Affibody molecules are small nonimmunoglobulin affinity proteins,which can precisely target to some cancer cells with specific overexpressed molecular signatures.However,the relatively short in vivo half-life of them ...Affibody molecules are small nonimmunoglobulin affinity proteins,which can precisely target to some cancer cells with specific overexpressed molecular signatures.However,the relatively short in vivo half-life of them seriously limited their application in drug targeted delivery for cancer therapy.Here an amphiphilic affibody-drug conjugate is self-assembled into nanomicelles to prolong circulation time for targeted cancer therapy.As an example of the concept,the nanoagent was prepared through molecular self-assembly of the amphiphilic conjugate of Z_(HHR2:342)-Cys with auristatin E derivate,where the affibody used is capable of binding to the human epidermal growth factor receptor 2(HER2).Such a nanodrug not only increased the blood circulation time,but also enhanced the tumor targeting capacity(abundant affibody arms on the nanoagent surface) and the drug accumulation in tumor.As a result,this affibody-based nanoagent showed excellent antitumor activity in vivo to HER2-positive ovary and breast tumor models,which nearly eradicated both small solid tumors(about 100 mm^(3)) and large established tumors(exceed 500 mm^(3)).The relative tumor proliferation inhibition ratio reaches 99.8% for both models.展开更多
Over the past decade,nanoparticle-based therapeutic modalities have become promising strategies in cancer therapy.Selective delivery of anticancer drugs to the lesion sites is critical for elimination of the tumor and...Over the past decade,nanoparticle-based therapeutic modalities have become promising strategies in cancer therapy.Selective delivery of anticancer drugs to the lesion sites is critical for elimination of the tumor and an improved prognosis.Innovative design and advanced biointerface engineering have promoted the development of various nanocarriers for optimized drug delivery.Keeping in mind the biological framework of the tumormicroenvironment,biomembrane-camouflaged nanoplatforms have been a research focus,reflecting their superiority in cancer targeting.In this review,we summarize the development of various biomimetic cell membrane-camouflaged nanoplatforms for cancertargeted drug delivery,which are classified according to the membranes fromdifferent cells.The challenges and opportunities of the advanced biointerface engineering drug delivery nanosystems in cancer therapy are discussed.展开更多
Triple-negative breast cancer(TNBC),which accounts for approximately 15%of breast cancers(BCs)is characterized by a lack of expression of the hormone receptors(HRs)(estrogen receptor(ER)and progesterone receptor(PR)),...Triple-negative breast cancer(TNBC),which accounts for approximately 15%of breast cancers(BCs)is characterized by a lack of expression of the hormone receptors(HRs)(estrogen receptor(ER)and progesterone receptor(PR)),and human epidermal growth factor receptor 2(HER2).TNBC reveals very aggressive behavior and often leads to poor prognosis.Unfortunately,standard chemotherapy(CHT)is related to low response rates and short progression-free survival(PFS)in patients with metastatic TNBC,creating an unmet need.However,recent recognition of different molecular subtypes and mutations within TNBC has allowed exploring some innovative targeted therapies,bringing new hope for women suffering from TNBC.Currently,some promising systemic treatment options in this area have been developed,including targeted therapies,such as poly(ADP-ribose)polymerase(PARP)inhibitors,immune checkpoint inhibitors,antibody-drug conjugates,and AKT inhibitors.The aim of this mini-review is to address these novel treatment modalities and highlight the main directions for further research and clinical practice in the advanced or metastatic forms of TNBC.This article presents poly(ADP-ribose)polymerase(PARP)inhibitors(e.g.,olaparib,talazoparib,and valaparib for treatment of BRCA-mutated,HER2-negative metastatic BC),immune checkpoint inhibitors(atezolizumab and pembrolizumab),an antibody-drug conjugate(ADC)(sacituzumab govitecan),and AKT inhibitors(ipatasertib and capivasertib).A brief outline of the main clinical trials leading to the approval of these new medications has been provided.Moreover,this overview discusses the efficacy and safety of these innovative treatment options,focusing on women with metastatic TNBC.In addition,this paper comments on some recent considerations,regarding avenues of delivering care and conduct clinical trials in patients with BC,during the COVID-19 pandemic.展开更多
The Editor welcomes submissions for possible publication in the Letters to the Editor section.Letters commenting on an article published in the Journal or other interesting pieces will be considered if they are receiv...The Editor welcomes submissions for possible publication in the Letters to the Editor section.Letters commenting on an article published in the Journal or other interesting pieces will be considered if they are received within 6 weeks of the time the article was published.Authors of the article being commented on will be given an opportunity to offer a timely response to the letter.Authors of letters will be notified that the letter has been received.Unpublished letters cannot be returned.展开更多
Stimuli-responsive polymers are promising to achieve targeted delivery,improved stability during circulation,and controlled release of therapeutic and diagnostic agents.Among them,pH-responsive polymeric nanocarriers ...Stimuli-responsive polymers are promising to achieve targeted delivery,improved stability during circulation,and controlled release of therapeutic and diagnostic agents.Among them,pH-responsive polymeric nanocarriers have attracted significant attention as pH varies in different body fluids(e.g.,stomach,intestine,and colon)and intracellular organelles(e.g.,endosome,lysosome,and mitochondria)to maintain homeostasis,while distinctive pH changes are also found in certain pathological states.For example,the extracellular environment of the tumor is acidic,which can be employed to drive selective delivery.During the internalization process,since most nanocarriers enter cells upon endocytosis where a drop of pH from 6.5 to 5.0 can occur from endosome to lysosome,pH-sensitive groups have been developed for enhanced cargo release.In this review,both non-covalent and covalent interactions responsive to pH changes are introduced,with a focus on the structure-property relationship and their applications in cancer targeting and endosomal escape.展开更多
The approved worldwide use of two messenger RNA(mRNA)vaccines(BNT162b2 and mRNA-1273)in late 2020 has proven the remarkable success of mRNA therapeutics together with lipid nanoformulation technology in protecting peo...The approved worldwide use of two messenger RNA(mRNA)vaccines(BNT162b2 and mRNA-1273)in late 2020 has proven the remarkable success of mRNA therapeutics together with lipid nanoformulation technology in protecting people against coronaviruses during COVID-19 pandemic.This unprecedented and exciting dual strategy with nanoformulations and mRNA therapeutics in play is believed to be a promising paradigm in targeted cancer immunotherapy in future.Recent advances in nanoformulation technologies play a prominent role in adapting mRNA platform in cancer treatment.In this review,we introduce the biologic principles and advancements of mRNA technology,and chemistry fundamentals of intriguing mRNA delivery nanoformulations.We discuss the latest promising nano-mRNA therapeutics for enhanced cancer immunotherapy by modulation of targeted specific subtypes of immune cells,such as dendritic cells(DCs)at peripheral lymphoid organs for initiating mRNA cancer vaccine-mediated antigen specific immunotherapy,and DCs,natural killer(NK)cells,cytotoxic T cells,or multiple immunosuppressive immune cells at tumor microenvironment(TME)for reversing immune evasion.We highlight the clinical progress of advanced nano-mRNA therapeutics in targeted cancer therapy and provide our perspectives on future directions of this transformative integrated technology toward clinical implementation.展开更多
Protein kinases and phosphatases signal by phosphorylation and dephosphorylation to precisely control the activities of their individual and common substrates for a coordinated cellular outcome. In many situations, a ...Protein kinases and phosphatases signal by phosphorylation and dephosphorylation to precisely control the activities of their individual and common substrates for a coordinated cellular outcome. In many situations, a kinase/phosphatase complex signals dynamically in time and space through their reciprocal regulations and their cooperative actions on a substrate. This complex may be essential for malignant transformation and progression and can therefore be considered as a target for therapeutic intervention. p38γ is a unique MAPK family member that contains a PDZ motif at its C-terminus and interacts with a PDZ domain-containing protein tyrosine phosphatase PTPH1. This PDZcoupled binding is required for both PTPH1 dephosphorylation and inactivation of p38γ and for p38γ phosphorylation and activation of PTPH1. Moreover, the p38γ/PTPH1 complex can further regulate their substrates phosphorylation and dephosphorylation, which impacts Ras transformation, malignant growth and progression, and therapeutic response. This review will use the p38γ/PTPH1 signaling network as an example to discuss the potential of targeting the kinase/phosphatase signaling complex for development of novel targeted cancer therapy.展开更多
The therapeutic limitations of conventional chemotherapeutic drugs present a challenge for cancer therapy;these shortcomings are largely attributed to the ability of cancer cells to repopulate and metastasize after in...The therapeutic limitations of conventional chemotherapeutic drugs present a challenge for cancer therapy;these shortcomings are largely attributed to the ability of cancer cells to repopulate and metastasize after initial therapies.Compelling evidence suggests that cancer stem cells(CSCs)have a crucial impact in current shortcomings of cancer therapy because they are largely responsible for tumor initiation,relapse,metastasis,and chemo-resistance.Thus,a better understanding of the properties and mechanisms underlying CSC resistance to treatments is necessary to improve patient outcomes and survival rates.In this review,the authors characterize and compare different CSC-specific biomarkers that are present in various types of tumors.We further discuss multiple targeting approaches currently in preclinical or clinical testing that show great potential for targeting CSCs.This review discusses numerous strategies to eliminate CSCs by targeting surface biomarkers,regulating CSC-associated oncogenes and signaling pathways,inhibiting drug-efflux pumps involved in drug resistance,modulating the tumor microenvironment and immune system,and applying drug combination therapy using nanomedicine.展开更多
Epidermal growth factor receptor (EGFR) is overexpressed in head and neck squamous-cell carcinoma (HNSCC) and its expression levels correlate with decreased patient survival. Nonetheless, therapies aiming at blocking ...Epidermal growth factor receptor (EGFR) is overexpressed in head and neck squamous-cell carcinoma (HNSCC) and its expression levels correlate with decreased patient survival. Nonetheless, therapies aiming at blocking EGFR has shown limited efficacy in a proportion of patients with HNSCC in clinical trials. Sok et al. in a recent paper (Clin Cancer Res, 2006, 12:5064-5073 ) attempted to ascertain whether it is due to mutation of EGFR. As the most common form of mutation of EGFR seen in several other types of cancer is a truncation mutation,展开更多
In situ and real-time monitoring of responsive drug release is critical for the assessment of pharmacodynamics in chemotherapy.In this study,a novel pH-responsive nanosystem is proposed for real-time monitoring of dru...In situ and real-time monitoring of responsive drug release is critical for the assessment of pharmacodynamics in chemotherapy.In this study,a novel pH-responsive nanosystem is proposed for real-time monitoring of drug release and chemo-phototherapy by surface-enhanced Raman spectroscopy(SERS).The Fe3O4@Au@Ag nanoparticles(NPs)deposited graphene oxide(GO)nanocomposites with a high SERS activity and stability are synthesized and labeled with a Raman reporter 4-mercaptophenylboronic acid(4-MPBA)to form SERS probes(GO-Fe3O4@Au@Ag-MPBA).Furthermore,doxorubicin(DOX)is attached to SERS probes through a pH-responsive linker boronic ester(GO-Fe3O4@Au@Ag-MPBA-DOX),accompanying the 4-MPBA signal change in SERS.After the entry into tumor,the breakage of boronic ester in the acidic environment gives rise to the release of DOX and the recovery of 4-MPBA SERS signal.Thus,the DOX dynamic release can be monitored by the real-time changes of 4-MPBA SERS spectra.Additionally,the strong T2 magnetic resonance(MR)signal and NIR photothermal transduction efficiency of the nanocomposites make it available for MR imaging and photothermal therapy(PTT).Altogether,this GO-Fe3O4@Au@Ag-MPBA-DOX can simultaneously fulfill the synergistic combination of cancer cell targeting,pH-sensitive drug release,SERS-traceable detection and MR imaging,endowing it great potential for SERS/MR imaging-guided efficient chemo-phototherapy on cancer treatment.展开更多
Modular protein engineering is suited to recruit complex and multiple functionalities in single-chain polypeptides. Although still unexplored in a systematic way, it is anticipated that the positioning of functional d...Modular protein engineering is suited to recruit complex and multiple functionalities in single-chain polypeptides. Although still unexplored in a systematic way, it is anticipated that the positioning of functional domains would impact and refine these activities, including the ability to organize as supramolecular entities and to generate multifunctional protein materials. To explore this concept, we have repositioned functional segments in the modular protein T22-GFP-H6 and characterized the resulting alternative fusions. In T22-GFP-H6, the combination of T22 and H6 promotes selfassembling as regular nanoparticles and selective binding and internalization of this material in CXCR4-overexpressing tumor cells, making them appealing as vehicles for selective drug delivery. The results show that the pleiotropic activities are dramatically affected in module-swapped constructs, proving the need of a carboxy terminal positioning of H6 for protein self-assembling, and the accommodation of T22 at the amino terminus as a requisite for CXCR4^+ cell binding and internalization. Furthermore, the failure of self-assembling as regular oligomers reduces cellular penetrability of the fusions while keeping the specificity of the T22-CXCR4 interaction.All these data instruct how multifunctional nanoscale protein carriers can be designed for smart, protein-driven drug delivery, not only for the treatment of CXCR4^+ human neoplasias, but also for the development of anti-HIV drugs and other pathologies in which CXCR4 is a relevant homing marker.展开更多
Chemotherapy has been used for treatment of human cancer since early 1900 with purified natural products or synthetic compounds to kill rapidly growing tumor cells or to reduce their growth.However,chemotherapy is als...Chemotherapy has been used for treatment of human cancer since early 1900 with purified natural products or synthetic compounds to kill rapidly growing tumor cells or to reduce their growth.However,chemotherapy is also toxic to some rapidly proliferating normal cells such as bone marrow,therefore causing undesirable展开更多
The cathepsin B-responsive prodrugs are promising strategies to reduce the serious adverse effects of anticancer drugs by improving the cancer selectivity that can be specifically activated by overexpressed cathepsin ...The cathepsin B-responsive prodrugs are promising strategies to reduce the serious adverse effects of anticancer drugs by improving the cancer selectivity that can be specifically activated by overexpressed cathepsin B in targeted cancer cells.However,clinical translation of such therapeutic approaches has been restricted by low antitumor efficacy that is mainly attributable to undesirable pharmacokinetic profiles and inefficient tumor-targeting of cathepsin B-responsive prodrugs,due to their small-molecule structure.In recent decades,many researchers have widely investigated the drug delivery system(DDS)to improve the in vivo pharmacokinetic profiles and tumor-targeting efficiency of cathepsin B-responsive prodrugs via the application of polymers,dendrimers,antibodies,lipids,and inorganic nanoparticles as drug carriers.In addition,the potential therapeutic efficacy of DDS for cathepsin B-responsive prodrugs is demonstrated in multiple studies and combinatorial treatment with typical therapeutic modalities can effectively overcome the challenges of tumor heterogeneity and multidrug resistance.In this review,recent advances and progress of new DDS for cathepsin B-responsive prodrugs are outlined,and their clinical trials are discussed.Besides,potential challenges and the outlooks for clinical translation of cathepsin B-responsive prodrugs are highlighted.展开更多
Radiotherapy,where ionizing radiation is locally delivered either through an external beam or by surgically implanting radionuclide-based seeds in the tumor,is one of the gold standard treatments for cancer.Due to the...Radiotherapy,where ionizing radiation is locally delivered either through an external beam or by surgically implanting radionuclide-based seeds in the tumor,is one of the gold standard treatments for cancer.Due to the non-selective nature of radiation,healthy tissue surrounding the cancerous region is usually affected by the treatment.Hence,new strategies,including targeted alpha therapy,are being studied to improve the selectivity of the treatment and minimize side effects.Several challenges,however,limit the current development of targeted radiotherapy,such as the functionalization of the therapeutic agent with targeting vectors and controlling the release of recoiling daughters.Nanoparticles offer unique opportunities as drug delivery vehicles,since they are biocompatible,enhance the cellular uptake of drugs,and are easily functionalized with targeting molecules.In this review,we examine how nanoparticles can be used for targeted radiotherapy,either as sensitizers of external beams or as delivery vehicles for therapeutic radionuclides.We describe the clinical relevance of different types of nanoparticles,followed by an analysis of how these nanoconstructs can solve some of the main limitations of conventional radiotherapy.Finally,we critically discuss the current situation of nanoparticle-based radiotherapy in clinical settings and challenges that need to be overcome in the future for further development of the field.展开更多
Mammalian cells have the ability to respond to a myriad of diverse extracellular stimuli that modulate cell function.This often involves ligands binding to cell surface receptors and subsequent activation of intracell...Mammalian cells have the ability to respond to a myriad of diverse extracellular stimuli that modulate cell function.This often involves ligands binding to cell surface receptors and subsequent activation of intracellular signaling pathways.These pathways can lead to changes in gene expression patterns that in turn regulate cell growth,differentiation,migration,and function.One important type of cell surface receptor is the receptor tyrosine kinase(RTK).In response to in response to ligand binding,RTKs dimerize,then trans-phosphorylate each other,leading to activation of downstream pathways.While the signaling proteins in these pathways are important for normal cell growth control,when improperly regulated they can lead to uncontrolled growth and sometimes cancer.For this reason,they are often considered to be good candidates for drug targets for chemotherapeutic drugs.RTKs can activate multiple different signaling pathways.Some of the signaling proteins in these pathways can have crosstalk with other RTK activated pathways,and some of them can be activated by multiple mechanisms in addition to activation by RTKs.While there is a wide array of different signaling proteins and pathways activated by RTKs,in this review we will discuss components of several key pathways including the MAPK pathway,the Her2/Neu pathway,mTOR,and Pak kinases.We provide an overview of the roles for these pathways in cell signaling and discuss how different components of these pathways are being considered as targets for cancer treatment.展开更多
Dr.Guan Chen previously worked in Sun Yat-sen University and German cancer research Center as well in Dana-Farber focused on investigating on biochemical mechanisms involved in cancer drug response by discovering Thal...Dr.Guan Chen previously worked in Sun Yat-sen University and German cancer research Center as well in Dana-Farber focused on investigating on biochemical mechanisms involved in cancer drug response by discovering Thaliblastine as a novel and non-toxic展开更多
Microorganisms with innate and artificial advantages have been regarded as intelligent drug delivery systems for cancer therapy with the help of engineering technology.Although numerous studies have confirmed the prom...Microorganisms with innate and artificial advantages have been regarded as intelligent drug delivery systems for cancer therapy with the help of engineering technology.Although numerous studies have confirmed the promising prospects of microorganisms in cancer,several problems such as immunogenicity and toxicity should be addressed before further clinical applications.This review aims to investigate the developments of engineered microorganisms-based delivery systems for targeted cancer therapy.The main types and characteristics of microorganisms such as bacteria,viruses,fungi,microalgae,and their components are introduced in detail.Moreover,the engineering strategies and biomaterials design of microorganisms are further discussed.Most importantly,we discussed the innovative attempts and therapeutic effects of engineered microorganisms in cancer.Taken together,engineered microorganisms-based delivery systems hold tremendous prospects for biomedical applications in targeted cancer therapy.展开更多
The Mediator co-activator complex is a highly conserved,multisubunit protein complex required for gene transcription by RNA polymerase Ⅱ(RNAPⅡ)in all eukaryotes(Allen and Taatjes,2015).This complex,which consists of...The Mediator co-activator complex is a highly conserved,multisubunit protein complex required for gene transcription by RNA polymerase Ⅱ(RNAPⅡ)in all eukaryotes(Allen and Taatjes,2015).This complex,which consists of at least 30 polypeptides,can be divided into four structurally distinct sub-modules including the head,middle,tail,and cyclin-dependent kinase 8(CDK8)展开更多
基金Research and Development Plan of China(No.2016YFA0201500,2020YFA0907702)National Facility for Translational Medi-cine(Shanghai)(No.TMST-2020-001)for financial support.
文摘Affibody molecules are small nonimmunoglobulin affinity proteins,which can precisely target to some cancer cells with specific overexpressed molecular signatures.However,the relatively short in vivo half-life of them seriously limited their application in drug targeted delivery for cancer therapy.Here an amphiphilic affibody-drug conjugate is self-assembled into nanomicelles to prolong circulation time for targeted cancer therapy.As an example of the concept,the nanoagent was prepared through molecular self-assembly of the amphiphilic conjugate of Z_(HHR2:342)-Cys with auristatin E derivate,where the affibody used is capable of binding to the human epidermal growth factor receptor 2(HER2).Such a nanodrug not only increased the blood circulation time,but also enhanced the tumor targeting capacity(abundant affibody arms on the nanoagent surface) and the drug accumulation in tumor.As a result,this affibody-based nanoagent showed excellent antitumor activity in vivo to HER2-positive ovary and breast tumor models,which nearly eradicated both small solid tumors(about 100 mm^(3)) and large established tumors(exceed 500 mm^(3)).The relative tumor proliferation inhibition ratio reaches 99.8% for both models.
基金Financially supported by the National Natural Science Foundation of China(Grant Nos.51973216,51873207,51803006,51673190,51603204,51673187,and 51520105004)the Science and Technology Development Program of Jilin Province(Grant Nos.20190201068JC,20170101102JC,and 20160414047GH)+2 种基金the Medical and Health Program of Jilin Province(Grant No.20190304047YY)the Youth Talents Promotion Project of Jilin Province(Grant No.181909)and the Youth Innovation Promotion Association of Chinese Academy of Sciences(Grant No.2019005).
文摘Over the past decade,nanoparticle-based therapeutic modalities have become promising strategies in cancer therapy.Selective delivery of anticancer drugs to the lesion sites is critical for elimination of the tumor and an improved prognosis.Innovative design and advanced biointerface engineering have promoted the development of various nanocarriers for optimized drug delivery.Keeping in mind the biological framework of the tumormicroenvironment,biomembrane-camouflaged nanoplatforms have been a research focus,reflecting their superiority in cancer targeting.In this review,we summarize the development of various biomimetic cell membrane-camouflaged nanoplatforms for cancertargeted drug delivery,which are classified according to the membranes fromdifferent cells.The challenges and opportunities of the advanced biointerface engineering drug delivery nanosystems in cancer therapy are discussed.
文摘Triple-negative breast cancer(TNBC),which accounts for approximately 15%of breast cancers(BCs)is characterized by a lack of expression of the hormone receptors(HRs)(estrogen receptor(ER)and progesterone receptor(PR)),and human epidermal growth factor receptor 2(HER2).TNBC reveals very aggressive behavior and often leads to poor prognosis.Unfortunately,standard chemotherapy(CHT)is related to low response rates and short progression-free survival(PFS)in patients with metastatic TNBC,creating an unmet need.However,recent recognition of different molecular subtypes and mutations within TNBC has allowed exploring some innovative targeted therapies,bringing new hope for women suffering from TNBC.Currently,some promising systemic treatment options in this area have been developed,including targeted therapies,such as poly(ADP-ribose)polymerase(PARP)inhibitors,immune checkpoint inhibitors,antibody-drug conjugates,and AKT inhibitors.The aim of this mini-review is to address these novel treatment modalities and highlight the main directions for further research and clinical practice in the advanced or metastatic forms of TNBC.This article presents poly(ADP-ribose)polymerase(PARP)inhibitors(e.g.,olaparib,talazoparib,and valaparib for treatment of BRCA-mutated,HER2-negative metastatic BC),immune checkpoint inhibitors(atezolizumab and pembrolizumab),an antibody-drug conjugate(ADC)(sacituzumab govitecan),and AKT inhibitors(ipatasertib and capivasertib).A brief outline of the main clinical trials leading to the approval of these new medications has been provided.Moreover,this overview discusses the efficacy and safety of these innovative treatment options,focusing on women with metastatic TNBC.In addition,this paper comments on some recent considerations,regarding avenues of delivering care and conduct clinical trials in patients with BC,during the COVID-19 pandemic.
文摘The Editor welcomes submissions for possible publication in the Letters to the Editor section.Letters commenting on an article published in the Journal or other interesting pieces will be considered if they are received within 6 weeks of the time the article was published.Authors of the article being commented on will be given an opportunity to offer a timely response to the letter.Authors of letters will be notified that the letter has been received.Unpublished letters cannot be returned.
基金financial support from the National Natural Science Foundation of China(No.81903574)the Joint Funds of the Zhejiang Provincial Natural Science Foundation of China(No.LTZ22B020001).
文摘Stimuli-responsive polymers are promising to achieve targeted delivery,improved stability during circulation,and controlled release of therapeutic and diagnostic agents.Among them,pH-responsive polymeric nanocarriers have attracted significant attention as pH varies in different body fluids(e.g.,stomach,intestine,and colon)and intracellular organelles(e.g.,endosome,lysosome,and mitochondria)to maintain homeostasis,while distinctive pH changes are also found in certain pathological states.For example,the extracellular environment of the tumor is acidic,which can be employed to drive selective delivery.During the internalization process,since most nanocarriers enter cells upon endocytosis where a drop of pH from 6.5 to 5.0 can occur from endosome to lysosome,pH-sensitive groups have been developed for enhanced cargo release.In this review,both non-covalent and covalent interactions responsive to pH changes are introduced,with a focus on the structure-property relationship and their applications in cancer targeting and endosomal escape.
基金This work was supported by the National Natural Science Foundation of China[32101146,81974391,82072806,82173265]Shanghai Science and Technology Program[21010500100,22140901700]+5 种基金Basic Research Program of Shanghai Municipal Government[21JC1406002]Shanghai Pujiang Program[21PJ1404500]Shanghai Excellent Overseas Young Scientiststhe Clinical Research Plan of SHDC[SHDC2020CR4025]the Natural Science Foundation of Shanghai[20ZR1470500]Hospital Funded Clinical Research,Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine[21XHDB06].
文摘The approved worldwide use of two messenger RNA(mRNA)vaccines(BNT162b2 and mRNA-1273)in late 2020 has proven the remarkable success of mRNA therapeutics together with lipid nanoformulation technology in protecting people against coronaviruses during COVID-19 pandemic.This unprecedented and exciting dual strategy with nanoformulations and mRNA therapeutics in play is believed to be a promising paradigm in targeted cancer immunotherapy in future.Recent advances in nanoformulation technologies play a prominent role in adapting mRNA platform in cancer treatment.In this review,we introduce the biologic principles and advancements of mRNA technology,and chemistry fundamentals of intriguing mRNA delivery nanoformulations.We discuss the latest promising nano-mRNA therapeutics for enhanced cancer immunotherapy by modulation of targeted specific subtypes of immune cells,such as dendritic cells(DCs)at peripheral lymphoid organs for initiating mRNA cancer vaccine-mediated antigen specific immunotherapy,and DCs,natural killer(NK)cells,cytotoxic T cells,or multiple immunosuppressive immune cells at tumor microenvironment(TME)for reversing immune evasion.We highlight the clinical progress of advanced nano-mRNA therapeutics in targeted cancer therapy and provide our perspectives on future directions of this transformative integrated technology toward clinical implementation.
基金R01 NIH CA91576Departments of Veterans Affairs (VA) Merit Review Grant 1I01BX002883+1 种基金Department of Defense Grant BC141898Cancer Center of Medical College of Wisconsin
文摘Protein kinases and phosphatases signal by phosphorylation and dephosphorylation to precisely control the activities of their individual and common substrates for a coordinated cellular outcome. In many situations, a kinase/phosphatase complex signals dynamically in time and space through their reciprocal regulations and their cooperative actions on a substrate. This complex may be essential for malignant transformation and progression and can therefore be considered as a target for therapeutic intervention. p38γ is a unique MAPK family member that contains a PDZ motif at its C-terminus and interacts with a PDZ domain-containing protein tyrosine phosphatase PTPH1. This PDZcoupled binding is required for both PTPH1 dephosphorylation and inactivation of p38γ and for p38γ phosphorylation and activation of PTPH1. Moreover, the p38γ/PTPH1 complex can further regulate their substrates phosphorylation and dephosphorylation, which impacts Ras transformation, malignant growth and progression, and therapeutic response. This review will use the p38γ/PTPH1 signaling network as an example to discuss the potential of targeting the kinase/phosphatase signaling complex for development of novel targeted cancer therapy.
基金supported by National Institutes of Health grants(R01AI068978,R01CA170820 and P01CA132681)a translational acceleration grant from the Joint Center for Translational Medicine,the National Cancer Institute(P30CA014089)a grant from the Ming Hsieh Institute for Research on Engineering Medicine for Cancer.
文摘The therapeutic limitations of conventional chemotherapeutic drugs present a challenge for cancer therapy;these shortcomings are largely attributed to the ability of cancer cells to repopulate and metastasize after initial therapies.Compelling evidence suggests that cancer stem cells(CSCs)have a crucial impact in current shortcomings of cancer therapy because they are largely responsible for tumor initiation,relapse,metastasis,and chemo-resistance.Thus,a better understanding of the properties and mechanisms underlying CSC resistance to treatments is necessary to improve patient outcomes and survival rates.In this review,the authors characterize and compare different CSC-specific biomarkers that are present in various types of tumors.We further discuss multiple targeting approaches currently in preclinical or clinical testing that show great potential for targeting CSCs.This review discusses numerous strategies to eliminate CSCs by targeting surface biomarkers,regulating CSC-associated oncogenes and signaling pathways,inhibiting drug-efflux pumps involved in drug resistance,modulating the tumor microenvironment and immune system,and applying drug combination therapy using nanomedicine.
文摘Epidermal growth factor receptor (EGFR) is overexpressed in head and neck squamous-cell carcinoma (HNSCC) and its expression levels correlate with decreased patient survival. Nonetheless, therapies aiming at blocking EGFR has shown limited efficacy in a proportion of patients with HNSCC in clinical trials. Sok et al. in a recent paper (Clin Cancer Res, 2006, 12:5064-5073 ) attempted to ascertain whether it is due to mutation of EGFR. As the most common form of mutation of EGFR seen in several other types of cancer is a truncation mutation,
基金supported by the National Natural Science Foundation of China(81872759 and 22177039)the National Key Research and Development Program of China(2021YFC2300400)+1 种基金Scien ceand Technology Program of Guangzhou(202102010097,China)Pearl River Talent Program(2017GC010363,China).
文摘In situ and real-time monitoring of responsive drug release is critical for the assessment of pharmacodynamics in chemotherapy.In this study,a novel pH-responsive nanosystem is proposed for real-time monitoring of drug release and chemo-phototherapy by surface-enhanced Raman spectroscopy(SERS).The Fe3O4@Au@Ag nanoparticles(NPs)deposited graphene oxide(GO)nanocomposites with a high SERS activity and stability are synthesized and labeled with a Raman reporter 4-mercaptophenylboronic acid(4-MPBA)to form SERS probes(GO-Fe3O4@Au@Ag-MPBA).Furthermore,doxorubicin(DOX)is attached to SERS probes through a pH-responsive linker boronic ester(GO-Fe3O4@Au@Ag-MPBA-DOX),accompanying the 4-MPBA signal change in SERS.After the entry into tumor,the breakage of boronic ester in the acidic environment gives rise to the release of DOX and the recovery of 4-MPBA SERS signal.Thus,the DOX dynamic release can be monitored by the real-time changes of 4-MPBA SERS spectra.Additionally,the strong T2 magnetic resonance(MR)signal and NIR photothermal transduction efficiency of the nanocomposites make it available for MR imaging and photothermal therapy(PTT).Altogether,this GO-Fe3O4@Au@Ag-MPBA-DOX can simultaneously fulfill the synergistic combination of cancer cell targeting,pH-sensitive drug release,SERS-traceable detection and MR imaging,endowing it great potential for SERS/MR imaging-guided efficient chemo-phototherapy on cancer treatment.
基金Agencia Estatal de Investigación and to Fondo Europeo de Desarrollo Regional (grant BIO2016-76063-R, AEI/FEDER, UE) to Villaverde A, AGAUR (2017SGR-229) to Villaverde A and 2017SGR-865 GRC to Mangues R CIBER-BBN (project NANOPROTHER) +6 种基金granted to Villaverde A and CIBER-BBN project 4Nano Mets to Mangues R ISCIII (PI15/00272 cofounding FEDER) to Vázquez E and ISCIII (Co-founding FEDER) PIE15//00028 and PI18/00650 to Mangues R, and to EU COST Action CA 17140indebted to the Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN) that is an initiative funded by the VI National R&D&I Plan 2008–2011Iniciativa Ingenio 2010, Consolider ProgramCIBER Actions and financed by the Instituto de Salud Carlos Ⅲ, with assistance from the European Regional Development FundSánchez-García L and López-Laguna H were supported by a predoctoral fellowship from AGAUR (2018FI_B2_00051 and 2019FI_B_00352) respectivelyUnzueta U by PERIS program from the Health Department of la Generalitat de Catalunya
文摘Modular protein engineering is suited to recruit complex and multiple functionalities in single-chain polypeptides. Although still unexplored in a systematic way, it is anticipated that the positioning of functional domains would impact and refine these activities, including the ability to organize as supramolecular entities and to generate multifunctional protein materials. To explore this concept, we have repositioned functional segments in the modular protein T22-GFP-H6 and characterized the resulting alternative fusions. In T22-GFP-H6, the combination of T22 and H6 promotes selfassembling as regular nanoparticles and selective binding and internalization of this material in CXCR4-overexpressing tumor cells, making them appealing as vehicles for selective drug delivery. The results show that the pleiotropic activities are dramatically affected in module-swapped constructs, proving the need of a carboxy terminal positioning of H6 for protein self-assembling, and the accommodation of T22 at the amino terminus as a requisite for CXCR4^+ cell binding and internalization. Furthermore, the failure of self-assembling as regular oligomers reduces cellular penetrability of the fusions while keeping the specificity of the T22-CXCR4 interaction.All these data instruct how multifunctional nanoscale protein carriers can be designed for smart, protein-driven drug delivery, not only for the treatment of CXCR4^+ human neoplasias, but also for the development of anti-HIV drugs and other pathologies in which CXCR4 is a relevant homing marker.
文摘Chemotherapy has been used for treatment of human cancer since early 1900 with purified natural products or synthetic compounds to kill rapidly growing tumor cells or to reduce their growth.However,chemotherapy is also toxic to some rapidly proliferating normal cells such as bone marrow,therefore causing undesirable
基金the National Research Foundation of Korea(NRF)grant funded by the Korea government(Nos.NRF2019R1A2C3006283 and NRF-2021R1C1C2005460)the KUKIST Graduate School of Converging Science and Technology(Korea University&KIST)the Intramural Research Program of KIST.
文摘The cathepsin B-responsive prodrugs are promising strategies to reduce the serious adverse effects of anticancer drugs by improving the cancer selectivity that can be specifically activated by overexpressed cathepsin B in targeted cancer cells.However,clinical translation of such therapeutic approaches has been restricted by low antitumor efficacy that is mainly attributable to undesirable pharmacokinetic profiles and inefficient tumor-targeting of cathepsin B-responsive prodrugs,due to their small-molecule structure.In recent decades,many researchers have widely investigated the drug delivery system(DDS)to improve the in vivo pharmacokinetic profiles and tumor-targeting efficiency of cathepsin B-responsive prodrugs via the application of polymers,dendrimers,antibodies,lipids,and inorganic nanoparticles as drug carriers.In addition,the potential therapeutic efficacy of DDS for cathepsin B-responsive prodrugs is demonstrated in multiple studies and combinatorial treatment with typical therapeutic modalities can effectively overcome the challenges of tumor heterogeneity and multidrug resistance.In this review,recent advances and progress of new DDS for cathepsin B-responsive prodrugs are outlined,and their clinical trials are discussed.Besides,potential challenges and the outlooks for clinical translation of cathepsin B-responsive prodrugs are highlighted.
基金support from the Nuclear Regulatory Commission under Faculty Development Grant NRC-HQ-84-14-G-0052 and from the U.S.Department of Energy,Office of Science,Office of Basic Energy Sciences,Chemical Sciences,Geosciences,and Biosciences Division at LBNL under Contract DE-AC02-05CH11231,during the writing of this review.
文摘Radiotherapy,where ionizing radiation is locally delivered either through an external beam or by surgically implanting radionuclide-based seeds in the tumor,is one of the gold standard treatments for cancer.Due to the non-selective nature of radiation,healthy tissue surrounding the cancerous region is usually affected by the treatment.Hence,new strategies,including targeted alpha therapy,are being studied to improve the selectivity of the treatment and minimize side effects.Several challenges,however,limit the current development of targeted radiotherapy,such as the functionalization of the therapeutic agent with targeting vectors and controlling the release of recoiling daughters.Nanoparticles offer unique opportunities as drug delivery vehicles,since they are biocompatible,enhance the cellular uptake of drugs,and are easily functionalized with targeting molecules.In this review,we examine how nanoparticles can be used for targeted radiotherapy,either as sensitizers of external beams or as delivery vehicles for therapeutic radionuclides.We describe the clinical relevance of different types of nanoparticles,followed by an analysis of how these nanoconstructs can solve some of the main limitations of conventional radiotherapy.Finally,we critically discuss the current situation of nanoparticle-based radiotherapy in clinical settings and challenges that need to be overcome in the future for further development of the field.
基金the lab and for Emma Cordover’s work was from the Busch Biomedical Grantthe New Jersey Health Foundation Grantthe Aresty Research Center.
文摘Mammalian cells have the ability to respond to a myriad of diverse extracellular stimuli that modulate cell function.This often involves ligands binding to cell surface receptors and subsequent activation of intracellular signaling pathways.These pathways can lead to changes in gene expression patterns that in turn regulate cell growth,differentiation,migration,and function.One important type of cell surface receptor is the receptor tyrosine kinase(RTK).In response to in response to ligand binding,RTKs dimerize,then trans-phosphorylate each other,leading to activation of downstream pathways.While the signaling proteins in these pathways are important for normal cell growth control,when improperly regulated they can lead to uncontrolled growth and sometimes cancer.For this reason,they are often considered to be good candidates for drug targets for chemotherapeutic drugs.RTKs can activate multiple different signaling pathways.Some of the signaling proteins in these pathways can have crosstalk with other RTK activated pathways,and some of them can be activated by multiple mechanisms in addition to activation by RTKs.While there is a wide array of different signaling proteins and pathways activated by RTKs,in this review we will discuss components of several key pathways including the MAPK pathway,the Her2/Neu pathway,mTOR,and Pak kinases.We provide an overview of the roles for these pathways in cell signaling and discuss how different components of these pathways are being considered as targets for cancer treatment.
文摘Dr.Guan Chen previously worked in Sun Yat-sen University and German cancer research Center as well in Dana-Farber focused on investigating on biochemical mechanisms involved in cancer drug response by discovering Thaliblastine as a novel and non-toxic
基金supported by the National Key Research and Development Program of China(No.2016YFC1100100)the Major Research Plan of the National Natural Science Foundation of China(No.91649204).
文摘Microorganisms with innate and artificial advantages have been regarded as intelligent drug delivery systems for cancer therapy with the help of engineering technology.Although numerous studies have confirmed the promising prospects of microorganisms in cancer,several problems such as immunogenicity and toxicity should be addressed before further clinical applications.This review aims to investigate the developments of engineered microorganisms-based delivery systems for targeted cancer therapy.The main types and characteristics of microorganisms such as bacteria,viruses,fungi,microalgae,and their components are introduced in detail.Moreover,the engineering strategies and biomaterials design of microorganisms are further discussed.Most importantly,we discussed the innovative attempts and therapeutic effects of engineered microorganisms in cancer.Taken together,engineered microorganisms-based delivery systems hold tremendous prospects for biomedical applications in targeted cancer therapy.
基金partially supported by the National Institutes of Health(R21CA185833 and R01GM113242 to H.S.)the National Natural Science Foundation of China(Nos.81660041 and 81260021 to L.D.)the Education Department of Jiangxi Province(GJJ150219to X.T.)
文摘The Mediator co-activator complex is a highly conserved,multisubunit protein complex required for gene transcription by RNA polymerase Ⅱ(RNAPⅡ)in all eukaryotes(Allen and Taatjes,2015).This complex,which consists of at least 30 polypeptides,can be divided into four structurally distinct sub-modules including the head,middle,tail,and cyclin-dependent kinase 8(CDK8)
