Cancer is a big challenge that has plagued the human beings for ages and one of the most effective treatments is chemotherapy. However, the low tumor-targeting ability limits the wide clinical application of chemother...Cancer is a big challenge that has plagued the human beings for ages and one of the most effective treatments is chemotherapy. However, the low tumor-targeting ability limits the wide clinical application of chemotherapy. The microenvironment plays a critical role in many aspects of tumor genesis. It generates the tumor vasculature and it is highly implicated in the progression to metastasis. To maintain a suitable environment for tumor progression, there are special microenvironment in tumor cell, such as low pH, high level of glutathione(GSH) and reactive oxygen species(ROS), and more special enzymes, which is different to normal cell. Microenvironment-targeted therapy strategy could create new opportunities for therapeutic targeting. Compared to other targeting strategies, microenvironment-targeted therapy strategy will control the drug release into tumor cells more accurately. Redox responsive drug delivery systems(DDSs) are developed based on the high level of GSH in tumor cells. However, there are also GSH in normal cell though its level is lower. In order to control the release of drugs more accurately and reduce side effects, other drug release stimuli have been introduced to redox responsive DDSs. Under the synergistic reaction of two stimuli, redox dual-stimuli responsive DDSs will control the release of drugs more accurately and quickly and even increase the accumulation. This review summarizes strategies of redox dual-stimuli responsive DDSs such as pH, light, enzyme, ROS, and magnetic guide to delivery chemotherapeutic agents more accurately, aiming at providing new ideas for further promoting the drug release,enhancing tumor-targeting and improving anticancer effects. To better illustrate the redox dual-stimuli responsive DDS, preparations of carriers are also briefly described in the review.展开更多
Amino acid transporters,which play a vital role in transporting amino acids for the biosynthesis of mammalian cells,are highly expressed in types of tumors.Increasing studies have shown the feasibility of amino acid t...Amino acid transporters,which play a vital role in transporting amino acids for the biosynthesis of mammalian cells,are highly expressed in types of tumors.Increasing studies have shown the feasibility of amino acid transporters as a component of tumortargeting therapy.In this review,we focus on tumor-related amino acid transporters and their potential use in tumor-targeting therapy.Firstly,the expression characteristics of amino acid transporters in cancer and their relationship with tumor growth are reviewed.Secondly,the recognition requirements are discussed,focusing on the“acidbase”properties,conformational isomerism and structural analogues.Finally,recent developments in amino acid transporter-targeting drug delivery strategies are highlighted,including prodrugs and nanocarriers,with special attention to the latest findings of molecular mechanisms and targeting efficiency of transporter-mediated endocytosis.We aim to offer related clues that might lead to valuable tumor-targeting strategies by the utilization of amino acid transporters.展开更多
The clinical outcome of chemotherapy for solid tumors is significantly restricted by adverse off-target side effects and heterogeneous microenvironments.Herein,we developed a series of ultrasound(US)-activated carrier...The clinical outcome of chemotherapy for solid tumors is significantly restricted by adverse off-target side effects and heterogeneous microenvironments.Herein,we developed a series of ultrasound(US)-activated carrier-free self-assembled nanoprodrugs(PBSN38-OSs)to enhance universality and efficiency of tumor-targeting chemo-therapy.The nanoprodrugs integrated reactive oxygen species(ROS)-responsive pinacol boronic esterconjugated SN38(PBSN38)and organic sonosensitizers(OSs).By screening the OSs library,six small mole-cules with strong binding ability with PBSN38 and high sonodynamic generation efficiency were identified.Then,various PBSN38-OSs nanoprodrugs with high drug-loading content and aqueous stability were fabricated using a facile nano-precipitation method.When exposed to US irradiation,PBSN38-OSs produced extensive ROS in situ,strongly disturbing the endogenous redox balance to overcome the heterogeneity of tumoral ROS content.They subsequently triggered the release of active SN38,thereby resulting in severe oxidative damage and microenvironment-independent cell apoptosis.The antitumor activity and biocompatibility of PBSN38-OSs were thoroughly examined in vitro and in vivo,and two optimal nanoprodrugs were screened,which exhibited potent therapeutical effects toward solid tumor models of colon adenocarcinoma,hepatocellular carcinoma,and pancreatic carcinoma.Overall,the versatile US-activated carrier-free nanoprodrugs could significantly minimize the side effects of chemo-drugs and improve the tumor-targeting chemotherapy efficacy in a spatial-controlled and microenvironment-independent manner,holding great prospects in further clinical translation.展开更多
Ultrasound-generated antigens combined with TLR7/8 agonists as adjuvants have demonstrated significant anti-tumor efficacy as an in-situ vaccine.However,the use of TLR7/8 agonists can cause severe inflammatory respons...Ultrasound-generated antigens combined with TLR7/8 agonists as adjuvants have demonstrated significant anti-tumor efficacy as an in-situ vaccine.However,the use of TLR7/8 agonists can cause severe inflammatory responses.In this study,we present a novel tumor-targeting nano-adjuvant termed aPDL1-PLG/R848 NPs,which are composed of aPDL1 antibody,Fc-III-4C peptide linker(Fc-linker)and poly(L-glutamic acid)-grafted-R848.Under ultrasound irradiation,antigen-presenting cells activate immune mechanisms in vivo under dual stimulation of in situ antigens and immune adjuvants.The strategy inhibits primary tumor growth and induces a strong antigen-specific immune memory effect to prevent tumor recurrence in vivo.This work offers a safe and potent platform for an in situ cancer vaccine based on ultrasound therapy.展开更多
Proteolysis-targeting chimera(PROTAC)has emerged as an efficient strategy to accurately control intracellular protein levels.However,conventional PROTACs are generally limited by nonspecific protein degradation and of...Proteolysis-targeting chimera(PROTAC)has emerged as an efficient strategy to accurately control intracellular protein levels.However,conventional PROTACs are generally limited by nonspecific protein degradation and off-tissue side effects.Particularly,there is a lack of effective chemical tools for visualizing protein degradation.Herein,a near-infrared fluorescent and theranostic PROTAC(PRO-S-DCM)was designed for imaging the degradation of bromodomain-containing protein 4(BRD4).PRO-S-DCM could be tumor-specifically activated and exhibited favorable imaging effects both in vitro and in vivo.PRO-S-DCM was proven to be a theranostic probe,which potently inhibited growth,invasion and migration of He La cells and induced cell apoptosis.展开更多
"Vasculogenic mimicry(VM)",is a term that describes the unique ability of highly aggressive tumor cells to express a multipotent,stem cell-like phenotype,and form a pattern of vasculogenic-like networks in t..."Vasculogenic mimicry(VM)",is a term that describes the unique ability of highly aggressive tumor cells to express a multipotent,stem cell-like phenotype,and form a pattern of vasculogenic-like networks in threedimensional culture.As an angiogenesis-independent pathway,VM and/or periodic acid-schiff-positive patterns are associated with poor prognosis in tumor patients.Moreover,VM is resistant to angiogenesis inhibitors.Here,we will review the advances in research on biochemical and molecular signaling pathways of VM in tumors and on potential anti-VM therapy strategy.展开更多
Recent days,aggregatable nanoparticles,which can specifically respond to certain stimulus,have shown great potential in tumor-targeted drug delivery with prolonged retention and deeper penetration.In this review,we su...Recent days,aggregatable nanoparticles,which can specifically respond to certain stimulus,have shown great potential in tumor-targeted drug delivery with prolonged retention and deeper penetration.In this review,we summarize recent advances in design of aggregatable nanoparticles by different stimuli.Internal(pH and enzyme)and external(light,temperature and ROS)stimuli are introduced for a comprehensive description.Moreover,the aggregated nanoparticles usually exhibit photothermal,photoacoustic,PET and enhanced MRI contrast,which is also described.In the end,we discuss about the potential applications and challenges for the future clinical translation.展开更多
In order to enhance the targeted delivery of anticancer drugs by polymeric micelles, folic acid(FA), the ligand of folate receptor(FR) over-expressed in the most cancer cells, modified p H-sensitive polymeric micelles...In order to enhance the targeted delivery of anticancer drugs by polymeric micelles, folic acid(FA), the ligand of folate receptor(FR) over-expressed in the most cancer cells, modified p H-sensitive polymeric micelles were designed and fabricated to encapsulate doxorubicin(DOX) by combination of p H-sensitive amphiphilic polymer poly(2-ethyl-2-oxazoline)-poly(D,L-lactide) with FA-conjugated poly(2-ethyl-2-oxazoline)-poly(D,L-lactide). The prepared micelles were characterized to have about 36 nm in diameter with narrow distribution, well-defined spherical shape observed under TEM and p H-responsive drug release behavior. Moreover, the tumor targeting ability of the FA-modified p H-sensitive polymeric micelles was demonstrated by the cellular uptake, in vitro cytotoxicity to FR-positive KB cells and in vivo real time near-infrared fluorescence imaging in KB tumor-bearing nude mice. The efficient drug delivery by the micelles was ascribed to the synergistic effects of FR-mediated targeting and p H-triggered drug release. In conclusion, the designed FR-targeted p H-sensitive polymeric micelles might be of great potential in tumor targeted delivery of water-insoluble anticancer drugs.展开更多
Immune checkpoint inhibitors(ICIs)therapy targeting programmed cell death ligand 1(PD-L1)and programmed death protein 1(PD-1)had exhibited significant clinical benefits for cancer treatment such as triple negative bre...Immune checkpoint inhibitors(ICIs)therapy targeting programmed cell death ligand 1(PD-L1)and programmed death protein 1(PD-1)had exhibited significant clinical benefits for cancer treatment such as triple negative breast cancer(TNBC).However,the relatively low anti-tumor immune response rate and ICIs drug resistance highlight the necessity of developing ICIs combination therapy strategies to improve the anti-tumor effect of immunotherapy.Herein,the immunomodulator epigallocatechin gallate palmitate(PEGCG)and the immunoadjuvant metformin(MET)self-assembled into tumor-targeted micelles via hydrogen bond and electrostatic interaction,which encapsulated the therapeutic agents doxorubicin(DOX)-loaded PEGCG-MET micelles(PMD)and combined with ICIs(anti-PD-1 antibody)as therapeutic strategy to reduce the endogenous expression of PD-L1 and improve the tumor immunosuppressive microenvironment.The results presented that PMD integrated chemotherapy and immunotherapy to enhance antitumor efficacy in vitro and in vivo,compared with DOX or anti-PD-1 antibody for the therapy of TNBC.PMD micelles might be a potential candidate,which could remedy the shortcomings of antibody-based ICIs and provide synergistic effect to enhance the antitumor effects of ICIs in tumor therapy.展开更多
The induction of antitumor immunity by tumor antigens released from cancer cells following regional photothermal therapy(PTT)alone may not be adequate for achieving complete tumor elimination.Combination therapy with ...The induction of antitumor immunity by tumor antigens released from cancer cells following regional photothermal therapy(PTT)alone may not be adequate for achieving complete tumor elimination.Combination therapy with immune adjuvants enhances antitumor immune responses,but faces challenges such as targeting deficiencies,systemic toxicity,and uncontrolled release behavior.Herein,we introduce a novel dual-functional hybrid membrane nanoparticle(HM-NP)incorporating gold nanorods(GNRs)and a thermally responsive polymer shell.HM-NP demonstrates exceptional homotypic targeting efficacy beneath the tumor cell membrane(TM),leading to substantial tumor accumulation.Upon in situ near-infrared(NIR)stimulation,GNRs within HM-NP generate heat,triggering the burst release of HM by facilitating the contraction and disintegration of the thermally responsive polymer shell.HM-NP exhibits excellent photothermal conversion efficiency under NIR irradiation,enabling effective destruction of primary tumors,release of tumor-associated antigens,and stimulation of potent anti-cancer immune.Simultaneously,the immune responses are strengthened by TM and Escherichia coli membrane(EM)through promoting the maturation of antigen presenting cells(APCs)and activating cytotoxic T lymphocytes(CTLs).Moreover,the use of polymer shells enables efficient cancer therapy with minimal host clearance and adverse effects.This photothermally triggered immunotherapy holds promise for precise and personalized treatment of tumors.展开更多
Near-infrared(NIR)light-triggered photothermal therapy(PTT)is a promising treatment strategy for treating cancer.The combination of nanotechnology and NIR has been widely applied.However,the therapeutic efficacy of th...Near-infrared(NIR)light-triggered photothermal therapy(PTT)is a promising treatment strategy for treating cancer.The combination of nanotechnology and NIR has been widely applied.However,the therapeutic efficacy of the drug-delivery system depends on their ability to avoid phagocytosis of endothelial system,cross the biological barriers,prolong circulation life,localize and rapidly release the therapeutic at target sites.In this work,we designed a platelet membrane(PM)-camouflaged hollow mesoporous bismuth selenide nanoparticles(BS NPs)loading with indocyanine green(ICG)(PM@BS-ICG NPs)to achieve the above advantages.PM-coating has active tumor-targe ting ability which could preve nt drug leakage and provide drug long circulation,causing drug delivery systems to accumulate in tumor sites effectively.Moreover,as a type of the photothermal sensitizers,BS NPs are used as the inner cores to improve ICG stability and are served as scaffolds to enhance the hardness of this drug delivery system.For one hand,the thermal vibration of BS NPs under NIR laser irradiation causes tumor inhibition through hyperthermia.For another hand,this hyperthermia process could damage PM and let ICG rapid release from PM@BS-ICG NPs.The in vitro and in vivo results showed that this biomimetic nano-drug delivery system exhibits obvious antitumor activity which has good application prospect.展开更多
Nanomaterials with multiple functions have become more and more popular in the domain of cancer research. MoS2 has a great potential in photothermal therapy, X-ray/CT imaging and drug delivery. In this study, a water ...Nanomaterials with multiple functions have become more and more popular in the domain of cancer research. MoS2 has a great potential in photothermal therapy, X-ray/CT imaging and drug delivery. In this study, a water soluble MoS2 nanosystem(MoS2-PEG) was synthesized and explored in drug delivery, photothermal therapy(PTT) and X-ray imaging.Doxorubicin(DOX) was loaded onto MoS2-PEG with a high drug loading efficiency(~69%)and obtained a multifunctional drug delivery system(MoS2-PEG/DOX). As the drug delivery, MoS2-PEG/DOX could efficiently cross the cell membranes, and escape from the endosome via NIR light irradiation, lead to more apoptosis in MCF-7 cells, and afford higher antitumor efficacy without obvious toxic effects to normal organs owing to its prolonged blood circulation and 11.6-fold higher DTX uptake of tumor than DOX. Besides, MoS2-PEG/DOX not only served as a drug delivery system, but also as a powerful PTT agent for thermal ablation of tumor and a strong X-ray contrast agent for tumor diagnosis. In the in vitro and in vivo studies, MoS2-PEG/DOX exhibited excellent tumor-targeting efficacy, outstanding synergistic anti-cancer effect of photothermal and chemotherapy and X-ray imaging property,demonstrating that MoS2-PEG/DOX had a great potential for simultaneous diagnosis and photothermal-chemotherapy in cancer treatment.展开更多
Folate-containing dextran ligand （FA-Dextran-DTPA） was synthesized by the incorporation of diethylenetriamine- pentaacetic acid （DTPA） and folate （FA） as a tumor-targeting group into dextran as a polymer carrier...Folate-containing dextran ligand （FA-Dextran-DTPA） was synthesized by the incorporation of diethylenetriamine- pentaacetic acid （DTPA） and folate （FA） as a tumor-targeting group into dextran as a polymer carrier. This ligand was further reacted with gadolinium chloride to make a dextran gadolinium complex FA-Dextran-DTPA-Gd. The ligand and its gadolinium complex were characterized by 1H-NMR, FTIR, UV-Vis, average particle sizes and zeta potential, as well. In vitro properties including relaxivity, cytotoxicity assay, cellular uptake assay, and magnetic resonance imaging （MRI） were also evaluated. Compared with Gd-DTPA, FA-Dextran-DTPA-Gd possessed obviously higher relaxation effectiveness and lower cytotoxicity to HeLa cells. FA-Dextran-DTPA-Gd had a high affinity to the H460 and MDA-MB-231 tumor cells and can be taken up selectively by these tumor cells. Moreover, FA-Dextran-DTPA-Gd showed enhanced signal intensities （SI） of MRI and enhanced the contrast of MR images of tumor cells. These results indicated that FA-Dextran-DTPA-Gd showed the potential as a tumor-targeting contrast agent in MRI.展开更多
Objective:We recombine the suicide gene CD,UPRT into plasmid pTRKH2 and clone the recombinant dual suicide gene therapy system into tumor-hypoxia-targeting vector Bifidobacterium infantis and characterize its function...Objective:We recombine the suicide gene CD,UPRT into plasmid pTRKH2 and clone the recombinant dual suicide gene therapy system into tumor-hypoxia-targeting vector Bifidobacterium infantis and characterize its function.Methods:CD gene,UPRT gene and lactic acid bacteria expression plasmid pTRKH2 were digested by restriction endonuclease BamH I and Sal I,and constructed recombinant plasmids pTRKH2/CD and pTRKH2/UPRT in E.coli.The recombinant plasmids were then transfected into Bifidobacterium Infantis by electroporation.Identification of pTRKH2/CD and pTRKH2/UPRT was processed by dual restriction endonuclease digesting and sequencing.RT-PCR and SDS-PAGE were used to examine the expression of CD and UPRT genes at RNA and protein levels.The killing effects on Melanoma B16-F10 cells by pTRKH2/CD and pTRKH2/UPRT suicide gene therapy system with 5-FC were examined by MTT assay.Results:The CD gene and UPRT gene was successfully recombined into lactic acid bacteria expression plasmid pTRKH2.After dual endonuclease digestion of plasmid purified from the positively transfected E.coli,two fragments of 6.9 Kb and 1.3 Kb were found for CD gene and two fragments of 6.9 Kb and 620 bp were found for UPRT gene.The sequencing of CD gene and UPRT gene proved consistent sequences with Genebank published data.A fragment of 1.3 Kb for CD gene and fragment of 620 bp for UPRT gene was found in recombinant Bifidobacterium by RT-PCR.A 52 KDa protein for CD gene was identified in whole-cell protein of recombinant Bifidobacterium and a 26 KDa protein for UPRT gene was identified in supernatant fluid of recombinant Bifidobacterium.The survival rate of tumor cells treated by extracts from culture of recombinant Bifidobacterium with 5-FC showed a strong killing effects of pTRKH2/CD and pTRKH2/UPRT dual suicide gene therapy system on Melanoma B16-F10 cells.Conclusion:CD gene and UPRT gene are successfully inserted into pTRKH2 and transfected into tumor-hypoxia-targeting vector Bifidobacterium Infantis.This dual suicide gene therapy system shows a high efficiency for tumor cells killing.展开更多
The cationic folic acid（CFA） was prepared by introducing triethylenetetramine into folic acid with EDCI/NHS and characterized by IR, NMR and mass spectra. It was found that approximately one of two carboxyls in the ...The cationic folic acid（CFA） was prepared by introducing triethylenetetramine into folic acid with EDCI/NHS and characterized by IR, NMR and mass spectra. It was found that approximately one of two carboxyls in the folic acid molecule was substituted to form CFA. The conversion of γ-carboxyl is found to be 59% higher than 30% of γ-carboxyl. The CFA and doxorubicin hydrochloride can be loaded on the ionic shell of PTX-encapsulated micelle to form CFA loaded binary drug carrier via static interaction in aqueous solutions. The successful loading was demonstrated by zeta potential measurement and the drug load amount（DLA） of CFA was measured by HPLC. In vitro cytotoxicity results revealed the CFA drug carrier showed higher cytotoxicity to cancer cell MDA-MB-321 than the binary drug carrier without CFA and the positive control, while it showed lower cytotoxicity to normal cell HUVEC than the positive control, and similar cytotoxicity with the binary drug carrier without CFA. These results as well as confocal laser scanning microscopy observation indicate the synthesized CFA drug carrier possesses active tumor-targeting property.展开更多
A novel composite carrier of folic acid(FA)-polyethyleneimine(PEI)-ethosome(Eth)(FA-PEI-Eth)was developed for the treatment of cancers through loading and targeting delivery of multidrug(including gene and other drugs...A novel composite carrier of folic acid(FA)-polyethyleneimine(PEI)-ethosome(Eth)(FA-PEI-Eth)was developed for the treatment of cancers through loading and targeting delivery of multidrug(including gene and other drugs)into cancer cells.Physical and chemical property tests were done to prove the grafting of the composite.Gel retardation test was done to determine the optimal ratio of DNA@PEI complex,and cytocompatibility tests and tumor cell uptake tests were done to evaluate the efficiency of the composite.The results demonstrated that the FA-PEI-Eth could effectively deliver a gene and other drugs into tumor cells simultaneously,and suggested that this composite would be a promising carrier in tumor-targeted therapy applications.展开更多
Conventional drug-delivery systems(DDSs)for oncology often face challenges such as insufficient tumor selectivity,rapid systemic clearance,limited penetration across stromal and immune barriers,and suboptimal biocompa...Conventional drug-delivery systems(DDSs)for oncology often face challenges such as insufficient tumor selectivity,rapid systemic clearance,limited penetration across stromal and immune barriers,and suboptimal biocompatibility.Live immune cell-based drug-delivery systems(LCDDSs)overcome these limitations by exploiting the innate tumor-homing capacity,high biocompatibility,and dynamic tumor microenvironment(TME)interactions intrinsic to leukocytes,facilitating precise targeting with minimal systemic toxicity.Furthermore,immune cells act as“mobile microprocessors”,actively converting precursor payloads into therapeutically functional cargos at the tumor site and dynamically reshaping the TME.Nonetheless,the clinical translation of LCDDSs remains impeded by limited drug-loading capacities,premature payload degradation,potential impairment of immune-cell function,and insufficient persistence in immunosuppressive environments.To overcome these hurdles,immune cell reprogramming via genetic,metabolic,or epigenetic modifications emerges as a promising strategy.Such interventions improve cellular fitness,enhance tumor infiltration,augment payload transport efficiency,confer programmable release profiles,mitigate cellular exhaustion,and increase adaptability to the hostile TME.This review systemically evaluates how immune cell reprogramming advances LCDDSs by examining mechanistic benefits,drug compatibility considerations,payload loading strategies,and design criteria essential for achieving clinical controllability,safety,and scalability.By integrating immune-cell engineering with cutting-edge drug delivery technologies,reprogrammed LCDDSs represent a versatile and powerful platform for next-generation precision oncology therapeutics.展开更多
Bacterial antitumor therapy has great application potential given its unique characteristics,including genetic manipulation, tumor targeting specificity and immune system modulation. However,the nonnegligible side eff...Bacterial antitumor therapy has great application potential given its unique characteristics,including genetic manipulation, tumor targeting specificity and immune system modulation. However,the nonnegligible side effects and limited efficacy of clinical treatment limit their biomedical applications. Engineered bacteria for therapeutic applications ideally need to avoid their accumulation in normal organs and possess potent antitumor activity. Here, we show that macrophage-mediated tumor-targeted delivery of Salmonella typhimurium VNP20009 can effectively reduce the toxicity caused by administrating VNP20009 alone in a melanoma mouse model. This benefits from tumor-induced chemotaxis for macrophages combined with their slow release of loaded strains. Inspired by changes in the tumor microenvironment, including a decrease in intratumoral dysfunctional CD8+T cells and an increase in PDL1 on the tumor cell surface, macrophages were loaded with the engineered strain VNP-PD1nb, which can express and secrete anti-PD1 nanoantibodies after they are released from macrophages. This novel triple-combined immunotherapy significantly inhibited melanoma tumors by reactivating the tumor microenvironment by increasing immune cell infiltration, inhibiting tumor cell proliferation, remodeling TAMs to an M1-like phenotype and prominently activating CD8+T cells. These data suggest that novel combination immunotherapy is expected to be a breakthrough relative to single immunotherapy.展开更多
Glioma is one of the most malignant primary tumors affecting the brain.The efficacy of therapeutics for glioma is seriously compromised by the restriction of blood-brain barrier(BBB),interstitial tumor pressure of res...Glioma is one of the most malignant primary tumors affecting the brain.The efficacy of therapeutics for glioma is seriously compromised by the restriction of blood-brain barrier(BBB),interstitial tumor pressure of resistance to chemotherapy/radiation,and the inevitable damage to normal brain tissues.Inspired by the natural structure and properties of high-density lipoprotein(HDL),a tumor-penetrating lipoprotein was prepared by the fusion tLyP-1 to apolipoprotein A-I-mimicking peptides(D4F),together with indocyanine green(ICG)incorporation and lipophilic small interfering RNA targeted HIF-1α(siHIF)surface anchor for site-specific photo-gene therapy.tLyP-1 peptide is fused to HDL-surface to facilitate BBB permeability,tumor-homing capacity and-site accumulation of photosensitizer and siRNA.Upon NIR light irradiation,ICG not only served as real-time targeted imaging agent,but also provided toxic reactive oxygen species and local hyperthermia for glioma phototherapy.The HIF-1αsiRNA in this nanoplatform downregulated the hypoxia-induced HIF-1αlevel in tumor microenvironment and enhanced the photodynamic therapy against glioma.These studies demonstrated that the nanoparticles could not only efficiently across BBB and carry the payloads to orthotopic glioma,but also modulate tumor microenvironment,thereby inhibiting tumor growth with biosafety.Overall,this study develops a new multifunctional drug delivery system for glioma theranostic,providing deeper insights into orthotopic brain tumor imaging and treatment.展开更多
Glioblastoma(GBM)interventions necessitate exceptional precision due to the presence of blood-brain barrier(BBB)and its intricate co-growth with neuron and glial cells.Here,we developed a blocked bioorthogonal chemist...Glioblastoma(GBM)interventions necessitate exceptional precision due to the presence of blood-brain barrier(BBB)and its intricate co-growth with neuron and glial cells.Here,we developed a blocked bioorthogonal chemistry enabled liposome,termed Bioorthosome,with switchable BBB-crossing ligand that could block the bioorthogonal moieties in normal tissue and blood circulation.Upon traversing the BBB and reaching tumor region,the BBB-crossing ligand could detach from the Bioorthosome under acidic tumor microenvironment and switch to the bioorthogonal moieties to react with the metabolically expressed azide-containing sialylations on GBM cell surface.This switchable bioorthogonal chemistry ensures that only GBM cells are targeted,thereby enhancing the precision of liposomal drug delivery.In vitro and in vivo studies have demonstrated that the Bioorthosome efficiently crosses the BBB and undergoes a ligand-switching process to selectively recognize GBM cells while sparing normal brain tissue,leading to enhanced therapeutic efficacy and reduced off-target accumulation.By integrating bioorthogonal reactions with a tumor microenvironment-responsive ligand-switching mechanism,our Bioorthosome design overcomes the limitations of inefficient BBB permeability and suboptimal anti-GBM drug delivery,paving the way for more precise GBM-targeted therapies and the advancement of more effective treatment strategies.展开更多
基金National Natural Science Foundation of China (81202480,81302723)Natural Science Foundation of Liaoning Province (2015020749)。
文摘Cancer is a big challenge that has plagued the human beings for ages and one of the most effective treatments is chemotherapy. However, the low tumor-targeting ability limits the wide clinical application of chemotherapy. The microenvironment plays a critical role in many aspects of tumor genesis. It generates the tumor vasculature and it is highly implicated in the progression to metastasis. To maintain a suitable environment for tumor progression, there are special microenvironment in tumor cell, such as low pH, high level of glutathione(GSH) and reactive oxygen species(ROS), and more special enzymes, which is different to normal cell. Microenvironment-targeted therapy strategy could create new opportunities for therapeutic targeting. Compared to other targeting strategies, microenvironment-targeted therapy strategy will control the drug release into tumor cells more accurately. Redox responsive drug delivery systems(DDSs) are developed based on the high level of GSH in tumor cells. However, there are also GSH in normal cell though its level is lower. In order to control the release of drugs more accurately and reduce side effects, other drug release stimuli have been introduced to redox responsive DDSs. Under the synergistic reaction of two stimuli, redox dual-stimuli responsive DDSs will control the release of drugs more accurately and quickly and even increase the accumulation. This review summarizes strategies of redox dual-stimuli responsive DDSs such as pH, light, enzyme, ROS, and magnetic guide to delivery chemotherapeutic agents more accurately, aiming at providing new ideas for further promoting the drug release,enhancing tumor-targeting and improving anticancer effects. To better illustrate the redox dual-stimuli responsive DDS, preparations of carriers are also briefly described in the review.
基金This work was supported by the National Natural Science Foundation of China(Nos.81803442 and 81703425).
文摘Amino acid transporters,which play a vital role in transporting amino acids for the biosynthesis of mammalian cells,are highly expressed in types of tumors.Increasing studies have shown the feasibility of amino acid transporters as a component of tumortargeting therapy.In this review,we focus on tumor-related amino acid transporters and their potential use in tumor-targeting therapy.Firstly,the expression characteristics of amino acid transporters in cancer and their relationship with tumor growth are reviewed.Secondly,the recognition requirements are discussed,focusing on the“acidbase”properties,conformational isomerism and structural analogues.Finally,recent developments in amino acid transporter-targeting drug delivery strategies are highlighted,including prodrugs and nanocarriers,with special attention to the latest findings of molecular mechanisms and targeting efficiency of transporter-mediated endocytosis.We aim to offer related clues that might lead to valuable tumor-targeting strategies by the utilization of amino acid transporters.
基金the National Natural Science Foundation of China (Grant No. 82030048, 82230069, 82371967, 82102191, 82001818, 82402264)Binjiang Institute of Zhejiang University and Post-Doctoral Research Center of Zhejiang SUKEAN Pharmaceutical Co., Ltd.
文摘The clinical outcome of chemotherapy for solid tumors is significantly restricted by adverse off-target side effects and heterogeneous microenvironments.Herein,we developed a series of ultrasound(US)-activated carrier-free self-assembled nanoprodrugs(PBSN38-OSs)to enhance universality and efficiency of tumor-targeting chemo-therapy.The nanoprodrugs integrated reactive oxygen species(ROS)-responsive pinacol boronic esterconjugated SN38(PBSN38)and organic sonosensitizers(OSs).By screening the OSs library,six small mole-cules with strong binding ability with PBSN38 and high sonodynamic generation efficiency were identified.Then,various PBSN38-OSs nanoprodrugs with high drug-loading content and aqueous stability were fabricated using a facile nano-precipitation method.When exposed to US irradiation,PBSN38-OSs produced extensive ROS in situ,strongly disturbing the endogenous redox balance to overcome the heterogeneity of tumoral ROS content.They subsequently triggered the release of active SN38,thereby resulting in severe oxidative damage and microenvironment-independent cell apoptosis.The antitumor activity and biocompatibility of PBSN38-OSs were thoroughly examined in vitro and in vivo,and two optimal nanoprodrugs were screened,which exhibited potent therapeutical effects toward solid tumor models of colon adenocarcinoma,hepatocellular carcinoma,and pancreatic carcinoma.Overall,the versatile US-activated carrier-free nanoprodrugs could significantly minimize the side effects of chemo-drugs and improve the tumor-targeting chemotherapy efficacy in a spatial-controlled and microenvironment-independent manner,holding great prospects in further clinical translation.
基金Ministry of Science and Technology of China,Grant/Award Number:2022YFE0110200Natural Science Foundation of Jilin Province,Grant/Award Number:20230101037JCNational Natural Science Foundation of China,Grant/Award Numbers:52203198,52025035。
文摘Ultrasound-generated antigens combined with TLR7/8 agonists as adjuvants have demonstrated significant anti-tumor efficacy as an in-situ vaccine.However,the use of TLR7/8 agonists can cause severe inflammatory responses.In this study,we present a novel tumor-targeting nano-adjuvant termed aPDL1-PLG/R848 NPs,which are composed of aPDL1 antibody,Fc-III-4C peptide linker(Fc-linker)and poly(L-glutamic acid)-grafted-R848.Under ultrasound irradiation,antigen-presenting cells activate immune mechanisms in vivo under dual stimulation of in situ antigens and immune adjuvants.The strategy inhibits primary tumor growth and induces a strong antigen-specific immune memory effect to prevent tumor recurrence in vivo.This work offers a safe and potent platform for an in situ cancer vaccine based on ultrasound therapy.
基金supported by the National Key Research and Development Program of China(No.2022YFC3401500 to C.Sheng)the National Natural Science Foundation of China(No.82030105 to C.Sheng and Nos.22077138,22377145 to S.Wu)Shanghai Rising-Star Program(No.22QA1411300 to S.Wu)。
文摘Proteolysis-targeting chimera(PROTAC)has emerged as an efficient strategy to accurately control intracellular protein levels.However,conventional PROTACs are generally limited by nonspecific protein degradation and off-tissue side effects.Particularly,there is a lack of effective chemical tools for visualizing protein degradation.Herein,a near-infrared fluorescent and theranostic PROTAC(PRO-S-DCM)was designed for imaging the degradation of bromodomain-containing protein 4(BRD4).PRO-S-DCM could be tumor-specifically activated and exhibited favorable imaging effects both in vitro and in vivo.PRO-S-DCM was proven to be a theranostic probe,which potently inhibited growth,invasion and migration of He La cells and induced cell apoptosis.
基金Supported by A grant from the National Nature Science Foundation of China,No. 30672073
文摘"Vasculogenic mimicry(VM)",is a term that describes the unique ability of highly aggressive tumor cells to express a multipotent,stem cell-like phenotype,and form a pattern of vasculogenic-like networks in threedimensional culture.As an angiogenesis-independent pathway,VM and/or periodic acid-schiff-positive patterns are associated with poor prognosis in tumor patients.Moreover,VM is resistant to angiogenesis inhibitors.Here,we will review the advances in research on biochemical and molecular signaling pathways of VM in tumors and on potential anti-VM therapy strategy.
基金supported by the National Natural Science Foundation of China(No.81961138009)the Young Elite Scientists Sponsorship Program by CAST(No.2017QNR001)+1 种基金the Fundamental Research Funds for the Central Universities,111 Project(No.B18035)RFBR and National Natural Science Foundation of China Collaboration Project(No.19-58-55001)。
文摘Recent days,aggregatable nanoparticles,which can specifically respond to certain stimulus,have shown great potential in tumor-targeted drug delivery with prolonged retention and deeper penetration.In this review,we summarize recent advances in design of aggregatable nanoparticles by different stimuli.Internal(pH and enzyme)and external(light,temperature and ROS)stimuli are introduced for a comprehensive description.Moreover,the aggregated nanoparticles usually exhibit photothermal,photoacoustic,PET and enhanced MRI contrast,which is also described.In the end,we discuss about the potential applications and challenges for the future clinical translation.
基金National Natural Science Foundation of China(Grant No.81673366)。
文摘In order to enhance the targeted delivery of anticancer drugs by polymeric micelles, folic acid(FA), the ligand of folate receptor(FR) over-expressed in the most cancer cells, modified p H-sensitive polymeric micelles were designed and fabricated to encapsulate doxorubicin(DOX) by combination of p H-sensitive amphiphilic polymer poly(2-ethyl-2-oxazoline)-poly(D,L-lactide) with FA-conjugated poly(2-ethyl-2-oxazoline)-poly(D,L-lactide). The prepared micelles were characterized to have about 36 nm in diameter with narrow distribution, well-defined spherical shape observed under TEM and p H-responsive drug release behavior. Moreover, the tumor targeting ability of the FA-modified p H-sensitive polymeric micelles was demonstrated by the cellular uptake, in vitro cytotoxicity to FR-positive KB cells and in vivo real time near-infrared fluorescence imaging in KB tumor-bearing nude mice. The efficient drug delivery by the micelles was ascribed to the synergistic effects of FR-mediated targeting and p H-triggered drug release. In conclusion, the designed FR-targeted p H-sensitive polymeric micelles might be of great potential in tumor targeted delivery of water-insoluble anticancer drugs.
基金the projects of the National Key Research and Development Program(No.2021YFA0716702)the National Natural Science Foundation of China(Nos.61805122,22022404 and 22074050)+5 种基金Green Industry Science and Technology Leading Project of Hubei University of Technology(No.XJ2021003301)the National Natural Science Foundation of Hubei Province(No.2022CFA033)supported by Chinese Society of Clinical Oncology(CSCO)supported by Jiangsu Hengrui Cancer Research Foundation(No.YHR2019–0325)supported by the Fundamental Research Funds for the Central Universities(No.CCNU22QN007)supported by the Opening Fund from the Jiangsu Key Laboratory of Medical Optics,Suzhou Institute of Biomedical Engineering and Technology(No.JKLMO202203)supported by the Key Laboratory of Optic-electric Sensing and Analytical Chemistry for Life Science,MO(No.M2022–5).
文摘Immune checkpoint inhibitors(ICIs)therapy targeting programmed cell death ligand 1(PD-L1)and programmed death protein 1(PD-1)had exhibited significant clinical benefits for cancer treatment such as triple negative breast cancer(TNBC).However,the relatively low anti-tumor immune response rate and ICIs drug resistance highlight the necessity of developing ICIs combination therapy strategies to improve the anti-tumor effect of immunotherapy.Herein,the immunomodulator epigallocatechin gallate palmitate(PEGCG)and the immunoadjuvant metformin(MET)self-assembled into tumor-targeted micelles via hydrogen bond and electrostatic interaction,which encapsulated the therapeutic agents doxorubicin(DOX)-loaded PEGCG-MET micelles(PMD)and combined with ICIs(anti-PD-1 antibody)as therapeutic strategy to reduce the endogenous expression of PD-L1 and improve the tumor immunosuppressive microenvironment.The results presented that PMD integrated chemotherapy and immunotherapy to enhance antitumor efficacy in vitro and in vivo,compared with DOX or anti-PD-1 antibody for the therapy of TNBC.PMD micelles might be a potential candidate,which could remedy the shortcomings of antibody-based ICIs and provide synergistic effect to enhance the antitumor effects of ICIs in tumor therapy.
基金supported by the National Natural Science Foundation of China(Nos.92059112,82072821 and 31470964)University of Shanghai for Science and Technology(No.10-21302-405)+1 种基金the Program of Shanghai Academic/Technology Research Leader(No.22XD1404700)the Shanghai Songjiang Municipal Science and Technology Commission Natural Science Foundation(No.20SJKJGG250)。
文摘The induction of antitumor immunity by tumor antigens released from cancer cells following regional photothermal therapy(PTT)alone may not be adequate for achieving complete tumor elimination.Combination therapy with immune adjuvants enhances antitumor immune responses,but faces challenges such as targeting deficiencies,systemic toxicity,and uncontrolled release behavior.Herein,we introduce a novel dual-functional hybrid membrane nanoparticle(HM-NP)incorporating gold nanorods(GNRs)and a thermally responsive polymer shell.HM-NP demonstrates exceptional homotypic targeting efficacy beneath the tumor cell membrane(TM),leading to substantial tumor accumulation.Upon in situ near-infrared(NIR)stimulation,GNRs within HM-NP generate heat,triggering the burst release of HM by facilitating the contraction and disintegration of the thermally responsive polymer shell.HM-NP exhibits excellent photothermal conversion efficiency under NIR irradiation,enabling effective destruction of primary tumors,release of tumor-associated antigens,and stimulation of potent anti-cancer immune.Simultaneously,the immune responses are strengthened by TM and Escherichia coli membrane(EM)through promoting the maturation of antigen presenting cells(APCs)and activating cytotoxic T lymphocytes(CTLs).Moreover,the use of polymer shells enables efficient cancer therapy with minimal host clearance and adverse effects.This photothermally triggered immunotherapy holds promise for precise and personalized treatment of tumors.
基金supported by the National Natural Science Foundation of China(Nos.81673021 and U1804183)the Scientific and Technological Project of Henan Province(No.182102310117)。
文摘Near-infrared(NIR)light-triggered photothermal therapy(PTT)is a promising treatment strategy for treating cancer.The combination of nanotechnology and NIR has been widely applied.However,the therapeutic efficacy of the drug-delivery system depends on their ability to avoid phagocytosis of endothelial system,cross the biological barriers,prolong circulation life,localize and rapidly release the therapeutic at target sites.In this work,we designed a platelet membrane(PM)-camouflaged hollow mesoporous bismuth selenide nanoparticles(BS NPs)loading with indocyanine green(ICG)(PM@BS-ICG NPs)to achieve the above advantages.PM-coating has active tumor-targe ting ability which could preve nt drug leakage and provide drug long circulation,causing drug delivery systems to accumulate in tumor sites effectively.Moreover,as a type of the photothermal sensitizers,BS NPs are used as the inner cores to improve ICG stability and are served as scaffolds to enhance the hardness of this drug delivery system.For one hand,the thermal vibration of BS NPs under NIR laser irradiation causes tumor inhibition through hyperthermia.For another hand,this hyperthermia process could damage PM and let ICG rapid release from PM@BS-ICG NPs.The in vitro and in vivo results showed that this biomimetic nano-drug delivery system exhibits obvious antitumor activity which has good application prospect.
基金supported by grants from the National Natural Science Foundation of China(Nos.81273451,81302717 and81101684)
文摘Nanomaterials with multiple functions have become more and more popular in the domain of cancer research. MoS2 has a great potential in photothermal therapy, X-ray/CT imaging and drug delivery. In this study, a water soluble MoS2 nanosystem(MoS2-PEG) was synthesized and explored in drug delivery, photothermal therapy(PTT) and X-ray imaging.Doxorubicin(DOX) was loaded onto MoS2-PEG with a high drug loading efficiency(~69%)and obtained a multifunctional drug delivery system(MoS2-PEG/DOX). As the drug delivery, MoS2-PEG/DOX could efficiently cross the cell membranes, and escape from the endosome via NIR light irradiation, lead to more apoptosis in MCF-7 cells, and afford higher antitumor efficacy without obvious toxic effects to normal organs owing to its prolonged blood circulation and 11.6-fold higher DTX uptake of tumor than DOX. Besides, MoS2-PEG/DOX not only served as a drug delivery system, but also as a powerful PTT agent for thermal ablation of tumor and a strong X-ray contrast agent for tumor diagnosis. In the in vitro and in vivo studies, MoS2-PEG/DOX exhibited excellent tumor-targeting efficacy, outstanding synergistic anti-cancer effect of photothermal and chemotherapy and X-ray imaging property,demonstrating that MoS2-PEG/DOX had a great potential for simultaneous diagnosis and photothermal-chemotherapy in cancer treatment.
基金financially supported by the National Natural Science Foundation of China(Nos.51173140 and 51373128)Wuhan Scientific and Technological Project(No.2013010501010131)+1 种基金Wuhan Science and Technology Innovation Team of Hi-tech Industrial Project,Hubei Province(No.2015070504020217)Innovation Fund for Post-graduate Education(Nos.CX2014058 and CX2013083),Wuhan Institute of Technology,China
文摘Folate-containing dextran ligand （FA-Dextran-DTPA） was synthesized by the incorporation of diethylenetriamine- pentaacetic acid （DTPA） and folate （FA） as a tumor-targeting group into dextran as a polymer carrier. This ligand was further reacted with gadolinium chloride to make a dextran gadolinium complex FA-Dextran-DTPA-Gd. The ligand and its gadolinium complex were characterized by 1H-NMR, FTIR, UV-Vis, average particle sizes and zeta potential, as well. In vitro properties including relaxivity, cytotoxicity assay, cellular uptake assay, and magnetic resonance imaging （MRI） were also evaluated. Compared with Gd-DTPA, FA-Dextran-DTPA-Gd possessed obviously higher relaxation effectiveness and lower cytotoxicity to HeLa cells. FA-Dextran-DTPA-Gd had a high affinity to the H460 and MDA-MB-231 tumor cells and can be taken up selectively by these tumor cells. Moreover, FA-Dextran-DTPA-Gd showed enhanced signal intensities （SI） of MRI and enhanced the contrast of MR images of tumor cells. These results indicated that FA-Dextran-DTPA-Gd showed the potential as a tumor-targeting contrast agent in MRI.
基金Supported by a grant from the Science and Technology Bureau of Sichuan Province (No. 04JY029-020-2)
文摘Objective:We recombine the suicide gene CD,UPRT into plasmid pTRKH2 and clone the recombinant dual suicide gene therapy system into tumor-hypoxia-targeting vector Bifidobacterium infantis and characterize its function.Methods:CD gene,UPRT gene and lactic acid bacteria expression plasmid pTRKH2 were digested by restriction endonuclease BamH I and Sal I,and constructed recombinant plasmids pTRKH2/CD and pTRKH2/UPRT in E.coli.The recombinant plasmids were then transfected into Bifidobacterium Infantis by electroporation.Identification of pTRKH2/CD and pTRKH2/UPRT was processed by dual restriction endonuclease digesting and sequencing.RT-PCR and SDS-PAGE were used to examine the expression of CD and UPRT genes at RNA and protein levels.The killing effects on Melanoma B16-F10 cells by pTRKH2/CD and pTRKH2/UPRT suicide gene therapy system with 5-FC were examined by MTT assay.Results:The CD gene and UPRT gene was successfully recombined into lactic acid bacteria expression plasmid pTRKH2.After dual endonuclease digestion of plasmid purified from the positively transfected E.coli,two fragments of 6.9 Kb and 1.3 Kb were found for CD gene and two fragments of 6.9 Kb and 620 bp were found for UPRT gene.The sequencing of CD gene and UPRT gene proved consistent sequences with Genebank published data.A fragment of 1.3 Kb for CD gene and fragment of 620 bp for UPRT gene was found in recombinant Bifidobacterium by RT-PCR.A 52 KDa protein for CD gene was identified in whole-cell protein of recombinant Bifidobacterium and a 26 KDa protein for UPRT gene was identified in supernatant fluid of recombinant Bifidobacterium.The survival rate of tumor cells treated by extracts from culture of recombinant Bifidobacterium with 5-FC showed a strong killing effects of pTRKH2/CD and pTRKH2/UPRT dual suicide gene therapy system on Melanoma B16-F10 cells.Conclusion:CD gene and UPRT gene are successfully inserted into pTRKH2 and transfected into tumor-hypoxia-targeting vector Bifidobacterium Infantis.This dual suicide gene therapy system shows a high efficiency for tumor cells killing.
基金financially supported by National Undergraduate Training Programs for Innovation and Entrepreneurship(201310007048)the Basic Research Foundation of Beijing Institute of Technology(No.20120942005)the National Natural Science Foundation of China(No.21104005)
文摘The cationic folic acid（CFA） was prepared by introducing triethylenetetramine into folic acid with EDCI/NHS and characterized by IR, NMR and mass spectra. It was found that approximately one of two carboxyls in the folic acid molecule was substituted to form CFA. The conversion of γ-carboxyl is found to be 59% higher than 30% of γ-carboxyl. The CFA and doxorubicin hydrochloride can be loaded on the ionic shell of PTX-encapsulated micelle to form CFA loaded binary drug carrier via static interaction in aqueous solutions. The successful loading was demonstrated by zeta potential measurement and the drug load amount（DLA） of CFA was measured by HPLC. In vitro cytotoxicity results revealed the CFA drug carrier showed higher cytotoxicity to cancer cell MDA-MB-321 than the binary drug carrier without CFA and the positive control, while it showed lower cytotoxicity to normal cell HUVEC than the positive control, and similar cytotoxicity with the binary drug carrier without CFA. These results as well as confocal laser scanning microscopy observation indicate the synthesized CFA drug carrier possesses active tumor-targeting property.
基金Shanghai Science and Technology Committee Project,China(No.18490740400)Open Foundation of Key Laboratory of Science&Technology of Eco-Textile,China(No.Eco-KF-201612)+1 种基金Opening Project of Zhejiang Provincial Preponderant and Characteristic Subject of Key University,Zhejiang Chinese Medical University,China(No.ZYAOX2018035)Project of Health and Family Planning Commission of Zhejiang Province,China(No.2018KY831)
文摘A novel composite carrier of folic acid(FA)-polyethyleneimine(PEI)-ethosome(Eth)(FA-PEI-Eth)was developed for the treatment of cancers through loading and targeting delivery of multidrug(including gene and other drugs)into cancer cells.Physical and chemical property tests were done to prove the grafting of the composite.Gel retardation test was done to determine the optimal ratio of DNA@PEI complex,and cytocompatibility tests and tumor cell uptake tests were done to evaluate the efficiency of the composite.The results demonstrated that the FA-PEI-Eth could effectively deliver a gene and other drugs into tumor cells simultaneously,and suggested that this composite would be a promising carrier in tumor-targeted therapy applications.
基金funded by the National Natural Science Foundation of China(No.82374050).
文摘Conventional drug-delivery systems(DDSs)for oncology often face challenges such as insufficient tumor selectivity,rapid systemic clearance,limited penetration across stromal and immune barriers,and suboptimal biocompatibility.Live immune cell-based drug-delivery systems(LCDDSs)overcome these limitations by exploiting the innate tumor-homing capacity,high biocompatibility,and dynamic tumor microenvironment(TME)interactions intrinsic to leukocytes,facilitating precise targeting with minimal systemic toxicity.Furthermore,immune cells act as“mobile microprocessors”,actively converting precursor payloads into therapeutically functional cargos at the tumor site and dynamically reshaping the TME.Nonetheless,the clinical translation of LCDDSs remains impeded by limited drug-loading capacities,premature payload degradation,potential impairment of immune-cell function,and insufficient persistence in immunosuppressive environments.To overcome these hurdles,immune cell reprogramming via genetic,metabolic,or epigenetic modifications emerges as a promising strategy.Such interventions improve cellular fitness,enhance tumor infiltration,augment payload transport efficiency,confer programmable release profiles,mitigate cellular exhaustion,and increase adaptability to the hostile TME.This review systemically evaluates how immune cell reprogramming advances LCDDSs by examining mechanistic benefits,drug compatibility considerations,payload loading strategies,and design criteria essential for achieving clinical controllability,safety,and scalability.By integrating immune-cell engineering with cutting-edge drug delivery technologies,reprogrammed LCDDSs represent a versatile and powerful platform for next-generation precision oncology therapeutics.
基金supported in part by grants from the National Natural Sciences Foundation of China (82130106)Jiangsu Provincial Department of Science and Technology (BK20192005, China)+1 种基金Changzhou Bureau of Science and Technology (CJ20210024, CZ20210010, China)Jiangsu TargetPharma Laboratories Inc., China
文摘Bacterial antitumor therapy has great application potential given its unique characteristics,including genetic manipulation, tumor targeting specificity and immune system modulation. However,the nonnegligible side effects and limited efficacy of clinical treatment limit their biomedical applications. Engineered bacteria for therapeutic applications ideally need to avoid their accumulation in normal organs and possess potent antitumor activity. Here, we show that macrophage-mediated tumor-targeted delivery of Salmonella typhimurium VNP20009 can effectively reduce the toxicity caused by administrating VNP20009 alone in a melanoma mouse model. This benefits from tumor-induced chemotaxis for macrophages combined with their slow release of loaded strains. Inspired by changes in the tumor microenvironment, including a decrease in intratumoral dysfunctional CD8+T cells and an increase in PDL1 on the tumor cell surface, macrophages were loaded with the engineered strain VNP-PD1nb, which can express and secrete anti-PD1 nanoantibodies after they are released from macrophages. This novel triple-combined immunotherapy significantly inhibited melanoma tumors by reactivating the tumor microenvironment by increasing immune cell infiltration, inhibiting tumor cell proliferation, remodeling TAMs to an M1-like phenotype and prominently activating CD8+T cells. These data suggest that novel combination immunotherapy is expected to be a breakthrough relative to single immunotherapy.
基金The authors acknowledge financial support from National Natural Science Foundation of China(No.81872819,82073401,82073795 and 81903557)Natural Science Foundation of Jiangsu Province(No.BK20190802)+2 种基金Natural Science Foundation Youth Project of Nanjing University of Chinese Medicine(No.NZY81903557)the Open Project of Chinese Materia Medica First-Class Discipline of Nanjing University of Chinese Medicine(No.2020YLXK019)Natural Science Foundation of the Jiangsu Higher Education Institutions of China(No.19KJB350003).
文摘Glioma is one of the most malignant primary tumors affecting the brain.The efficacy of therapeutics for glioma is seriously compromised by the restriction of blood-brain barrier(BBB),interstitial tumor pressure of resistance to chemotherapy/radiation,and the inevitable damage to normal brain tissues.Inspired by the natural structure and properties of high-density lipoprotein(HDL),a tumor-penetrating lipoprotein was prepared by the fusion tLyP-1 to apolipoprotein A-I-mimicking peptides(D4F),together with indocyanine green(ICG)incorporation and lipophilic small interfering RNA targeted HIF-1α(siHIF)surface anchor for site-specific photo-gene therapy.tLyP-1 peptide is fused to HDL-surface to facilitate BBB permeability,tumor-homing capacity and-site accumulation of photosensitizer and siRNA.Upon NIR light irradiation,ICG not only served as real-time targeted imaging agent,but also provided toxic reactive oxygen species and local hyperthermia for glioma phototherapy.The HIF-1αsiRNA in this nanoplatform downregulated the hypoxia-induced HIF-1αlevel in tumor microenvironment and enhanced the photodynamic therapy against glioma.These studies demonstrated that the nanoparticles could not only efficiently across BBB and carry the payloads to orthotopic glioma,but also modulate tumor microenvironment,thereby inhibiting tumor growth with biosafety.Overall,this study develops a new multifunctional drug delivery system for glioma theranostic,providing deeper insights into orthotopic brain tumor imaging and treatment.
基金the National Natural Science Foundation of China(Nos.82172084,81803002,and 32371342)STI2030-Major Projects(No.2022ZD0212500)+3 种基金Shanghai Frontiers Science Center of Drug Target Identification and Delivery(No.ZXWH2170101)Shaanxi Provincial Education Department serves local industrialization projects(No.20JC035)Xi'an Science and Technology Bureau of Shaanxi province-scientific and technological personnel service enterprise project(No.22GXFW0133)Shaanxi innovation team project(No.2023-CXTD-58).
文摘Glioblastoma(GBM)interventions necessitate exceptional precision due to the presence of blood-brain barrier(BBB)and its intricate co-growth with neuron and glial cells.Here,we developed a blocked bioorthogonal chemistry enabled liposome,termed Bioorthosome,with switchable BBB-crossing ligand that could block the bioorthogonal moieties in normal tissue and blood circulation.Upon traversing the BBB and reaching tumor region,the BBB-crossing ligand could detach from the Bioorthosome under acidic tumor microenvironment and switch to the bioorthogonal moieties to react with the metabolically expressed azide-containing sialylations on GBM cell surface.This switchable bioorthogonal chemistry ensures that only GBM cells are targeted,thereby enhancing the precision of liposomal drug delivery.In vitro and in vivo studies have demonstrated that the Bioorthosome efficiently crosses the BBB and undergoes a ligand-switching process to selectively recognize GBM cells while sparing normal brain tissue,leading to enhanced therapeutic efficacy and reduced off-target accumulation.By integrating bioorthogonal reactions with a tumor microenvironment-responsive ligand-switching mechanism,our Bioorthosome design overcomes the limitations of inefficient BBB permeability and suboptimal anti-GBM drug delivery,paving the way for more precise GBM-targeted therapies and the advancement of more effective treatment strategies.
