Natural phytoconstituents exhibit distinct advantages in the management and prevention of inflammatory bowel disease(IBD),attributed to their robust biological activity,multi-target effects,and elevated safety profile...Natural phytoconstituents exhibit distinct advantages in the management and prevention of inflammatory bowel disease(IBD),attributed to their robust biological activity,multi-target effects,and elevated safety profile.Although promising,the clinical application of phytoconstituents have been impeded by poor water solubility,low oral bioavailability,and inadequate colonic targeting.Recent advancements in nanotechnology has offered prospective avenues for the application of phytoconstituents in the treatment of IBD.A common strategy involves encapsulating or conjugating phytoconstituents with nanocarriers to enhance their stability,prolong intestinal retention,and facilitate targeted delivery to colonic inflammatory tissues.Furthermore,drawing inspiration from the self-assembling nanostructures that emerge during the decoction process of Chinese herbs,a variety of natural active compounds-based nanoassemblies have been developed for the treatment of IBD.They exhibit high drug-loading capacities and surmount the challenges posed by poor water solubility and low bioavailability.Notably,phyto-derived nanovesicles,owing to their unique structure and biological functions,can serve as therapeutic agents or novel delivery vehicles for the treatment of IBD.Consequently,this review provides an extensive overview of emerging phytoconstituent-derived nano-medicines/vesicles for the treatment of IBD,intending to offer novel insights for the clinical management of IBD.展开更多
Self-assembled prodrug nanomedicine has emerged as an advanced platform for antitumor therapy,mainly comprise drug modules,response modules and modification modules.However,existing studies usually compare the differe...Self-assembled prodrug nanomedicine has emerged as an advanced platform for antitumor therapy,mainly comprise drug modules,response modules and modification modules.However,existing studies usually compare the differences between single types of modification modules,neglecting the impact of steric-hindrance effect caused by chemical structure.Herein,single-tailed modification module with low-steric-hindrance effect and two-tailed modification module with high-steric-hindrance effect were selected to construct paclitaxel prodrugs(P-LA_(C18)and P-BAC18),and the in-depth insights of the sterichindrance effect on prodrug nanoassemblies were explored.Notably,the size stability of the two-tailed prodrugs was enhanced due to improved intermolecular interactions and steric hindrance.Single-tailed prodrug nanoassemblies were more susceptible to attack by redox agents,showing faster drug release and stronger antitumor efficacy,but with poorer safety.In contrast,two-tailed prodrug nanoassemblies exhibited significant advantages in terms of pharmacokinetics,tumor accumulation and safety due to the good size stability,thus ensuring equivalent antitumor efficacy at tolerance dose.These findings highlighted the critical role of steric-hindrance effect of the modification module in regulating the structureactivity relationship of prodrug nanoassemblies and proposed new perspectives into the precise design of self-assembled prodrugs for high-performance cancer therapeutics.展开更多
Local precise drug delivery is conducive to improving therapeutic efficacy and minimizing off-target toxicity.Current local delivery approaches are focused mostly on superficial or postoperative tumor lesions,due to t...Local precise drug delivery is conducive to improving therapeutic efficacy and minimizing off-target toxicity.Current local delivery approaches are focused mostly on superficial or postoperative tumor lesions,due to the challenges posed by the inaccessibility of deep-seated tumors.Herein,we report a magnetic continuum soft robot capable of non-invasive and site-specific delivery of prodrug nanoassemblies-loaded hydrogel.The nanoassemblies are co-assembled from redox-responsive docetaxel prodrug and oxaliplatin prodrug,and subsequently embedded into a hydrogel matrix.The hydrogel precursor and crosslinker are synchronously delivered using the soft robot under magnetic guidance and in situ crosslinked at the gastric cancer lesions,forming a drug depot for sustained release and long-lasting treatment.As the hydrogel gradually degrades,the nanoassemblies are internalized by tumor cells.The redox response ability enables them to be selectively activatedwithin tumor cells to trigger the release of docetaxel and oxaliplatin,exerting a synergistic anti-tumor effect.We find that the combination effectively induces immunogenic cell death of gastric tumor,enhancing antitumor immune responses.This strategy offers an intelligent and controllable integration platform for precise drug delivery and combined chemo-immunotherapy.展开更多
Ferroptosis can serve as a potent strategy for regulating cell death via lipid peroxidation and the imbalance of the antioxidant system resulting from iron accumulation in triple-negative breast cancer(TNBC)therapy.Ho...Ferroptosis can serve as a potent strategy for regulating cell death via lipid peroxidation and the imbalance of the antioxidant system resulting from iron accumulation in triple-negative breast cancer(TNBC)therapy.However,the ferroptosis accompanied with down-regulation of glutathione peroxidase 4(GPX4)lead to CD36-mediated tumor-infiltrating CD8^(+)T cells uptaking fatty acids,resulting in the negative action on immunotherapeutic efficacy.Herein,the albumin nanoparticles,abbreviated as LHS NPs,were designed by co-assembly of hemin,linoleic acid-cystamine,and a CD36 inhibitor sulfosuccinimide oleate,to bi-directionally manipulated ferroptosis in tumor and CD8^(+)T cells for TNBC therapy.LHS NPs exerted more efficient reactive oxygen species generation,glutathione depletion and malondialdehyde production by the combinatory strategy of classical and non-classical ferroptosis modes,which amplified the positive action on ferroptosis in tumor cells.Meanwhile,LHS manipulated the negative action of ferroptosis by inhibiting the CD36 mediated-lipid peroxidation in CD8^(+)T cells,thereby activating the immunotherapeutic efficacy with the improvements on induction of immunogenic cell death,proliferation of CD4+CD8^(+)T cells and natural killer cells,alleviation immunosuppressive regulatory T cells and myeloid-derived suppressor cells,and repolarization of the M2-to M1-phenotype tumor-associated macrophages.Thus,LHS NPs demonstrated an improved antitumor efficacy in suppressing the tumor growth and lungmetastasis of 4T1-tumormice.Our work gives novel insights for the bi-directionally manipulating ferroptosis in tumor and CD8^(+)T cells on TNBC chemoimmunotherapy.展开更多
Successful chemotherapy with paclitaxel(PTX)is impeded by multidrug resistance(MDR)in tumor cells.In this study,lipid-albumin nanoassemblies co-loaded with borneol and paclitaxel(BOR/PTX LANs)were prepared to circumve...Successful chemotherapy with paclitaxel(PTX)is impeded by multidrug resistance(MDR)in tumor cells.In this study,lipid-albumin nanoassemblies co-loaded with borneol and paclitaxel(BOR/PTX LANs)were prepared to circumvent MDR in C6 glioma cells.The physiochemical properties including particle size,encapsulation efficiency and morphology were evaluated in vitro.Quantitative and qualitative investigations of cellular uptake were carried out in C6 glioma cells.The cytotoxicity of the BOR/PTX LANs was determined by MTT assay.After that,the tumor targeting was also evaluated in C6 glioma bearing mice by in vivo imaging analysis.BOR/PTX LANs have a higher entrapment efficiency(90.4±1.2%),small particle size(107.5±3.2 nm),narrow distribution(P.I.=0.171±0.02).The cellular uptake of PTX was significantly increased by BOR/PTX LANs compared with paclitaxel loaded lipidalbumin nanoassemblies(PTX LANs)in quantitative research.The result was further confirmed by confocal laser scanning microscopy qualitatively.The cellular uptake was energy-,timeand concentration-dependent,and clathrin-and endosome/lysosome-associated pathways were involved.The BOR/PTX LANs displayed a higher cytotoxicity agaist C6 glioma cells in comparion with PTX LANs and Taxol.Moreover,the encapsulation of BOR in LANs obviously increased the accumulation of the drug in tumor tissues,demonstrating the tumor targeted ability of BOR/PTX LANs.These results indicated that BOR/PTX LANs could overcome MDR by combination of drug delivery systems and P-gp inhibition,and shown the potential for treatment of gliomas.展开更多
Photodynamic therapy(PDT) has been widely investigated for cancer therapy. The intracellular accumulation of reactive oxygen species(ROS)-damaged protein facilitates tumor cell apoptosis. However, there is growing evi...Photodynamic therapy(PDT) has been widely investigated for cancer therapy. The intracellular accumulation of reactive oxygen species(ROS)-damaged protein facilitates tumor cell apoptosis. However, there is growing evidence that the ubiquitin-proteasome pathway(UPP) significantly impedes PDT by preventing the enrichment of ROS-damaged proteins in tumor cells. To tackle this challenge, we report a facile dual-drug nanoassembly based on the discovery of an interesting co-assembly of bortezomib(BTZ, a proteasome inhibitor) and pyropheophorbide a(PPa) for proteasome inhibition-mediated PDT sensitization.The precisely engineered nanoassembly with the optimal dose ratio of BTZ and PPa demonstrates multiple advantages, including simple fabrication, high drug co-loading efficiency, flexible dose adjustment,good colloidal stability, long systemic circulation, favorable tumor-specific accumulation, as well as significant enrichment of ROS-damaged proteins in tumor cells. As a result, the cooperative nanoassembly exhibits potent synergistic antitumor activity in vivo. This study provides a novel dual-drug engineering modality for multimodal cancer treatment.展开更多
Chemotherapy has been recommended as the standard protocol for triple-negative breast cancer(TNBC)at the advanced stage.However,the current treatment is unsatisfactory due to inefficient drug accumulation and rapid ch...Chemotherapy has been recommended as the standard protocol for triple-negative breast cancer(TNBC)at the advanced stage.However,the current treatment is unsatisfactory due to inefficient drug accumulation and rapid chemo-resistance.Thus,rational design of advanced drug delivery systems that can induce multiple cell death pathways is a promising strategy to combat TNBC.Ferroptosis is a powerful non-apoptotic cell death modality,showing potential in tumor inhibition.Herein,we propose a binary prodrug nanoassemblies that combines chemotherapy with ferroptosis for TNBC treatment.In this system,paclitaxel is linked with paracetamol(ferroptosis activator)by a disulfide linkage to construct self-assembly prodrug.Meanwhile,2-distearoyl-sn-glycerol-3-phosphoethanolamine-N-methyl(polyethylene glycol)-2000-tyrosine(DSPE-PEG2k-tyrosine)is applied for large neutral amino acid transporter 1(LAT1)targeting,which is highly expressed in TNBC.The prodrug nanoassemblies exhibit good stability and a glutathione(GSH)-responsive release profile.Furthermore,the LAT1-targeted nanoassemblies show stronger cytotoxicity,higher cellular uptake,and more obvious ferroptosis activation than non-decorated ones.In a TNBC mice model,the prodrug nanoassemblies demonstrate strong anti-tumor efficacy.The application of ferroptosis-assisting chemotherapy may provide a promising strategy for TNBC therapy.展开更多
Nanomedicine has made great progress in the targeted therapy of cancer. Here, we established a novel drug-mate strategy by studying the formulation of nanodrugs at the molecular level. In the drug-mate combination, th...Nanomedicine has made great progress in the targeted therapy of cancer. Here, we established a novel drug-mate strategy by studying the formulation of nanodrugs at the molecular level. In the drug-mate combination, the drug is a hydrophobic drug that is poorly soluble in water, and the mate is an amphiphilic small molecule (SMA) that has both hydrophilic and lipophilic properties. We proposed that the hydrophobic drug could co-assemble with a suitable SMA on a nanoscale without additive agents. The proof-ofconcept methodology and results were presented to support our hypothesis. We selected five hydrophobic drugs and more than ten amphiphilic small molecules to construct a library. Through molecular dynamic simulation and quantum chemistry computation,we speculated that the formation of nanoassemblies was related to the binding energy of the drug-mate, and the drug-mate interaction must overcome drug-drug interaction.Furthermore, the obtained SF/VECOONa nanoassemblieswas selected as a model, which had an ultra-high drug loading content (46%), improved pharmacokinetics, increased bioavailability, and enhanced therapeutic efficacy. In summary, the drug-mate strategy is an essential resource to design exact SMA for many hydrophobic drugs and provides a reference for the design of a carrier-free drug delivery system.展开更多
Monodisperse nanoparticle assembly with tunable structure, composition and properties can be taken as a superstructured building block for the construction of hierarchical nanostruc tures from the bottom up, which als...Monodisperse nanoparticle assembly with tunable structure, composition and properties can be taken as a superstructured building block for the construction of hierarchical nanostruc tures from the bottom up, which also represents a great challenge in nanotechnology. Here we report on a facile and controllable method that enables a high yield fabricatioa of uniform gold nanoparticle （AuNP） coresatellites with definable number （in average） of the satellite particles and tunable coretosatellite distance. The formation of the coresatellite nanostruc tures is driven by programmable DNAbasepairing, with the resulting nanocomplexes being isolatable via gel electrophoresis. By rationally controlling the DNA coverages on the core and shell particles, high production yields are achieved for the assembly/isolation process. As well, benefiting from a minimum DNA coverage on the satellite AuNPs, a strong affinity is observed for the asprepared coresatellites to get adsorbed on proteincoated graphene ox ide, which allows for a twodimensional hierarchical assembly of the coresatellite structures. The resulting hierarchical nanoassemblies are expected to find applications in various areas, including plasmonics, biosensing, and nanocatalysis. The method should be generalizable to make even more complicated and higherorder structures by making use of the structural programmability of DNA molecules.展开更多
As a representative type of self-supported templates, cyano-bridged cyanogels provide ideal plateaus for synthesis of three-dimensional(3 D) nanostructures. Herein, 3 D pomegranate-like Fe-doped NiCo nanoassemblies(3 ...As a representative type of self-supported templates, cyano-bridged cyanogels provide ideal plateaus for synthesis of three-dimensional(3 D) nanostructures. Herein, 3 D pomegranate-like Fe-doped NiCo nanoassemblies(3 D PG-NiCoFe NAs) were synthesized via facile one-step bi-component cyanogel reduction with NaBH_4 as the reducing agent. Specifically, the influence of the incorporated Fe amount was carefully investigated by finely adjusting the feeding molar ratios of the Ni/Co/Fe atoms in the precursors.By virtue of the unique structure and enriched oxygen vacancies originated from well-modulated electronic structures, the 3 D PG-NiCoFe-211 NAs exhibited outstanding electrocatalytic performances for oxygen evolution reaction(OER) in alkaline solution, outperforming commercial RuO_2 catalyst. The current incorporation of foreign metal atom into host material provides some valuable insights into design and synthesis of metal-based nanocatalysts for constructing practical water splitting devices.展开更多
Here,a new designed core/satellite gold nanoprobe was developed for detecting trace mount of benzoyl peroxide(BPO) based on its deboronation.This gold nanoassembly(the BE-Au NPs_(12/65)) wa s constructed via borate es...Here,a new designed core/satellite gold nanoprobe was developed for detecting trace mount of benzoyl peroxide(BPO) based on its deboronation.This gold nanoassembly(the BE-Au NPs_(12/65)) wa s constructed via borate ester formation between large 4-mercaptophenylboronic acid(MPBA) modified Au NPs(the MPBAAu NPs_(65),as cores) and small dopamine modified AuNPs(the D PA-AuNPs_(12),as satellites).Particularly,upon addition of BPO,it would trigger the deboronation for the BE-AuNPs_(12/65) probes accompanying with distinct color changes from blue,purple to wine red,which implied the disassembly of the core/satellite nanostructure after the breakage of carbon to boron chemical bond.By measuring the absorbance ratio at 665 nm and 545 nm,quantification of BPO was achieved in the range of 10.0-100.0 nmol/L,which could also be easily observed by naked eyes.The nanoprobe utilized a boronate deprotection mechanism and the LSPR properties of Au NPs to provide high selectivity for detecting BPO over similar ROS/RNS with the limit of detection as low as 7.2 nmol/L.The practical applicability of this assay was verified through successful determining BPO in flour samples,which demonstrated its great potentials in food safety field.展开更多
Small-molecule prodrug nanoassembly technology with a unique advantage in off-target toxicity reduction has been widely used for antitumor drug delivery.However,prodrug activation remains a rate-limiting step for exer...Small-molecule prodrug nanoassembly technology with a unique advantage in off-target toxicity reduction has been widely used for antitumor drug delivery.However,prodrug activation remains a rate-limiting step for exerting therapeutic actions,which requires to quickly reach the minimum valid concentrations of free drugs.Fortunately,we find that a natural compound(BL-193)selectively improves the chemotherapy sensitivity of breast cancer cells to podophyllotoxin(PPT)at ineffective dose concentrations.Based on this,we propose to combine prodrug nanoassembly with chemotherapy sensitization to fully unleash the chemotherapeutic potential of PPT.Specifically,a redox-sensitive prodrug(PSSF)of PPT is synthesized by coupling 9-fluorenyl-methanol(Fmoc-OH)with PPT linked via disulfide bond.Intriguingly,PSSF with aπ-conjugated structure readily co-assembles with BL-193 into stable nanoassembly.Significantly,BL-193 serves as an excellent chemosensitizer that creates an ultra-low-dose chemotherapeutic windowfor PPT.Moreover,prodrug design and precise hybrid nanoassembly well manage off-target toxicity.As expected,such a BL-193-empowered prodrug nanoassembly elicits potent antitumor responses.This study offers a novel paradigm to magnify chemotherapy efficacy-toxicity benefits.展开更多
In this paper, cucurbit[7]uril(CB[7])-mediated three-dimensional gold nanoassemblies were successfully prepared to increase the loaded amount of CB[7] and enhance the electrochemical detection of amino acids. Particle...In this paper, cucurbit[7]uril(CB[7])-mediated three-dimensional gold nanoassemblies were successfully prepared to increase the loaded amount of CB[7] and enhance the electrochemical detection of amino acids. Particle sizes of gold nanoparticles(Au NPs) significantly affect stability and detection sensitivity of nanoassemblies. The volume of gold nanoassemblies first increased and then decreased with the increase of CB[7] concentration. The 3D gold nanoassemblies composed of 16 nm Au NPs and 100 μmol/L CB[7]had excellent stability and maximum volume, exhibiting more sensitive detection for a variety of amino acids. And the detection limits of aromatic amino acids are lower in virtue of the higher binding constant between aromatic amino acids and CB[7]. This study will develop and deepen our understanding of molecular recognition in amino acids detection.展开更多
The tremendous potential of triboelectric generators-TENGs for converting mechanical energy into electrical energy places them as one of the most promising energy harvesting technologies. In this work, the fabrication...The tremendous potential of triboelectric generators-TENGs for converting mechanical energy into electrical energy places them as one of the most promising energy harvesting technologies. In this work, the fabrication of enhanced performance TENGs using Ag octahedron nano-assemblies on ITO as electrodes significantly increases the electric charge collection of the induced tribocharges. Thereby, nanostructured electrical contacts coated with Ag macroscale nano-assemblies with octahedral features were obtained by the electrodeposition technique on flexible PET/ITO substrates. Consequently, the nanostructured triboelectric generator-TENG exhibited 65 times more maximum output power, and almost 10 times more open circuit output voltage than that of a TENG with non-nanostructured contacts passing from μW to m W capabilities, which was attributed to the increment of intrinsic interface states due to a higher effective contact area in the former. Likewise, output performances of TENGs also displayed an asymptotic behavior on the output voltage as the operating frequency of the mechanical oscillations increased, which is attributed to a decrement in the internal impedance of the device with frequency. Furthermore, it is shown that the resulting electrical output power can successfully drive low power consumption electronic devices. On that account, the present research establishes a promising platform which contributes in an original way to the development of the TENGs technology.展开更多
Oxaliplatin(OXA)has shown excellent potential in inducing immunogenic cell death and enhancing immunotherapy.However,the poor physicochemical properties of oxaliplatin make it difficult to achieve efficient synchronou...Oxaliplatin(OXA)has shown excellent potential in inducing immunogenic cell death and enhancing immunotherapy.However,the poor physicochemical properties of oxaliplatin make it difficult to achieve efficient synchronous delivery and synergistic immunotherapy with immune checkpoint inhibitors.To address this,we designed structurally optimized dual-wing butterfly prodrugs:oxaliplatin prodrug(POP)that enhances immunogenicity and reducible NLG919 homodimer(NSSN)that mitigates immunosuppression.Structural optimization of dual-wing butterfly prodrugs significantly enhanced lipid solubility compared to the parent drugs.It is worth noting that we assembled two dual-wing butterfly prodrugs,POP and NSSN,together into hybrid nanoassemblies(NAs),achieving advantages such as stable assembly,flexible dosing,and collaborative therapy.Dual-wing butterfly prodrug-driven hybrid NAs demonstrated enhanced antitumor efficacy and metastasis control in experimental models,with biocompatibility confirmed through biosafety evaluations.This work proposes a co-delivery strategy based on dual-wing butterfly prodrugs as a clinically translatable candidate.展开更多
Despite demonstrating significant anti-tumor potential as an artemisinin derivative,artesunate faces delivery efficiency challenges due to low water solubility and insufficient targeting specificity.To improve the del...Despite demonstrating significant anti-tumor potential as an artemisinin derivative,artesunate faces delivery efficiency challenges due to low water solubility and insufficient targeting specificity.To improve the delivery efficiency,we engineered three artesunate(ART) derivatives,AC_(15)-L(linear),AC_(15)-B(branched),and AC_(15)-C(cyclic) with distinct aliphatic chain architectures.Unexpectedly,we observed that AC_(15)-C exhibited superior cytotoxicity against 4T1 breast cancer cells,and had the highest binding affinity for Lon protease 1(LONP1)(-72.6 kcal/mol).Subsequently,disulfide bond-containing lipid-PEG(DSPESS-PEG2K) modified chain architecture-engineered ART derivatives nanoassemblies(NAs) were developed to mitigate solubility-related limitations while enhancing targeting precision.Molecular docking and experimental validation demonstrated that ART derivatives inhibited LONP1 through hydrophobic interactions while preserved Fe^(2+)-mediated Fenton-like reaction activity.In vitro and in vivo evaluations demonstrated that AC_(15)-C NAs outperformed free ART and other NAs,suppressing 4T1 tumor growth via dual action:LONP1-directed mitochondrial proteostasis collapse and reactive oxygen species(ROS) amplification through Fe^(2+)-ART interactions.This study elucidated a novel anti-tumor mechanism of ART through the rational design of derivatives with spatially configured aliphatic chains,and developed reductionresponsive NAs to provide an advanced delivery strategy.展开更多
The clinical utility of irinotecan is restricted by individual variability in carboxylesterase expression.Direct administration of its active metabolite,7-ethyl-10-hydroxycamptothecin(SN38),presents an appealing alter...The clinical utility of irinotecan is restricted by individual variability in carboxylesterase expression.Direct administration of its active metabolite,7-ethyl-10-hydroxycamptothecin(SN38),presents an appealing alternative due to its potent anti-tumor efficacy.However,the undesirable properties of SN38,such as poor water solubility and nontarget toxicity,present significant hurdles to its clinical development.Prodrug nanoassemblies based on modular design strategy show promise in overcoming these challenges by enhancing drug delivery and selective activation.In modular design,the modification module plays a crucial role in improving the self-assembly capability of prodrugs.While current studies mainly focus on using straight aliphatic chains for prodrug design,branched aliphatic chains emerge as superior alternatives warranting further investigation.In this study,we selected 2-heptylundecanol(BAlc18)as modification module to construct an SN38 prodrug.Through exquisite design,SN38-SS-BAlc18 NPs integrated prominent properties in selfassembly capability,specific activation and biocompatibility,resolving the challenges of irinotecan and SN38,ultimately demonstrating excellent anti-tumor efficacy.This exploration enriched the design theory of prodrug nanoassemblies that can effectively balance safety and colorectal anti-tumor efficacy.展开更多
Clinical chemotherapy for prostate cancer is still compromised by high treatment thresholds and severe off-target toxicity of drugs.Given the limited progress in improving therapeutic outcomes and reducing toxicity wi...Clinical chemotherapy for prostate cancer is still compromised by high treatment thresholds and severe off-target toxicity of drugs.Given the limited progress in improving therapeutic outcomes and reducing toxicity with the existing toolbox,efforts to broaden the chemotherapeutic window are highly desired.Here,we discover that gossypol(GSP,a natural compound)dramatically enhances the chemosensitivity of cabazitaxel(CTX),even at previously ineffective concentrations.Based on this interesting finding,we exploit a carrier-free chemotherapeutic nano-booster for prostate cancer treatment,which is molecularly co-assembled by GSP and cabazitaxel(CTX).GSP not only readily forms nanoassembly with CTX,but also functions as a chemotherapeutic enhancer that unlocks an ultra-low-dose chemotherapeutic window.Not only that,precise dual-drug nanoassembly confers CTX a significantly larger maximum tolerable dose.As expected,the nano-booster exerts striking therapeutic benefits in mouse prostate tumor xenograft models.This study advances chemotherapeutic window expansion and selfsensitized chemotherapy toward clinical applicability.展开更多
Irinotecan,one of the most effective chemotherapeutic agents for the treatment of advanced colorectal cancer,suffers from extremely low activatability and non-selective tumor activation.7-Ethyl-10-hydroxy-camptothecin...Irinotecan,one of the most effective chemotherapeutic agents for the treatment of advanced colorectal cancer,suffers from extremely low activatability and non-selective tumor activation.7-Ethyl-10-hydroxy-camptothecin(SN38),the active metabolite of irinotecan,has been limited in clinical development due to poor water solubility and stability.Here,the thioether bond and disulfide bond were employed as response modules to construct tumor-selective SN38 prodrug nanoassemblies(SN38-S-C_(21) NPs and SN38-SS-C_(21) NPs).11-Henicosanol was chosen as a self-assembly module to enhance stability.Both SN38-S-C_(21) NPs and SN38-SS-C_(21) NPs presented ultra-high in vivo stability with a 12146-fold and 23151-fold elevation in the area under the curve(AUC)compared to SN38.Moreover,SN38-S-C_(21) NPs and SN38-SS-C_(21) NPs showed a significant reduction of SN38exposure in blood compared to irinotecan.Importantly,the prodrug nanoassemblies enabled selective activation within tumor cells,and the conversion rates of SN38-SS-C_(21) NPs and SN38-S-C_(21) NPs to SN38 were 10-and 7-fold higher than irinotecan.Compared with SN38-S-C_(21) NPs,the superior in vivo stability,SN38 conversion efficiency and tumor selectivity of SN38-SSC_(21) NPs resulted in potent antitumor effects and safety.Our findings proved that the disulfide bond was more suitable for constructing high-performance SN38 prodrug nanoassemblies,which showed significant promise for the rational design of SN38 nanomedicines.展开更多
Prodrug-based nanoassemblies have emerged as advanced carrier-free nanomedicines.These prodrugs typically consist of drug modules,response modules,and modification modules.The general role of modification modules is t...Prodrug-based nanoassemblies have emerged as advanced carrier-free nanomedicines.These prodrugs typically consist of drug modules,response modules,and modification modules.The general role of modification modules is to modulate the self-assembly ability of the prodrugs.How to optimize the structure of modification modules for balanced efficacy and safety of high-toxicity chemotherapeutic drugs deserves to be further investigated.In this study,a modification strategy of aliphatic alcohols with various chain lengths(SC_(4),SC_(8),SC_(12),SC_(16) and SC_(20))was carried out to design five cabazitaxel(CBZ)prodrugs.Among them,CBZ-SC NPs with shorter chain length(SC_(4) and SC_(8))showed poor self-assembly stability.CBZ-SC_(12) NPs also failed to remain stable while the other two CBZ-SC NPs exhibited good stability.In turn,the drug release rate was hindered by the increasing chain length.CBZ-SC_(12) NPs caused kidney damage due to their high redox-sensitivity and rapid release rate during circulation.By contrast,CBZ-SC NPs with longer chain length(SC_(16) and SC_(20))not only demonstrated superior stability with improved pharmacokinetic behavior,but also might solve the dilemma of dose-related toxicity caused by CBZ.Overall,these findings emphasized the importance of chain length in modification module to modulate the efficacy and safety of CBZ prodrug nanoassemblies.展开更多
基金supported by the National Natural Science Foundation of China(Nos.82273824,31670359 and 82372111)the Liao Ning Revitalization Talents Program(No.XLYC 1905019)。
文摘Natural phytoconstituents exhibit distinct advantages in the management and prevention of inflammatory bowel disease(IBD),attributed to their robust biological activity,multi-target effects,and elevated safety profile.Although promising,the clinical application of phytoconstituents have been impeded by poor water solubility,low oral bioavailability,and inadequate colonic targeting.Recent advancements in nanotechnology has offered prospective avenues for the application of phytoconstituents in the treatment of IBD.A common strategy involves encapsulating or conjugating phytoconstituents with nanocarriers to enhance their stability,prolong intestinal retention,and facilitate targeted delivery to colonic inflammatory tissues.Furthermore,drawing inspiration from the self-assembling nanostructures that emerge during the decoction process of Chinese herbs,a variety of natural active compounds-based nanoassemblies have been developed for the treatment of IBD.They exhibit high drug-loading capacities and surmount the challenges posed by poor water solubility and low bioavailability.Notably,phyto-derived nanovesicles,owing to their unique structure and biological functions,can serve as therapeutic agents or novel delivery vehicles for the treatment of IBD.Consequently,this review provides an extensive overview of emerging phytoconstituent-derived nano-medicines/vesicles for the treatment of IBD,intending to offer novel insights for the clinical management of IBD.
基金supported by the National Natural Science Foundation of China,(Nos.82272151,82204318)Liaoning Revitalization Talents Program(No.XLYC2203083)+2 种基金Shenyang Young and Middle-aged Science and Technology Innovation Talent Support Program(No.RC220389)Postdoctoral Fellowship Program of CPSF(No.GZC20231732)China Postdoctoral Science Foundation(Nos.2023TQ0222,2023MD744229).
文摘Self-assembled prodrug nanomedicine has emerged as an advanced platform for antitumor therapy,mainly comprise drug modules,response modules and modification modules.However,existing studies usually compare the differences between single types of modification modules,neglecting the impact of steric-hindrance effect caused by chemical structure.Herein,single-tailed modification module with low-steric-hindrance effect and two-tailed modification module with high-steric-hindrance effect were selected to construct paclitaxel prodrugs(P-LA_(C18)and P-BAC18),and the in-depth insights of the sterichindrance effect on prodrug nanoassemblies were explored.Notably,the size stability of the two-tailed prodrugs was enhanced due to improved intermolecular interactions and steric hindrance.Single-tailed prodrug nanoassemblies were more susceptible to attack by redox agents,showing faster drug release and stronger antitumor efficacy,but with poorer safety.In contrast,two-tailed prodrug nanoassemblies exhibited significant advantages in terms of pharmacokinetics,tumor accumulation and safety due to the good size stability,thus ensuring equivalent antitumor efficacy at tolerance dose.These findings highlighted the critical role of steric-hindrance effect of the modification module in regulating the structureactivity relationship of prodrug nanoassemblies and proposed new perspectives into the precise design of self-assembled prodrugs for high-performance cancer therapeutics.
基金supported by National Natural Science Foundation of China(No.82161138029)Liaoning Revitalization Talents Program(No.XLYC2402040)the Project of China-Japan Joint International Laboratory of Advanced Drug Delivery System Research and Translation of Liaoning Province(No.2024JH2/102100007).
文摘Local precise drug delivery is conducive to improving therapeutic efficacy and minimizing off-target toxicity.Current local delivery approaches are focused mostly on superficial or postoperative tumor lesions,due to the challenges posed by the inaccessibility of deep-seated tumors.Herein,we report a magnetic continuum soft robot capable of non-invasive and site-specific delivery of prodrug nanoassemblies-loaded hydrogel.The nanoassemblies are co-assembled from redox-responsive docetaxel prodrug and oxaliplatin prodrug,and subsequently embedded into a hydrogel matrix.The hydrogel precursor and crosslinker are synchronously delivered using the soft robot under magnetic guidance and in situ crosslinked at the gastric cancer lesions,forming a drug depot for sustained release and long-lasting treatment.As the hydrogel gradually degrades,the nanoassemblies are internalized by tumor cells.The redox response ability enables them to be selectively activatedwithin tumor cells to trigger the release of docetaxel and oxaliplatin,exerting a synergistic anti-tumor effect.We find that the combination effectively induces immunogenic cell death of gastric tumor,enhancing antitumor immune responses.This strategy offers an intelligent and controllable integration platform for precise drug delivery and combined chemo-immunotherapy.
基金supported by the National Nature Science Foundation of China(NO.82260699)the Science and Technology Leading Talents of Ningxia(NO.2022GKLRLX011)the West Light Foundation of The Chinese Academy of Sciences(the Science and Technology Department of Ningxia,Department of Science and Technology Cooperation[2021]NO.2).
文摘Ferroptosis can serve as a potent strategy for regulating cell death via lipid peroxidation and the imbalance of the antioxidant system resulting from iron accumulation in triple-negative breast cancer(TNBC)therapy.However,the ferroptosis accompanied with down-regulation of glutathione peroxidase 4(GPX4)lead to CD36-mediated tumor-infiltrating CD8^(+)T cells uptaking fatty acids,resulting in the negative action on immunotherapeutic efficacy.Herein,the albumin nanoparticles,abbreviated as LHS NPs,were designed by co-assembly of hemin,linoleic acid-cystamine,and a CD36 inhibitor sulfosuccinimide oleate,to bi-directionally manipulated ferroptosis in tumor and CD8^(+)T cells for TNBC therapy.LHS NPs exerted more efficient reactive oxygen species generation,glutathione depletion and malondialdehyde production by the combinatory strategy of classical and non-classical ferroptosis modes,which amplified the positive action on ferroptosis in tumor cells.Meanwhile,LHS manipulated the negative action of ferroptosis by inhibiting the CD36 mediated-lipid peroxidation in CD8^(+)T cells,thereby activating the immunotherapeutic efficacy with the improvements on induction of immunogenic cell death,proliferation of CD4+CD8^(+)T cells and natural killer cells,alleviation immunosuppressive regulatory T cells and myeloid-derived suppressor cells,and repolarization of the M2-to M1-phenotype tumor-associated macrophages.Thus,LHS NPs demonstrated an improved antitumor efficacy in suppressing the tumor growth and lungmetastasis of 4T1-tumormice.Our work gives novel insights for the bi-directionally manipulating ferroptosis in tumor and CD8^(+)T cells on TNBC chemoimmunotherapy.
文摘Successful chemotherapy with paclitaxel(PTX)is impeded by multidrug resistance(MDR)in tumor cells.In this study,lipid-albumin nanoassemblies co-loaded with borneol and paclitaxel(BOR/PTX LANs)were prepared to circumvent MDR in C6 glioma cells.The physiochemical properties including particle size,encapsulation efficiency and morphology were evaluated in vitro.Quantitative and qualitative investigations of cellular uptake were carried out in C6 glioma cells.The cytotoxicity of the BOR/PTX LANs was determined by MTT assay.After that,the tumor targeting was also evaluated in C6 glioma bearing mice by in vivo imaging analysis.BOR/PTX LANs have a higher entrapment efficiency(90.4±1.2%),small particle size(107.5±3.2 nm),narrow distribution(P.I.=0.171±0.02).The cellular uptake of PTX was significantly increased by BOR/PTX LANs compared with paclitaxel loaded lipidalbumin nanoassemblies(PTX LANs)in quantitative research.The result was further confirmed by confocal laser scanning microscopy qualitatively.The cellular uptake was energy-,timeand concentration-dependent,and clathrin-and endosome/lysosome-associated pathways were involved.The BOR/PTX LANs displayed a higher cytotoxicity agaist C6 glioma cells in comparion with PTX LANs and Taxol.Moreover,the encapsulation of BOR in LANs obviously increased the accumulation of the drug in tumor tissues,demonstrating the tumor targeted ability of BOR/PTX LANs.These results indicated that BOR/PTX LANs could overcome MDR by combination of drug delivery systems and P-gp inhibition,and shown the potential for treatment of gliomas.
基金financially supported by the Liaoning Revitalization Talents Program (No. XLYC1907129)the Excellent Youth Science Foundation of Liaoning Province (No. 2020-YQ-06)the China Postdoctoral Science Foundation (No. 2020M670794)。
文摘Photodynamic therapy(PDT) has been widely investigated for cancer therapy. The intracellular accumulation of reactive oxygen species(ROS)-damaged protein facilitates tumor cell apoptosis. However, there is growing evidence that the ubiquitin-proteasome pathway(UPP) significantly impedes PDT by preventing the enrichment of ROS-damaged proteins in tumor cells. To tackle this challenge, we report a facile dual-drug nanoassembly based on the discovery of an interesting co-assembly of bortezomib(BTZ, a proteasome inhibitor) and pyropheophorbide a(PPa) for proteasome inhibition-mediated PDT sensitization.The precisely engineered nanoassembly with the optimal dose ratio of BTZ and PPa demonstrates multiple advantages, including simple fabrication, high drug co-loading efficiency, flexible dose adjustment,good colloidal stability, long systemic circulation, favorable tumor-specific accumulation, as well as significant enrichment of ROS-damaged proteins in tumor cells. As a result, the cooperative nanoassembly exhibits potent synergistic antitumor activity in vivo. This study provides a novel dual-drug engineering modality for multimodal cancer treatment.
基金supported by the National Nature Science Foundation of China(No.81803029)the Science and Technology Foundation of Yuzhong District,Chongqing(No.20210179)the Nature Science Foundation of Chongqing(No.cstc2021jcyjmsxmX1089)。
文摘Chemotherapy has been recommended as the standard protocol for triple-negative breast cancer(TNBC)at the advanced stage.However,the current treatment is unsatisfactory due to inefficient drug accumulation and rapid chemo-resistance.Thus,rational design of advanced drug delivery systems that can induce multiple cell death pathways is a promising strategy to combat TNBC.Ferroptosis is a powerful non-apoptotic cell death modality,showing potential in tumor inhibition.Herein,we propose a binary prodrug nanoassemblies that combines chemotherapy with ferroptosis for TNBC treatment.In this system,paclitaxel is linked with paracetamol(ferroptosis activator)by a disulfide linkage to construct self-assembly prodrug.Meanwhile,2-distearoyl-sn-glycerol-3-phosphoethanolamine-N-methyl(polyethylene glycol)-2000-tyrosine(DSPE-PEG2k-tyrosine)is applied for large neutral amino acid transporter 1(LAT1)targeting,which is highly expressed in TNBC.The prodrug nanoassemblies exhibit good stability and a glutathione(GSH)-responsive release profile.Furthermore,the LAT1-targeted nanoassemblies show stronger cytotoxicity,higher cellular uptake,and more obvious ferroptosis activation than non-decorated ones.In a TNBC mice model,the prodrug nanoassemblies demonstrate strong anti-tumor efficacy.The application of ferroptosis-assisting chemotherapy may provide a promising strategy for TNBC therapy.
基金supported by the National Natural Science Foundation of China (grant numbers:81974498)Natural Science Foundation of Shandong Province (grant numbers:ZR2019BH079)。
文摘Nanomedicine has made great progress in the targeted therapy of cancer. Here, we established a novel drug-mate strategy by studying the formulation of nanodrugs at the molecular level. In the drug-mate combination, the drug is a hydrophobic drug that is poorly soluble in water, and the mate is an amphiphilic small molecule (SMA) that has both hydrophilic and lipophilic properties. We proposed that the hydrophobic drug could co-assemble with a suitable SMA on a nanoscale without additive agents. The proof-ofconcept methodology and results were presented to support our hypothesis. We selected five hydrophobic drugs and more than ten amphiphilic small molecules to construct a library. Through molecular dynamic simulation and quantum chemistry computation,we speculated that the formation of nanoassemblies was related to the binding energy of the drug-mate, and the drug-mate interaction must overcome drug-drug interaction.Furthermore, the obtained SF/VECOONa nanoassemblieswas selected as a model, which had an ultra-high drug loading content (46%), improved pharmacokinetics, increased bioavailability, and enhanced therapeutic efficacy. In summary, the drug-mate strategy is an essential resource to design exact SMA for many hydrophobic drugs and provides a reference for the design of a carrier-free drug delivery system.
文摘Monodisperse nanoparticle assembly with tunable structure, composition and properties can be taken as a superstructured building block for the construction of hierarchical nanostruc tures from the bottom up, which also represents a great challenge in nanotechnology. Here we report on a facile and controllable method that enables a high yield fabricatioa of uniform gold nanoparticle （AuNP） coresatellites with definable number （in average） of the satellite particles and tunable coretosatellite distance. The formation of the coresatellite nanostruc tures is driven by programmable DNAbasepairing, with the resulting nanocomplexes being isolatable via gel electrophoresis. By rationally controlling the DNA coverages on the core and shell particles, high production yields are achieved for the assembly/isolation process. As well, benefiting from a minimum DNA coverage on the satellite AuNPs, a strong affinity is observed for the asprepared coresatellites to get adsorbed on proteincoated graphene ox ide, which allows for a twodimensional hierarchical assembly of the coresatellite structures. The resulting hierarchical nanoassemblies are expected to find applications in various areas, including plasmonics, biosensing, and nanocatalysis. The method should be generalizable to make even more complicated and higherorder structures by making use of the structural programmability of DNA molecules.
基金supported by the National Natural Science Foundation of China (No. 21805245)the Zhejiang Public Welfare Technology Application Research Project (LGG19B050001)the National Students’ Innovation and Entrepreneurship Training Program of Zhejiang Normal University (201910345032, Z.J. Wang)。
文摘As a representative type of self-supported templates, cyano-bridged cyanogels provide ideal plateaus for synthesis of three-dimensional(3 D) nanostructures. Herein, 3 D pomegranate-like Fe-doped NiCo nanoassemblies(3 D PG-NiCoFe NAs) were synthesized via facile one-step bi-component cyanogel reduction with NaBH_4 as the reducing agent. Specifically, the influence of the incorporated Fe amount was carefully investigated by finely adjusting the feeding molar ratios of the Ni/Co/Fe atoms in the precursors.By virtue of the unique structure and enriched oxygen vacancies originated from well-modulated electronic structures, the 3 D PG-NiCoFe-211 NAs exhibited outstanding electrocatalytic performances for oxygen evolution reaction(OER) in alkaline solution, outperforming commercial RuO_2 catalyst. The current incorporation of foreign metal atom into host material provides some valuable insights into design and synthesis of metal-based nanocatalysts for constructing practical water splitting devices.
基金financial support from the National Natural Science Foundation of China(Nos.U1736201,21677019 and 41403021)Capital Health Research and Development of Special(No.2018-4-1014)the Key Research and Development Program of Beijing(No.D171100008317001)。
文摘Here,a new designed core/satellite gold nanoprobe was developed for detecting trace mount of benzoyl peroxide(BPO) based on its deboronation.This gold nanoassembly(the BE-Au NPs_(12/65)) wa s constructed via borate ester formation between large 4-mercaptophenylboronic acid(MPBA) modified Au NPs(the MPBAAu NPs_(65),as cores) and small dopamine modified AuNPs(the D PA-AuNPs_(12),as satellites).Particularly,upon addition of BPO,it would trigger the deboronation for the BE-AuNPs_(12/65) probes accompanying with distinct color changes from blue,purple to wine red,which implied the disassembly of the core/satellite nanostructure after the breakage of carbon to boron chemical bond.By measuring the absorbance ratio at 665 nm and 545 nm,quantification of BPO was achieved in the range of 10.0-100.0 nmol/L,which could also be easily observed by naked eyes.The nanoprobe utilized a boronate deprotection mechanism and the LSPR properties of Au NPs to provide high selectivity for detecting BPO over similar ROS/RNS with the limit of detection as low as 7.2 nmol/L.The practical applicability of this assay was verified through successful determining BPO in flour samples,which demonstrated its great potentials in food safety field.
基金supported by the Basic Research Projects of Liaoning Provincial Department of Education(LJKZZ20220109)the Shenyang Youth Science and Technology Innovation Talents Program(No.RC210452)+1 种基金the National Natural Science Foundation of China(No.82204317)the Natural Science Foundation of Liaoning Province(No.2022-BS-162).
文摘Small-molecule prodrug nanoassembly technology with a unique advantage in off-target toxicity reduction has been widely used for antitumor drug delivery.However,prodrug activation remains a rate-limiting step for exerting therapeutic actions,which requires to quickly reach the minimum valid concentrations of free drugs.Fortunately,we find that a natural compound(BL-193)selectively improves the chemotherapy sensitivity of breast cancer cells to podophyllotoxin(PPT)at ineffective dose concentrations.Based on this,we propose to combine prodrug nanoassembly with chemotherapy sensitization to fully unleash the chemotherapeutic potential of PPT.Specifically,a redox-sensitive prodrug(PSSF)of PPT is synthesized by coupling 9-fluorenyl-methanol(Fmoc-OH)with PPT linked via disulfide bond.Intriguingly,PSSF with aπ-conjugated structure readily co-assembles with BL-193 into stable nanoassembly.Significantly,BL-193 serves as an excellent chemosensitizer that creates an ultra-low-dose chemotherapeutic windowfor PPT.Moreover,prodrug design and precise hybrid nanoassembly well manage off-target toxicity.As expected,such a BL-193-empowered prodrug nanoassembly elicits potent antitumor responses.This study offers a novel paradigm to magnify chemotherapy efficacy-toxicity benefits.
基金supported in part by grants from the National Natural Science Foundation of China (No. 21871108)the Program for Innovative Teams of Outstanding Young and Middle-Aged Researchers in the Higher Education Institutions of Hubei Province(No. T201702)。
文摘In this paper, cucurbit[7]uril(CB[7])-mediated three-dimensional gold nanoassemblies were successfully prepared to increase the loaded amount of CB[7] and enhance the electrochemical detection of amino acids. Particle sizes of gold nanoparticles(Au NPs) significantly affect stability and detection sensitivity of nanoassemblies. The volume of gold nanoassemblies first increased and then decreased with the increase of CB[7] concentration. The 3D gold nanoassemblies composed of 16 nm Au NPs and 100 μmol/L CB[7]had excellent stability and maximum volume, exhibiting more sensitive detection for a variety of amino acids. And the detection limits of aromatic amino acids are lower in virtue of the higher binding constant between aromatic amino acids and CB[7]. This study will develop and deepen our understanding of molecular recognition in amino acids detection.
基金Consejo Nacional de Ciencia y Tecnología of México (CONACYT) for her Doctoral scholarshippostgraduate studies department at CIMAVMonterrey for fellowship support。
文摘The tremendous potential of triboelectric generators-TENGs for converting mechanical energy into electrical energy places them as one of the most promising energy harvesting technologies. In this work, the fabrication of enhanced performance TENGs using Ag octahedron nano-assemblies on ITO as electrodes significantly increases the electric charge collection of the induced tribocharges. Thereby, nanostructured electrical contacts coated with Ag macroscale nano-assemblies with octahedral features were obtained by the electrodeposition technique on flexible PET/ITO substrates. Consequently, the nanostructured triboelectric generator-TENG exhibited 65 times more maximum output power, and almost 10 times more open circuit output voltage than that of a TENG with non-nanostructured contacts passing from μW to m W capabilities, which was attributed to the increment of intrinsic interface states due to a higher effective contact area in the former. Likewise, output performances of TENGs also displayed an asymptotic behavior on the output voltage as the operating frequency of the mechanical oscillations increased, which is attributed to a decrement in the internal impedance of the device with frequency. Furthermore, it is shown that the resulting electrical output power can successfully drive low power consumption electronic devices. On that account, the present research establishes a promising platform which contributes in an original way to the development of the TENGs technology.
基金financially supported by the National Natural Science Foundation of China(No.82204317)the Liaoning Revitalization Talents Program(No.XLYC2403107)+1 种基金the Excellent Youth Science Foundation of Liaoning Province(No.2024JH3/10200046)the Basic Scientific Research Project of Liaoning Provincial Department of Education(No.LJ212410163015).
文摘Oxaliplatin(OXA)has shown excellent potential in inducing immunogenic cell death and enhancing immunotherapy.However,the poor physicochemical properties of oxaliplatin make it difficult to achieve efficient synchronous delivery and synergistic immunotherapy with immune checkpoint inhibitors.To address this,we designed structurally optimized dual-wing butterfly prodrugs:oxaliplatin prodrug(POP)that enhances immunogenicity and reducible NLG919 homodimer(NSSN)that mitigates immunosuppression.Structural optimization of dual-wing butterfly prodrugs significantly enhanced lipid solubility compared to the parent drugs.It is worth noting that we assembled two dual-wing butterfly prodrugs,POP and NSSN,together into hybrid nanoassemblies(NAs),achieving advantages such as stable assembly,flexible dosing,and collaborative therapy.Dual-wing butterfly prodrug-driven hybrid NAs demonstrated enhanced antitumor efficacy and metastasis control in experimental models,with biocompatibility confirmed through biosafety evaluations.This work proposes a co-delivery strategy based on dual-wing butterfly prodrugs as a clinically translatable candidate.
基金financially supported by the Liaoning Revitalization Talents Program (No.XLYC2403107)the Excellent Youth Science Foundation of Liaoning Province (No.2024JH3/10200046)the Basic Scientific Research Project of Liaoning Provincial Department of Education (No.LJ212410163015)。
文摘Despite demonstrating significant anti-tumor potential as an artemisinin derivative,artesunate faces delivery efficiency challenges due to low water solubility and insufficient targeting specificity.To improve the delivery efficiency,we engineered three artesunate(ART) derivatives,AC_(15)-L(linear),AC_(15)-B(branched),and AC_(15)-C(cyclic) with distinct aliphatic chain architectures.Unexpectedly,we observed that AC_(15)-C exhibited superior cytotoxicity against 4T1 breast cancer cells,and had the highest binding affinity for Lon protease 1(LONP1)(-72.6 kcal/mol).Subsequently,disulfide bond-containing lipid-PEG(DSPESS-PEG2K) modified chain architecture-engineered ART derivatives nanoassemblies(NAs) were developed to mitigate solubility-related limitations while enhancing targeting precision.Molecular docking and experimental validation demonstrated that ART derivatives inhibited LONP1 through hydrophobic interactions while preserved Fe^(2+)-mediated Fenton-like reaction activity.In vitro and in vivo evaluations demonstrated that AC_(15)-C NAs outperformed free ART and other NAs,suppressing 4T1 tumor growth via dual action:LONP1-directed mitochondrial proteostasis collapse and reactive oxygen species(ROS) amplification through Fe^(2+)-ART interactions.This study elucidated a novel anti-tumor mechanism of ART through the rational design of derivatives with spatially configured aliphatic chains,and developed reductionresponsive NAs to provide an advanced delivery strategy.
基金gotapproval from the Institutional Animal Ethical Care Committee(IAEC)of Shenyang Pharmaceutical University(ethical code:SYPU-IACUC-2022-0302-010).
文摘The clinical utility of irinotecan is restricted by individual variability in carboxylesterase expression.Direct administration of its active metabolite,7-ethyl-10-hydroxycamptothecin(SN38),presents an appealing alternative due to its potent anti-tumor efficacy.However,the undesirable properties of SN38,such as poor water solubility and nontarget toxicity,present significant hurdles to its clinical development.Prodrug nanoassemblies based on modular design strategy show promise in overcoming these challenges by enhancing drug delivery and selective activation.In modular design,the modification module plays a crucial role in improving the self-assembly capability of prodrugs.While current studies mainly focus on using straight aliphatic chains for prodrug design,branched aliphatic chains emerge as superior alternatives warranting further investigation.In this study,we selected 2-heptylundecanol(BAlc18)as modification module to construct an SN38 prodrug.Through exquisite design,SN38-SS-BAlc18 NPs integrated prominent properties in selfassembly capability,specific activation and biocompatibility,resolving the challenges of irinotecan and SN38,ultimately demonstrating excellent anti-tumor efficacy.This exploration enriched the design theory of prodrug nanoassemblies that can effectively balance safety and colorectal anti-tumor efficacy.
基金financially supported by the National Natural Science Foundation of China(No.82161138029)the Basic Research Projects of Liaoning Provincial Department of Education(LJKZZ20220109,China)the Shenyang Youth Science and Technology Innovation Talents Program(No.RC210452,China).
文摘Clinical chemotherapy for prostate cancer is still compromised by high treatment thresholds and severe off-target toxicity of drugs.Given the limited progress in improving therapeutic outcomes and reducing toxicity with the existing toolbox,efforts to broaden the chemotherapeutic window are highly desired.Here,we discover that gossypol(GSP,a natural compound)dramatically enhances the chemosensitivity of cabazitaxel(CTX),even at previously ineffective concentrations.Based on this interesting finding,we exploit a carrier-free chemotherapeutic nano-booster for prostate cancer treatment,which is molecularly co-assembled by GSP and cabazitaxel(CTX).GSP not only readily forms nanoassembly with CTX,but also functions as a chemotherapeutic enhancer that unlocks an ultra-low-dose chemotherapeutic window.Not only that,precise dual-drug nanoassembly confers CTX a significantly larger maximum tolerable dose.As expected,the nano-booster exerts striking therapeutic benefits in mouse prostate tumor xenograft models.This study advances chemotherapeutic window expansion and selfsensitized chemotherapy toward clinical applicability.
基金supported by the National Key R&D Program of China(2022YFE0111600)the Key Research and Development Program of Liaoning Province(2024JH2/102500061)+7 种基金the Youth Innovation Team of Liaoning Provincial Department of Education(LJ222410163049)the Liaoning Revitalization Talents Program(XLYC2203083)the Open Fund of High-level Key Discipline of Chemistry of Chinese Medicine of the State Administration of Traditional Chinese Medicinethe Anhui University of Chinese Medicine(HKDCCM2024007)the Postdoctoral Fellowship Program of China Postdoctoral Science Foundation(CPSF)(GZC20231-732)the China Postdoctoral Science Foundation(2023TQ0222,2023MD744229)the General Program of Department of Education of Liaoning Province(JYTMS20231372)the Doctoral Scientific Research Staring Foundation of Liaoning Province(2024-BS-073)。
文摘Irinotecan,one of the most effective chemotherapeutic agents for the treatment of advanced colorectal cancer,suffers from extremely low activatability and non-selective tumor activation.7-Ethyl-10-hydroxy-camptothecin(SN38),the active metabolite of irinotecan,has been limited in clinical development due to poor water solubility and stability.Here,the thioether bond and disulfide bond were employed as response modules to construct tumor-selective SN38 prodrug nanoassemblies(SN38-S-C_(21) NPs and SN38-SS-C_(21) NPs).11-Henicosanol was chosen as a self-assembly module to enhance stability.Both SN38-S-C_(21) NPs and SN38-SS-C_(21) NPs presented ultra-high in vivo stability with a 12146-fold and 23151-fold elevation in the area under the curve(AUC)compared to SN38.Moreover,SN38-S-C_(21) NPs and SN38-SS-C_(21) NPs showed a significant reduction of SN38exposure in blood compared to irinotecan.Importantly,the prodrug nanoassemblies enabled selective activation within tumor cells,and the conversion rates of SN38-SS-C_(21) NPs and SN38-S-C_(21) NPs to SN38 were 10-and 7-fold higher than irinotecan.Compared with SN38-S-C_(21) NPs,the superior in vivo stability,SN38 conversion efficiency and tumor selectivity of SN38-SSC_(21) NPs resulted in potent antitumor effects and safety.Our findings proved that the disulfide bond was more suitable for constructing high-performance SN38 prodrug nanoassemblies,which showed significant promise for the rational design of SN38 nanomedicines.
基金support from the Key research and development program of Liaoning Province(No.2024JH2/102500061)Youth innovation team of Liaoning Province Department of Education(No.LJ222410163049)Liaoning Revitalization Talents Program(No.XLYC2203083).
文摘Prodrug-based nanoassemblies have emerged as advanced carrier-free nanomedicines.These prodrugs typically consist of drug modules,response modules,and modification modules.The general role of modification modules is to modulate the self-assembly ability of the prodrugs.How to optimize the structure of modification modules for balanced efficacy and safety of high-toxicity chemotherapeutic drugs deserves to be further investigated.In this study,a modification strategy of aliphatic alcohols with various chain lengths(SC_(4),SC_(8),SC_(12),SC_(16) and SC_(20))was carried out to design five cabazitaxel(CBZ)prodrugs.Among them,CBZ-SC NPs with shorter chain length(SC_(4) and SC_(8))showed poor self-assembly stability.CBZ-SC_(12) NPs also failed to remain stable while the other two CBZ-SC NPs exhibited good stability.In turn,the drug release rate was hindered by the increasing chain length.CBZ-SC_(12) NPs caused kidney damage due to their high redox-sensitivity and rapid release rate during circulation.By contrast,CBZ-SC NPs with longer chain length(SC_(16) and SC_(20))not only demonstrated superior stability with improved pharmacokinetic behavior,but also might solve the dilemma of dose-related toxicity caused by CBZ.Overall,these findings emphasized the importance of chain length in modification module to modulate the efficacy and safety of CBZ prodrug nanoassemblies.
