and the challenges that it will face in the future.展开更多
Cancer has nowadays become one of the leading causes of death worldwide.Conventional anticancer approaches are associated with different limitations.Therefore,innovative methodologies are being investigated,and severa...Cancer has nowadays become one of the leading causes of death worldwide.Conventional anticancer approaches are associated with different limitations.Therefore,innovative methodologies are being investigated,and several researchers propose the use of remotely activated nanoparticles to trigger cancer cell death.The idea is to conjugate two different components,i.e.,an external physical input and nanoparticles.Both are given in a harmless dose that once combined together act synergistically to therapeutically treat the cell or tissue of interest,thus also limiting the negative outcomes for the surrounding tissues.Tuning both the properties of the nanomaterial and the involved triggering stimulus,it is possible furthermore to achieve not only a therapeutic effect,but also a powerful platform for imaging at the same time,obtaining a nano-theranostic application.In the present review,we highlight the role of nanoparticles as therapeutic or theranostic tools,thus excluding the cases where a molecular drug is activated.We thus present many examples where the highly cytotoxic power only derives from the active interaction between different physical inputs and nanoparticles.We perform a special focus on mechanical waves responding nanoparticles,in which remotely activated nanoparticles directly become therapeutic agents without the need of the administration of chemotherapeutics or sonosensitizing drugs.展开更多
Cancer remains one of the leading causes of mortal-ity and morbidity throughout the world. To a signifi-cant extent, current conventional cancer therapies are symptomatic and passive in nature. The major obstacle to t...Cancer remains one of the leading causes of mortal-ity and morbidity throughout the world. To a signifi-cant extent, current conventional cancer therapies are symptomatic and passive in nature. The major obstacle to the development of effective cancer therapy is be-lieved to be the absence of suffi cient specifi city. Since the discovery of the tumor-oriented homing capacity of mesenchymal stem cells (MSCs), the application of specific anticancer gene-engineered MSCs has held great potential for cancer therapies. The dual-targeted strategy is based on MSCs’ capacity of tumor-directed migration and incorporation and in situ expression of tumor-specifi c anticancer genes. With the aim of trans-lating bench work into meaningful clinical applications, we describe the tumor tropism of MSCs and their use as therapeutic vehicles, the dual-targeted anticancer potential of engineered MSCs and a putative personal-ized strategy with anticancer gene-engineered MSCs.展开更多
Toll-like receptors(TLRs)are germ line encoded innate immune sensors that recognize conserved microbial structures and host alarmins,and signal expression of major histocompatibility complex proteins,costimulatory mol...Toll-like receptors(TLRs)are germ line encoded innate immune sensors that recognize conserved microbial structures and host alarmins,and signal expression of major histocompatibility complex proteins,costimulatory molecules,and inflammatory mediators by macrophages,neutrophils,dendritic cells,and other cell types.These protein receptors are characterized by their ability to respond to invading pathogens promptlyby recognizing particular TLR ligands,including flagellin and lipopolysaccharide of bacteria,nucleic acids derived from viruses,and zymosan of fungi.There are2 major TLR pathways;one is mediated by myeloid differentiation factor 88(MYD88)adaptor proteins,and the other is independent of MYD88.The MYD88-dependent pathway involves early-phase activation of nuclear factor of kappa light polypeptide gene enhancer in B-cells 1(NF-κB1)and all the TLRs,except TLR3,have been shown to activate this pathway.TLR3and TLR4 act via MYD88-independent pathways with delayed activation of NF-κB signaling.TLRs play a vital role in activating immune responses.TLRs have been shown to mediate inflammatory responses and maintain epithelial barrier homeostasis,and are highly likely to be involved in the activation of a number of pathways following cancer therapy.Colorectal cancer(CRC)is one of the most common cancers,and accounts for almost half a million deaths annually worldwide.Inflammation is considered a risk factor for many common malignancies including cancers of the colorectum.The key molecules involved in inflammation-driven carcinogenesis include TLRs.As sensors of cell death and tissue remodeling,TLRs may have a universal role in cancer;stimulation of TLRs to activate the innate immune system has been a legitimate therapeutic strategy for some years.TLRs 3/4/7/8/9 are all validated targets for cancer therapy,and a number of companies are developing agonists and vaccine adjuvants.On the other hand,antagonists may favor inhibition of signaling responsible for autoimmune responses.In this paper,we review TLR signaling in CRC from carcinogenesis to cancer therapy.展开更多
文摘Esophageal cancer(ESC)is a malignant tumor that originates from the mucosal epithelium of the esophagus and is part of the digestive tract.Although the exact pathogenesis of ESC has not been fully elucidated,excessive oxidative stress is an important characteristic that leads to the development of many cancers.Abnormal expression of several proteins and transcription factors contributes to oxidative stress in ESCs,which alters the growth and proliferation of ESCs and promotes their metastasis.Natural compounds,including alkaloids,terpenes,polyphenols,and xanthine compounds,can inhibit reactive oxygen species production in ESCs.These compounds reduce oxidative stress levels and subsequently inhibit the oc-currence and progression of ESC through the regulation of targets and pathways such as the cytokine interleukins 6 and 10,superoxide dismutase,the NF-+ACY-kappa+ADs-B/MAPK pathway,and the mammalian Nrf2/ARE target pathway.Thus,targeting tumor oxidative stress has become a key focus in anti-ESC therapy.This review discusses the potential of Natural products(NPs)for treating ESCs and summarizes the application prospects of oxidative stress as a new target for ESC treatment.The findings of this review provide a reference for drug development targeting ESCs.Nonetheless,further high-quality studies will be necessary to determine the clinical efficacy of these various NPs.
基金supported by the National Natural Science Foundation of China (51922111)the Science and Technology Development Fund, Macao SAR (File no. 0124/2019/A3)+1 种基金the University of Macao (File no. MYRG2022-00203-ICMS)Guangdong-Hong Kong-Macao Joint Laboratory of Optoelectronic and Magnetic Functional Materials (2019B121205002)
文摘Nano drug delivery systems have made significant progress in delivering anticancer drugs camptothecin(CPT).However,many challenges for CPT delivery remain,including low drug loading efficiency,premature drug leakage,and poor cellular internalization.Herein,we report a novel dual-sensitive polypeptide-based micelle with remarkably high drug loading of CPT for cancer therapy.This self-assembled micelle possesses the following essential components for CPT:(1)pH-sensitive PEG(OHC-PEG-CHO)for prolonging blood circulation and allowing biocompatibility by shielding the cationic micelles,which can be detached under the tumor acidic microenvironment and facilitates the cellular uptake;(2)polypeptide polylysine-polyphenylalanine(PKF)synthesized via ring-opening polymerization for micelle formation and CPT analogue loading;(3)dimeric CPT(DCPT)with redox-sensitive linker for increasing CPT loading and ensuring drug release at tumor sites.Interestingly,the linear-like morphology of PEG-PKF/DCPT micelles was able to enhance their cellular internalization when compared with the spherical blank PKF micelles.Also,the anticancer efficacy of DCPT against lung cancer cells was significantly improved by the micelle formation.In conclusion,this work provides a promising strategy facilitating the safety and effective application of CPT in cancer therapy.
基金supported by the National Natural Science Foundation of China (31970696, 81502975, 82188102, and 81830089)Zhejiang Provincial Natural Science Foundation for Distinguished Young Scholar (LR22H160010)+2 种基金National Key Research and Development Program of China (2019YFC1316000)Zhejiang Provincial Key Research and Development Program (2019C03019)Zhejiang Provincial College Student Science and Technology Innovation Activity Plan-College Student Innovation and Entrepreneurship Incubation Program (Young Talent Program)(2022R40122)
文摘Pancreatic cancer is characterized by inter-tumoral and intra-tumoral heterogeneity,especially in genetic alteration and microenvironment.Conventional therapeutic strategies for pancreatic cancer usually suffer resistance,highlighting the necessity for personalized precise treatment.Cancer vaccines have become promising alternatives for pancreatic cancer treatment because of their multifaceted advantages including multiple targeting,minimal nonspecific effects,broad therapeutic window,low toxicity,and induction of persistent immunological memory.Multiple conventional vaccines based on the cells,microorganisms,exosomes,proteins,peptides,or DNA against pancreatic cancer have been developed;however,their overall efficacy remains unsatisfactory.Compared with these vaccine modalities,messager RNA(mRNA)-based vaccines offer technical and conceptional advances in personalized precise treatment,and thus represent a potentially cutting-edge option in novel therapeutic approaches for pancreatic cancer.This review summarizes the current progress on pancreatic cancer vaccines,highlights the superiority of mRNA vaccines over other conventional vaccines,and proposes the viable tactic for designing and applying personalized mRNA vaccines for the precise treatment of pancreatic cancer.
基金the financial support from the National Key Research and Development Program of China(2020YFA0908200)the National Natural Science Foundation of China(52103196 and 52073060)+1 种基金Guangdong Basic and Applied Basic Research Foundation(2021B1515120054)the Shenzhen Fundamental Research Program(JCYJ20190813152616459 and JCYJ20210324133214038)。
文摘Gene therapy provides a promising approach in treating cancers with high efficacy and selectivity and few adverse effects.Currently,the development of functional vectors with safety and effectiveness is the intense focus for improving the delivery of nucleic acid drugs for gene therapy.For this purpose,stimuli-responsive nanocarriers displayed strong potential in improving the overall efficiencies of gene therapy and reducing adverse effects via effective protection,prolonged blood circulation,specific tumor accumulation,and controlled release profile of nucleic acid drugs.Besides,synergistic therapy could be achieved when combined with other therapeutic regimens.This review summarizes recent advances in various stimuliresponsive nanocarriers for gene delivery.Particularly,the nanocarriers responding to endogenous stimuli including pH,reactive oxygen species,glutathione,and enzyme,etc.,and exogenous stimuli including light,thermo,ultrasound,magnetic field,etc.,are introduced.Finally,the future challenges and prospects of stimuli-responsive gene delivery nanocarriers toward potential clinical translation are well discussed.The major objective of this review is to present the biomedical potential of stimuli-responsive gene delivery nanocarriers for cancer therapy and provide guidance for developing novel nanoplatforms that are clinically applicable.
基金supported by the National Natural Science Foundation of China(Grant Nos.NSF-82072876 and NSF-82002618)。
文摘The endoplasmic reticulum(ER),an organelle present in various eukaryotic cells,is responsible for intracellular protein synthesis,post-translational modification,and folding and transport,as well as the regulation of lipid and steroid metabolism and Ca2+homeostasis.Hypoxia,nutrient deficiency,and a low pH tumor microenvironment lead to the accumulation of misfolded or unfolded proteins in the ER,thus activating ER stress(ERS)and the unfolded protein response,and resulting in either restoration of cellular homeostasis or cell death.ERS plays a crucial role in cancer oncogenesis,progression,and response to therapies.This article reviews current studies relating ERS to ovarian cancer,the most lethal gynecologic malignancy among women globally,and discusses pharmacological agents and possible targets for therapeutic intervention.
基金Supported by Scientific Research Project of Hunan Education Department,No.21A0054.
文摘Developing novel cancer therapies that exploit programmed cell death pathways holds promise for advancing cancer treatment.According to a recently published study in Science,copper death(cuproptosis)occurs when intracellular copper is overloaded,triggering aggregation of lipidated mitochondrial proteins and Fe–S cluster proteins.This intriguing phenomenon is triggered by the instability of copper ions.Understanding the molecular mechanisms behind cuproptosis and its associated genes,as identified by Tsvetkov,including ferredoxin 1,lipoic acid synthase,lipoyltransferase 1,dihydrolipid amide dehydrogenase,dihydrolipoamide transacetylase,pyruvate dehydrogenaseα1,pyruvate dehydrogenaseβ,metallothionein,glutaminase,and cyclin-dependent kinase inhibitor 2A,may open new avenues for cancer therapy.Here,we provide a new understanding of the role of copper death and related genes in cancer.
文摘A recent study published in Gut(doi:10.1136/gutjnl-2022-326928)reveals a novel potential strategy for cancer immunotherapy:a methioninerestricted diet(MRD).A research team,led by Dr.JU Huaiqiang and Dr.XU Ruihua from the Sun Yat-sen University Cancer Center,and Dr.PIAO Hailong from the CAS Dalian Institute of Chemical Physics(DICP),discovered that a diet deficient in methionine,an essential amino acid,can reduce tumor growth and boost antitumor immunity.This is achieved by increasing the number and cytotoxicity of tumor-infiltrating CD8+T cells,a type of immune cell that plays a crucial role in fighting cancer.
基金supported by the National Natural Science Foundation of China(Grant Nos.:81974500,81773678)the CAMS Innovation Fund for Medical Sciences(Grant No.:2022-I2M-2-001).
文摘Against tumor-dependent metabolic vulnerability is an attractive strategy for tumor-targeted therapy.However,metabolic inhibitors are limited by the drug resistance of cancerous cells due to their metabolic plasticity and heterogeneity.Herein,choline metabolism was discovered by spatially resolved metabolomics analysis as metabolic vulnerability which is highly active in different cancer types,and a choline-modified strategy for small molecule-drug conjugates(SMDCs)design was developed to fool tumor cells into indiscriminately taking in choline-modified chemotherapy drugs for targeted cancer therapy,instead of directly inhibiting choline metabolism.As a proof-of-concept,choline-modified SMDCs were designed,screened,and investigated for their druggability in vitro and in vivo.This strategy improved tumor targeting,preserved tumor inhibition and reduced toxicity of paclitaxel,through targeted drug delivery to tumor by highly expressed choline transporters,and site-specific release by carboxylesterase.This study expands the strategy of targeting metabolic vulnerability and provides new ideas of developing SMDCs for precise cancer therapy.
基金the Science and Technology Commission of Shanghai,China(Grant Nos.:20DZ2270800 and 19JC1410200)Innovative Research Team of High-Level Local Universities in Shanghai,China(Grant No.:SHSMU-ZDCX20210900)the National Natural Science Foundation of China(Grant No.:82073889).
文摘The reversible and precise temporal and spatial regulation of histone lysine methyltransferases(KMTs)is essential for epigenome homeostasis.The dysregulation of KMTs is associated with tumor initiation,metastasis,chemoresistance,invasiveness,and the immune microenvironment.Therapeutically,their promising effects are being evaluated in diversified preclinical and clinical trials,demonstrating encouraging outcomes in multiple malignancies.In this review,we have updated recent understandings of KMTs'functions and the development of their targeted inhibitors.First,we provide an updated overview of the regulatory roles of several KMT activities in oncogenesis,tumor suppression,and immune regulation.In addition,we summarize the current targeting strategies in different cancer types and multiple ongoing clinical trials of combination therapies with KMT inhibitors.In summary,we endeavor to depict the regulation of KMT-mediated epigenetic landscape and provide potential epigenetic targets in the treatment of cancers.
文摘The development of cancer nanotherapeutics has attracted great interest in the recent decade. Cancer nanotherapeutics have overcome several limitations of conventional therapies, such as nonspecific biodistribution, poor water solubility, and limited bioavailability. Nanoparticles with tuned size and surface characteristics are the key components of nanotherapeutics, and are designed to passively or actively deliver anti-cancer drugs to tumor cells. We provide an overview of nanoparticle-based drug delivery methods and cancer therapies based on tumor-targeting delivery strategies that have been developed in recent years.
文摘Since the discovery of the Nobel prize-winning mechanism of RNA interference(RNAi)ten years ago,it has become a promising drug target for the treatment of multiple diseases,including cancer.There have already been some successful applications of siRNA drugs in the treatment of age-related macular degeneration and respiratory syncytial virus infection.However,significant barriers still exist on the road to clinical applications of siRNA drugs,including poor cellular uptake,instability under physiological conditions,off-target effects and possible immunogenicity.The successful application of siRNA for cancer therapy requires the development of clinically suitable,safe and effective drug delivery systems.Herein,we review the design criteria for siRNA delivery systems and potential siRNA drug delivery systems for cancer therapy,including chemical modifications,lipidbased nanovectors,polymer-mediated delivery systems,conjugate delivery systems,and others.
基金Supported by National Natural Science Foundation of China,No.81773656Liaoning Revitalization Talents Program,No.XLYC1808017Shenyang Youth Science and Technology Innovation Talents Program,No.RC190454.
文摘The use of bacteria to specifically migrate to cancerous tissue and elicit an antitumor immune response provides a promising platform against cancer with significantly high potency.With dozens of clinical trials underway,some researchers hold the following views:“humans are nearing the first commercial live bacteria therapeutic.”However,the facultative anaerobe Salmonella typhimurium VNP20009,which is particularly safe and shows anticancer effects in preclinical studies,had failed in a phase I clinical trial due to low tumor regression and undesired dose-dependent side effects.This is almost certain to disappoint people’s inflated expectations,but it is noted that recent stateof-the-art research has turned attention to bacteria-mediated synergistic cancer therapy(BMSCT).In this review,the foundation of bacteria-mediated bio-therapy is outlined.Then,we summarize the potential benefits and challenges of bacterial bio-therapy in combination with different traditional anticancer therapeutic modalities(chemotherapy,photothermal therapy,reactive oxygen and nitrogen species therapy,immunotherapy,or prodrug-activating therapy)in the past 5 years.Next,we discuss multiple administration routes of BMSCT,highlighting potentiated antitumor responses and avoidance of potential side effects.Finally,we envision the opportunities and challenges for BMSCT development,with the purpose of inspiring medicinal scientists to widely utilize the microbiome approach in patient populations.
基金supported by the Natural Science Foundation of China (Grant Nos. 52022090, 22005265, 82070739, 81870641)National Key R&D Program of China (Grant No. 2018YFC1106104)+3 种基金Key Research and Development Program of Zhejiang Province (Grant No. 2020C03035)Zhejiang Provincial Natural Science Foundation of China (Grant No. LQ20E030011)Zhejiang Medical Health Science and Technology Program (Grant No. 2021RC061)Zhejiang Provincial Ten Thousand Talents Program (2018R52001)。
文摘Gemcitabine has been extensively applied in treating various solid tumors. Nonetheless,the clinical performance of gemcitabine is severely restricted by its unsatisfactory pharmacokinetic parameters and easy deactivation mainly because of its rapid deamination, deficiencies in deoxycytidine kinase (DCK), and alterations in nucleoside transporter. On this account, repeated injections with a high concentration of gemcitabine are adopted, leading to severe systemic toxicity to healthy cells. Accordingly, it is highly crucial to fabricate efficient gemcitabine delivery systems to obtain improved therapeutic efficacy of gemcitabine. A large number of gemcitabine pro-drugs were synthesized by chemical modification of gemcitabine to improve its biostability and bioavailability. Besides,gemcitabine-loaded nano-drugs were prepared to improve the delivery efficiency. In this review article, we introduced different strategies for improving the therapeutic performance of gemcitabine by the fabrication of pro-drugs and nano-drugs. We hope this review will provide new insight into the rational design of gemcitabine-based delivery strategies for enhanced cancer therapy.
文摘Natural products,with remarkable chemical diversity,have been extensively investigated for their anticancer potential for more than a half-century.The collective efforts of the community have achieved the tremendous advancements,bringing natural products to clinical use and discovering new therapeutic opportunities,yet the challenges remain ahead.With remarkable changes in the landscape of cancer therapy and growing role of cutting-edge technologies,we may have come to a crossroads to revisit the strategies to understand nature products and to explore their therapeutic utility.This review summarizes the key advancements in nature product-centered cancer research and calls for the implementation of systematic approaches,new pharmacological models,and exploration of emerging directions to revitalize natural products search in cancer therapy.
基金This work was supported by National Natural Science Foundation of China(nos.81872816,81773656,U1608283)Liaoning Revitalization Talents Program,No XLYC1808017.
文摘The therapeutic strategy that gives consideration to the combination of photodynamic therapy and chemotherapy,has emerged as a potential development of effective anti-cancer medicine.Nevertheless,co-delivery of photosensitizers(PSs)and chemotherapeutic drugs in traditional carriers still remains great limitations due to low drug loadings and poor biocompatibility.Herein,we have utilized a computer-aided strategy to achieve a desired carrier-free self-delivery of pyropheophorbide a(PPa,a common PS)and podophyllotoxin(PPT,a classical chemotherapeutic drug)for synergistic cancer therapy.First,the computational simulation method identified the similar molecular sizes and rigid molecular structures between two drugs molecules.Based on the molecular docking,the intermolecular interactions were found to includeπ-πstackings,hydrophobic interactions and hydrogen bonds.Next,both drugs could co-assemble into nanoparticles(NPs)via one-step nanoprecipitation method.The various spectral experiments(UV,IR and FL)were conducted to evaluate the formation mechanism of spherical NPs.Moreover,in vitro and in vivo experiments systematically demonstrated that PPT/PPa NPs not only showed better cellular uptake efficiency,stronger cytotoxicity and higher accumulation in tumor sites,but also exhibited synergistic antitumor effect in female BALB/C bearing-4T1 tumor mice.Such a computer-aided design strategy of chem-photodynamic drugs self-delivery systems pave the way for efficient synergistic cancer therapy.
基金the National Natural Science Foundation of China,No.8180306the Natural Science Foundation of Zhejiang Province,No.LY18C070002the 521 Talent Project of Zhejiang Sci-Tech University,No.2021437620 and No.2019337459.
文摘The transforming growth factor(TGF)-βsignaling pathway controls many cellular processes,including proliferation,differentiation,and apoptosis.Abnormalities in the TGF-βsignaling pathway and its components are closely related to the occurrence of many human diseases,including cancer.Mothers against decapentaplegic homolog 4(Smad4),also known as deleted in pancreatic cancer locus 4,is a typical tumor suppressor candidate gene locating at q21.1 of human chromosome 18 and the common mediator of the TGF-β/Smad and bone morphogenetic protein/Smad signaling pathways.It is believed that Smad4 inactivation correlates with the development of tumors and stem cell fate decisions.Smad4 also interacts with cytokines,miRNAs,and other signaling pathways,jointly regulating cell behavior.However,the regulatory function of Smad4 in tumorigenesis,stem cells,and drug resistance is currently controversial.In addition,Smad4 represents an attractive therapeutic target for cancer.Elucidating the specific role of Smad4 is important for understanding the mechanism of tumorigenesis and cancer treatment.Here,we review the identification and characterization of Smad4,the canonical TGF-β/Smad pathway,as well as the multiple roles of Smad4 in tumorigenesis,stem cells,and drug resistance.Furthermore,we provide novel insights into the prospects of Smad4-targeted cancer therapy and the challenges that it will face in the future.
基金the European Research Council(ERC)under the European Union’s Horizon 2020 research and innovation programme(Grant Agreement No 678151-Project Acronym“TROJANANOHORSE”-ERC starting Grant)the Politecnico di Torino and the Moschini Spa Company through a seed funding of Proof-of-Concept Grant No.16417.
文摘Cancer has nowadays become one of the leading causes of death worldwide.Conventional anticancer approaches are associated with different limitations.Therefore,innovative methodologies are being investigated,and several researchers propose the use of remotely activated nanoparticles to trigger cancer cell death.The idea is to conjugate two different components,i.e.,an external physical input and nanoparticles.Both are given in a harmless dose that once combined together act synergistically to therapeutically treat the cell or tissue of interest,thus also limiting the negative outcomes for the surrounding tissues.Tuning both the properties of the nanomaterial and the involved triggering stimulus,it is possible furthermore to achieve not only a therapeutic effect,but also a powerful platform for imaging at the same time,obtaining a nano-theranostic application.In the present review,we highlight the role of nanoparticles as therapeutic or theranostic tools,thus excluding the cases where a molecular drug is activated.We thus present many examples where the highly cytotoxic power only derives from the active interaction between different physical inputs and nanoparticles.We perform a special focus on mechanical waves responding nanoparticles,in which remotely activated nanoparticles directly become therapeutic agents without the need of the administration of chemotherapeutics or sonosensitizing drugs.
基金Supported by Guangxi Ministry of Science and Technology, Juvenile Diabetes Research Foundation (No. 1-2008-474)VGH and UBC Hospital Foundation
文摘Cancer remains one of the leading causes of mortal-ity and morbidity throughout the world. To a signifi-cant extent, current conventional cancer therapies are symptomatic and passive in nature. The major obstacle to the development of effective cancer therapy is be-lieved to be the absence of suffi cient specifi city. Since the discovery of the tumor-oriented homing capacity of mesenchymal stem cells (MSCs), the application of specific anticancer gene-engineered MSCs has held great potential for cancer therapies. The dual-targeted strategy is based on MSCs’ capacity of tumor-directed migration and incorporation and in situ expression of tumor-specifi c anticancer genes. With the aim of trans-lating bench work into meaningful clinical applications, we describe the tumor tropism of MSCs and their use as therapeutic vehicles, the dual-targeted anticancer potential of engineered MSCs and a putative personal-ized strategy with anticancer gene-engineered MSCs.
基金Supported by grant from United States National Institute of Health(NIH),No.P01 CA87969(to SE Hankinson),No.UM1 CA167552,and No.P01 CA55075(to WC Willett),No.R01 CA137178(to AT Chan),No.P50 CA127003(to CS Fuchs),No.R01 CA151993(to S Ogino)Bennett Family Fund for Targeted Therapies ResearchEntertainment Industry Foundation through National Colorectal Cancer Research Alliance
文摘Toll-like receptors(TLRs)are germ line encoded innate immune sensors that recognize conserved microbial structures and host alarmins,and signal expression of major histocompatibility complex proteins,costimulatory molecules,and inflammatory mediators by macrophages,neutrophils,dendritic cells,and other cell types.These protein receptors are characterized by their ability to respond to invading pathogens promptlyby recognizing particular TLR ligands,including flagellin and lipopolysaccharide of bacteria,nucleic acids derived from viruses,and zymosan of fungi.There are2 major TLR pathways;one is mediated by myeloid differentiation factor 88(MYD88)adaptor proteins,and the other is independent of MYD88.The MYD88-dependent pathway involves early-phase activation of nuclear factor of kappa light polypeptide gene enhancer in B-cells 1(NF-κB1)and all the TLRs,except TLR3,have been shown to activate this pathway.TLR3and TLR4 act via MYD88-independent pathways with delayed activation of NF-κB signaling.TLRs play a vital role in activating immune responses.TLRs have been shown to mediate inflammatory responses and maintain epithelial barrier homeostasis,and are highly likely to be involved in the activation of a number of pathways following cancer therapy.Colorectal cancer(CRC)is one of the most common cancers,and accounts for almost half a million deaths annually worldwide.Inflammation is considered a risk factor for many common malignancies including cancers of the colorectum.The key molecules involved in inflammation-driven carcinogenesis include TLRs.As sensors of cell death and tissue remodeling,TLRs may have a universal role in cancer;stimulation of TLRs to activate the innate immune system has been a legitimate therapeutic strategy for some years.TLRs 3/4/7/8/9 are all validated targets for cancer therapy,and a number of companies are developing agonists and vaccine adjuvants.On the other hand,antagonists may favor inhibition of signaling responsible for autoimmune responses.In this paper,we review TLR signaling in CRC from carcinogenesis to cancer therapy.
