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
Ferroptosis is a new mode of cell death,which can be induced by Fenton reactionmediated lipid peroxidation.However,the insufficient H2O2 and high GSH in tumor cells restrict the efficiency of Fenton reaction-dependent...Ferroptosis is a new mode of cell death,which can be induced by Fenton reactionmediated lipid peroxidation.However,the insufficient H2O2 and high GSH in tumor cells restrict the efficiency of Fenton reaction-dependent ferroptosis.Herein,a self-supplying lipid peroxide nanoreactor was developed to co-delivery of doxorubicin(DOX),iron and unsaturated lipid for efficient ferroptosis.By leveraging the coordination effect between DOX and Fe3+,trisulfide bond-bridged DOX dimeric prodrug was actively loaded into the core of the unsaturated lipids-rich liposome via iron ion gradient method.First,Fe3+could react with the overexpressed GSH in tumor cells,inducing the GSH depletion and Fe2+generation.Second,the cleavage of trisulfide bond could also consume GSH,and the released DOX induces the generation of H2O2,which would react with the generated Fe2+in step one to induce efficient Fenton reaction-dependent ferroptosis.Third,the formed Fe3+/Fe2+couple could directly catalyze peroxidation of unsaturated lipids to boost Fenton reaction-independent ferroptosis.This iron-prodrug liposome nanoreactor precisely programs multimodal ferroptosis by integrating GSH depletion,ROS generation and lipid peroxidation,providing new sights for efficient cancer therapy.展开更多
Homodimeric prodrug-based self-assembled nanoparticles,with carrier-free structure and ultrahigh drug loading,is drawing more and more attentions.Homodimeric prodrugs are composed of two drug molecules and a pivotal l...Homodimeric prodrug-based self-assembled nanoparticles,with carrier-free structure and ultrahigh drug loading,is drawing more and more attentions.Homodimeric prodrugs are composed of two drug molecules and a pivotal linkage.The influence of the linkages on the self-assembly,in vivo fate and antitumor activity of homodimeric prodrugs is the focus of research.Herein,three docetaxel(DTX)homodimeric prodrugs are developed using different lengths of diselenide bond-containing linkages.Interestingly,compared with the other two linkages,the longest diselenide bond-containing linkage could facilitate the self-delivery of DTX prodrugs,thus improving the stability,circulation time and tumor targeting of prodrug nanoassemblies.Besides,the extension of linkages reduces the redox-triggered drug release and cytotoxicity of prodrug nanoassemblies in tumor cells.Although the longest diselenide bond-containing prodrug nanoassemblies possessed the lowest cytotoxicity to 4T1 cells,their stable nanostructure maintained intact during circulation and achieve the maximum accumulation of DTX in tumor cells,which finally“turned the table”.Our study illustrates the crucial role of linkages in homodimeric prodrugs,and gives valuable proposal for the development of advanced nano-DDS for cancer treatment.展开更多
PEGylation has been widely used to improve the pharmacokinetic properties of prodrug self-assembled nanoparticles(prodrug-SANPs).However,the impacts of the amount of PEG on the self-assemble stability,cellular uptake,...PEGylation has been widely used to improve the pharmacokinetic properties of prodrug self-assembled nanoparticles(prodrug-SANPs).However,the impacts of the amount of PEG on the self-assemble stability,cellular uptake,pharmacokinetics,and antitumor efficacy of prodrug-SANPs are still unknown.Herein,selenoether bond bridged docetaxel dimeric prodrug was synthesized as the model prodrug.Five prodrug-SANPs were designed by using different mass ratios of prodrugs to PEG(W_(prodrug)/W_(DSPE-mPEG2000)=10:0,9:1,8:2,7:3 and 6:4),and defined as Pure drug NPs,9:1NPs,8:2NPs,7:3 NPs and 6:4 NPs,respectively.Interestingly,8:2 NPs formed the most compact nanostructure,thus improving the self-assemble stability and pharmacokinetics behavior.In addition,the difference of these prodrug-SANPs in cellular uptake was investigated,and the influence of PEG on cytotoxicity and antitumor efficacy was also clarified in details.The 8:2 NPs exhibited much better antitumor efficacy than other prodrug-SANPs and even commercial product.Our findings demonstrated the pivotal role of the amount of PEG on prodrug-SANPs.展开更多
Disulfide bond-bridging strategy has been extensively utilized to construct tumor specificity-responsive aliphatic prodrug nanoparticles(PNPs) for precise cancer therapy. Yet, there is no research shedding light on th...Disulfide bond-bridging strategy has been extensively utilized to construct tumor specificity-responsive aliphatic prodrug nanoparticles(PNPs) for precise cancer therapy. Yet, there is no research shedding light on the impacts of the saturation and cis-trans configuration of aliphatic tails on the self-assembly capacity of disulfide bond-linked prodrugs and the in vivo delivery fate of PNPs. Herein, five disulfide bond-linked docetaxelfatty acid prodrugs are designed and synthesized by using stearic acid, elaidic acid, oleic acid, linoleic acid and linolenic acid as the aliphatic tails, respectively. Interestingly, the cistrans configuration of aliphatic tails significantly influences the self-assembly features of prodrugs, and elaidic acid-linked prodrug with a trans double bond show poor self-assembly capacity. Although the aliphatic tails have almost no effect on the redox-sensitive drug release and cytotoxicity, different aliphatic tails significantly influence the chemical stability of prodrugs and the colloidal stability of PNPs, thus affecting the in vivo pharmacokinetics, biodistribution and antitumor efficacy of PNPs. Our findings illustrate how aliphatic tails affect the assembly characteristic of disulfide bond-linked aliphatic prodrugs and the in vivo delivery fate of PNPs, and thus provide theoretical basis for future development of disulfide bond-bridged aliphatic prodrugs.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
In coal mining roadway support design,the working resistance of the rock bolt is the key factor affecting its maximum support load.Effective improvement of the working resistance is of great significance to roadway su...In coal mining roadway support design,the working resistance of the rock bolt is the key factor affecting its maximum support load.Effective improvement of the working resistance is of great significance to roadway support.Based on the rock bolt’s tensile characteristics and the mining roadway surrounding rock deformation,a mechanical model for calculating the working resistance of the rock bolt was established and solved.Taking the mining roadway of the 17102(3)working face at the Panji No.3 Coal Mine of China as a research site,with a quadrilateral section roadway,the influence of pretension and anchorage length on the working resistance of high-strength and ordinary rock bolts in the middle and corner of the roadway is studied.The results show that when the bolt is in the elastic stage,increasing the pretension and anchorage length can effectively improve the working resistance.When the bolt is in the yield and strain-strengthening stages,increasing the pretension and anchorage length cannot effectively improve the working resistance.The influence of pretension and anchorage length on the ordinary and high-strength bolts is similar.The ordinary bolt’s working resistance is approximately 25 kN less than that of the high-strength bolt.When pretension and anchorage length are considered separately,the best pretensions of the high-strength bolt in the middle of the roadway side and the roadway corner are 41.55 and 104.26 kN,respectively,and the best anchorage lengths are 1.54 and 2.12 m,respectively.The best anchorage length of the ordinary bolt is the same as that of the high-strength bolt,and the best pretension for the ordinary bolt in the middle of the roadway side and at the roadway corner is 33.51 and 85.12 kN,respectively.The research results can provide a theoretical basis for supporting the design of quadrilateral mining roadways.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
Self-nanoemulsifying drug delivery system(SNEDDS) has emerged as a promising platform to improve oral absorption of drugs with poor solubility and low permeability. However,large polarity molecules with insufficient l...Self-nanoemulsifying drug delivery system(SNEDDS) has emerged as a promising platform to improve oral absorption of drugs with poor solubility and low permeability. However,large polarity molecules with insufficient lipid solubility,such as paclitaxel(PTX),would suffer from inferior formulation of SNEDDS due to poor compatibility. Herein,phospholipid-drug complex(PLDC) and SNEDDS were integrated into one system to facilitate oral delivery of PTX. First,PTX was formulated into PLDC in response to its inferior physicochemical properties. Then,the prepared PLDC was further formulated into SNEDDS by integrating these two drug delivery technologies into one system(PLDC-SNEDDS). After PLDC-SNEDDS dispersed in aqueous medium,nanoemulsion was formed immediately with an average particle size of ~30 nm. Furthermore,the nanomulsion of PLDC-SNEDDS showed good colloidal stability in both HCl solution(0.1 mol/l,p H 1.0) and phosphate buffer solution(PBS,p H 6.8). In vivo,PTX-PLDC-SNEDDS showed distinct advantages in terms of oral absorption efficiency,with a3.42-fold and 2.13-fold higher bioavailability than PTX-PLDC and PTX solution,respectively.Our results suggest that the integration of PLDC into SNEDDS could be utilized to facilitate the oral delivery of hydrophobic drugs with large polarity.展开更多
The filling mining method is important in realizing the green mining of mineral resources.Aiming at the problems of land resource occupation,environmental pollution,and rational utilization of coal-based solid wastes ...The filling mining method is important in realizing the green mining of mineral resources.Aiming at the problems of land resource occupation,environmental pollution,and rational utilization of coal-based solid wastes such as coal gangue,fly ash,and desulfurization gypsum,a new paste filling material was developed with coal gangue,fly ash,and desulfurization gypsum as raw materials.The microstructure of the raw materials was analyzed by XRD and SEM.Combined with the Box-Behnken experimental design,the effect of each component on the fluidity of the filling slurry was analyzed through the response surface analysis.The significance of each component on its bleeding and fluidity was determined,and the optimal ratio of the filling slurry was obtained.Experimental results show that the microcosmic morphology of coal gangue,desulfurization gypsum,and gasification slag presents an irregular block and rough particle surface;the microcosmic morphology of fly ash and bottom slag presents first out spherical or quasi spherical particles.Moreover,obvious sintering traces exist on the surface of the bottom slag.The main crystal mineral of coal gangue and fly ash is SiO_(2),the desulfurization gypsum is composed of Ca(SO_(4))(H_(2)O)and Ca(CO_(3))crystal minerals,the gasification slag is composed of carbon and nitrogen compounds,and the main crystal mineral components in the bottom slag sample are SiO_(2) and Al_(x)Si_(y)O_(z) compounds.The order of significance of each key factor on slurry fluidity is as follows:C(desulfurization gypsum)>D(gasification slag and bottom slag 1:1)>A(coal gangue)>B(fly ash).The order of the significance of each key factor on slurry bleeding is as follows:B(fly ash)>C(desulfurization gypsum)>D(gasification slag and bottom slag 1:1)>A(coal gangue).Considering the material preparation,field application,and other conditions,the mass percentage of each factor content of the new paste filling material is as follows:49.5%coal gangue,8.3%fly ash,4.1%desulfurization gypsum,6.2%gasification slag,and 6.2%bottom slag.展开更多
Taibai Mountains,located at the northern foot of the Qinling Mountains,are composed of the Yuan Taibai Mountain(also known as East Taibai Mountain),Aoshan Mountain(also known as West Taibai Mountain)and their connecti...Taibai Mountains,located at the northern foot of the Qinling Mountains,are composed of the Yuan Taibai Mountain(also known as East Taibai Mountain),Aoshan Mountain(also known as West Taibai Mountain)and their connection part.With its complex geographical and climatic conditions,Taibai Mountains are extremely rich in wild plant resources.Based on field investigation,literature review and specimen identification,wild vascular plants resources and their diversity in Taibai Mountains were studied by the sixth Traditional Chinese Medicine(TCM)Resources Scientific Expedition Team of Shenyang Pharmaceutical University.222 species of vascular plants belonging to 163 genera and 63 families were collected during July 2012 in this area,and most of the plants are angiosperms.The families with more species are Liliaceae,Ranunculaceae,Asteraceae,Rosaceae,and Saxifragaceae,and the dominant genus are Aconitum,Sedum,Eleutherococcus,Pedicularis,Polygonatum,and Patrinia.In terms of life form,perennial herbs are the main species,accounting for 72.97%of the total species,with others being some annual(or biennial)herbs,shrubs and lianas.Among all the collected vascular plants,170 species of them are medicinal vascular plants,accounting for 76.58%of the total.Most of the medicinal parts are roots and rhizomes,followed by the whole plants.Finally,on the basis of investigation and study,some suggestions are put forward to strengthen the protection and utilization of plant resources in Taibai Mountains.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
In the originally published version of this article,the authors identified inadvertent errors in the preparation of Fig.7A and B.During assembly of the figure,incorrect images from the same batch of raw data were mist...In the originally published version of this article,the authors identified inadvertent errors in the preparation of Fig.7A and B.During assembly of the figure,incorrect images from the same batch of raw data were mistakenly selected and duplicated across two separate studies.The figure has now been replaced with the correct images sourced from the same original dataset.展开更多
Forming electrostatic nanocomplexes(ENCs)with counter-ions can improve the delivery efficiency of chemotherapy drugs.However,water-soluble chemotherapy drugs like mitoxantrone(MTO),have limited affinity for counter-io...Forming electrostatic nanocomplexes(ENCs)with counter-ions can improve the delivery efficiency of chemotherapy drugs.However,water-soluble chemotherapy drugs like mitoxantrone(MTO),have limited affinity for counter-ions,posing challenges in the creation of stable ENCs.Herein,MTO was connected to fatty alcohols of varying chain lengths(C8,C12,C16)via disulfide bonds,forming hydrophobic prodrugs.We found that conjugating MTO to fatty alcohols significantly improved its affinity for the counter-ion sodium cholesterol sulfate(SCS).Among the designed prodrugs,conjugated to fatty alcohols with longer carbon chain lengths exhibited heightened affinity for SCS,resulting in the formation of more stable ENCs.However,extending the carbon chain also slowed the rate of drug release.Overall,compared with MTO solution,these ENCs demonstrated comparable therapeutic efficacy while causing minimal damage to healthy tissues,especially for MTO-SS-C16 ENCs.Our research provides new insights for constructing stable and safe ENCs for hydrophilic drugs like MTO.展开更多
Dimeric prodrug nanoassemblies(DPNAs)offer great potential in improving the efficacy of chemotherapy.Previously,we developed tetrasulfide bonds as a novel response module and the obtainedγ-4S-2CTX NPs demonstrated su...Dimeric prodrug nanoassemblies(DPNAs)offer great potential in improving the efficacy of chemotherapy.Previously,we developed tetrasulfide bonds as a novel response module and the obtainedγ-4S-2CTX NPs demonstrated superlative self-assembly stability and enhanced anti-tumor efficacy.However,current DPNAs mainly rely on simple PEGylation for surface modification to improve blood circulation,which lacks tumor-selective functionality and limits their further application.To address these limitations,we introduced a new surface modification strategy using RM-1 tumor cell membranes(CMs)to enhance biofunctionality.The initial attempt to use CMs as a single surface modification failed because the affinity of nanocores-CMs remains a problem,which affected the stability of membrane-coated DPNAs.To address this,we used 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N[methoxy(polyethyleneglycol)-2000](DSPE-PEG2k)as an adhesive bridge to improve the affinity between CMs and DPNAs,resulting in a dual-modified formulation termed CM-pDPNAs.This dual modification strategy enhanced CMs binding to DPNAs,enabling precise tumor recognition and internalization,thereby improving tumor elimination efficacy.Furthermore,this approach addressed key challenges associated with current CM-coated nanoparticles(CM-NPs),including complex preparation procedures and poor drug-carrier compatibility.This work elucidates the application of CMs as surface modification modules,paving the way for the next generation of biomimetic prodrug nanoassemblies with superior stability and tumor specficity.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
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
Photodynamic therapy(PDT)employs lasers to activate photosensitizers,generating reactive oxygen species(ROS)for tumor cell destruction.However,the extremely short half-life of ROS and limited diffusion range restrict ...Photodynamic therapy(PDT)employs lasers to activate photosensitizers,generating reactive oxygen species(ROS)for tumor cell destruction.However,the extremely short half-life of ROS and limited diffusion range restrict PDT’s therapeutic efficiency.Recent studies have shown that lysosome-targeted PDT can directly disrupt the“explosive depot”of tumor cells by triggering the release of abundant hydrolases from lysosomes.Nevertheless,existing lysosometargeted strategies rely predominantly on a single protonation mechanism,resulting in low targeted efficiency.To enhance lysosome-targeted bursting,this study adopted a dual-mode recognition strategy,combining“hydrophobic interactionaided fusion”with“charge-directed anchoring”.Specifically,pyropheophorbide-a(PPa)was employed as a model photosensitizer and covalently conjugated with alkyl tertiary amines of varying chain lengths(C1,C4,C8,and C12),yielding lysosome-targeted bursting photosensitizers(PPa1,PPa4,PPa8,and PPa12).Self-assembled nanoparticles(LPPa NPs)were then prepared to facilitate tumor delivery.The objective of this study was to determine the optimal chain length by evaluating the balance among ROS production efficiency,lysosomal targeted capability,and assembly stability of LPPa NPs.Notably,PPa4 NPs demonstrated superior cellular uptake,enhanced ROS generation,and effective lysosometargeted bursting,thereby markedly improving antitumor efficacy.In summary,the dual-mode recognition strategy offered an advanced strategy for enhancing the efficiency of PDT.展开更多
Pure drug-assembled nanomedicines(PDANs)are currently under intensive investigation as promising nanoplatforms for cancer therapy.However,poor colloidal stability and less tumor-homing ability remain critical unresolv...Pure drug-assembled nanomedicines(PDANs)are currently under intensive investigation as promising nanoplatforms for cancer therapy.However,poor colloidal stability and less tumor-homing ability remain critical unresolved problems that impede their clinical translation.Herein,we report a core-matched nanoassembly of pyropheophorbide a(PPa)for photodynamic therapy(PDT).Pure PPa molecules are found to self-assemble into nanoparticles(NPs),and an amphiphilic PEG polymer(PPaPEG_(2K))is utilized to achieve core-matched PEGylating modification via the p-p stacking effect and hydrophobic interaction between the PPa core and the PPa-PEG_(2K) shell.Compared to PCL-PEG_(2K) with similar molecular weight,PPa-PEG_(2K) significantly increases the stability,prolongs the systemic circulation and improves the tumor-homing ability and ROS generation efficiency of PPa-nanoassembly.As a result,PPa/PPa-PEG_(2K) NPs exert potent antitumor activity in a 4T1 breast tumor-bearing BALB/c mouse xenograft model.Together,such a core-matched nanoassembly of pure photosensitizer provides a new strategy for the development of imaging-guided theragnostic nanomedicines.展开更多
Phototherapy has been intensively investigated as a non-invasive cancer treatment option.However,its clinical translation is still impeded by unsatisfactory therapeutic efficacy and severe phototoxicity.To achieve hig...Phototherapy has been intensively investigated as a non-invasive cancer treatment option.However,its clinical translation is still impeded by unsatisfactory therapeutic efficacy and severe phototoxicity.To achieve high therapeutic efficiency and high security,a nanoassembly of Forster Resonance Energy Transfer(FRET)photosensitizer pairs is developed on basis of dual-mode photosensitizer co-loading and photocaging strategy.For proof-of-concept,an erythrocyte-camouflaged FRET pair co-assembly of chlorine e6(Ce6,FRET donor)and 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindotricarbocyanine iodide(DiR,FRET acceptor)is investigated for breast cancer treatment.Notably,Ce6 in the nanoassemby is quenched by DiR and could be unlocked for photodynamic therapy(PDT)only when DiR is photobleached by 808-nm laser.As a result,Ce6-caused phototoxicity could be well controlled.Under cascaded laser irradiation(808-660 nm),tumor-localizing temperature rise following laser irradiation on DiR not only induces tumor cell apoptosis but also facilitates the tumor penetration of NPs,relieves tumor hypoxia,and promotes the PDT efficacy of Ce6.Such FRET pair-based nanoassembly provides a new strategy for developing multimodal phototherapy nanomedicines with high efficiency and good security.展开更多
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 the National Natural Science Foundation of China(no.81872816)the Liaoning Revitalization Talents Program(no.XLYC180801)+1 种基金China Postdoctoral Innovative Talents Support Program(no.BX20190219)China Postdoctoral Science Foundation(no.2019M661134).
文摘Ferroptosis is a new mode of cell death,which can be induced by Fenton reactionmediated lipid peroxidation.However,the insufficient H2O2 and high GSH in tumor cells restrict the efficiency of Fenton reaction-dependent ferroptosis.Herein,a self-supplying lipid peroxide nanoreactor was developed to co-delivery of doxorubicin(DOX),iron and unsaturated lipid for efficient ferroptosis.By leveraging the coordination effect between DOX and Fe3+,trisulfide bond-bridged DOX dimeric prodrug was actively loaded into the core of the unsaturated lipids-rich liposome via iron ion gradient method.First,Fe3+could react with the overexpressed GSH in tumor cells,inducing the GSH depletion and Fe2+generation.Second,the cleavage of trisulfide bond could also consume GSH,and the released DOX induces the generation of H2O2,which would react with the generated Fe2+in step one to induce efficient Fenton reaction-dependent ferroptosis.Third,the formed Fe3+/Fe2+couple could directly catalyze peroxidation of unsaturated lipids to boost Fenton reaction-independent ferroptosis.This iron-prodrug liposome nanoreactor precisely programs multimodal ferroptosis by integrating GSH depletion,ROS generation and lipid peroxidation,providing new sights for efficient cancer therapy.
基金This work was supported by China Postdoctoral Innovative Talents Support Program(no.BX20190219)China Postdoctoral Science Foundation(no.2019M661134)National Natural Science Foundation of China(no.81872816).
文摘Homodimeric prodrug-based self-assembled nanoparticles,with carrier-free structure and ultrahigh drug loading,is drawing more and more attentions.Homodimeric prodrugs are composed of two drug molecules and a pivotal linkage.The influence of the linkages on the self-assembly,in vivo fate and antitumor activity of homodimeric prodrugs is the focus of research.Herein,three docetaxel(DTX)homodimeric prodrugs are developed using different lengths of diselenide bond-containing linkages.Interestingly,compared with the other two linkages,the longest diselenide bond-containing linkage could facilitate the self-delivery of DTX prodrugs,thus improving the stability,circulation time and tumor targeting of prodrug nanoassemblies.Besides,the extension of linkages reduces the redox-triggered drug release and cytotoxicity of prodrug nanoassemblies in tumor cells.Although the longest diselenide bond-containing prodrug nanoassemblies possessed the lowest cytotoxicity to 4T1 cells,their stable nanostructure maintained intact during circulation and achieve the maximum accumulation of DTX in tumor cells,which finally“turned the table”.Our study illustrates the crucial role of linkages in homodimeric prodrugs,and gives valuable proposal for the development of advanced nano-DDS for cancer treatment.
基金financially supported by National Natural Science Foundation of China (no. 81872816)Doctoral Scientific Research Staring Foundation of Liaoning Province (no. 2021BS-130)General Program of Department of Education of Liaoning Province (no. LJKZ0953)
文摘PEGylation has been widely used to improve the pharmacokinetic properties of prodrug self-assembled nanoparticles(prodrug-SANPs).However,the impacts of the amount of PEG on the self-assemble stability,cellular uptake,pharmacokinetics,and antitumor efficacy of prodrug-SANPs are still unknown.Herein,selenoether bond bridged docetaxel dimeric prodrug was synthesized as the model prodrug.Five prodrug-SANPs were designed by using different mass ratios of prodrugs to PEG(W_(prodrug)/W_(DSPE-mPEG2000)=10:0,9:1,8:2,7:3 and 6:4),and defined as Pure drug NPs,9:1NPs,8:2NPs,7:3 NPs and 6:4 NPs,respectively.Interestingly,8:2 NPs formed the most compact nanostructure,thus improving the self-assemble stability and pharmacokinetics behavior.In addition,the difference of these prodrug-SANPs in cellular uptake was investigated,and the influence of PEG on cytotoxicity and antitumor efficacy was also clarified in details.The 8:2 NPs exhibited much better antitumor efficacy than other prodrug-SANPs and even commercial product.Our findings demonstrated the pivotal role of the amount of PEG on prodrug-SANPs.
基金funding from the National Natural Science Foundation of China(No.81703451 and 81773656)the Excellent Youth Science Foundation of Liaoning Province(No.2020-YQ-06)+2 种基金the Liaoning Revitalization Talents Program(No.XLYC1808017 and XLYC1907129)the China Postdoctoral Science Foundation(No.2020M670794)the Science and Technology Major Project of Liaoning(No.2019JH1/10300004)。
文摘Disulfide bond-bridging strategy has been extensively utilized to construct tumor specificity-responsive aliphatic prodrug nanoparticles(PNPs) for precise cancer therapy. Yet, there is no research shedding light on the impacts of the saturation and cis-trans configuration of aliphatic tails on the self-assembly capacity of disulfide bond-linked prodrugs and the in vivo delivery fate of PNPs. Herein, five disulfide bond-linked docetaxelfatty acid prodrugs are designed and synthesized by using stearic acid, elaidic acid, oleic acid, linoleic acid and linolenic acid as the aliphatic tails, respectively. Interestingly, the cistrans configuration of aliphatic tails significantly influences the self-assembly features of prodrugs, and elaidic acid-linked prodrug with a trans double bond show poor self-assembly capacity. Although the aliphatic tails have almost no effect on the redox-sensitive drug release and cytotoxicity, different aliphatic tails significantly influence the chemical stability of prodrugs and the colloidal stability of PNPs, thus affecting the in vivo pharmacokinetics, biodistribution and antitumor efficacy of PNPs. Our findings illustrate how aliphatic tails affect the assembly characteristic of disulfide bond-linked aliphatic prodrugs and the in vivo delivery fate of PNPs, and thus provide theoretical basis for future development of disulfide bond-bridged aliphatic prodrugs.
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This work was supported by the National Natural Science Foundation of China(51774009,51874006,and 51904010)Key Research and Development Projects in Anhui Province(202004a07020045)+2 种基金Colleges and Universities Natural Science Foundation of Anhui(KJ2019A0134)Anhui Provincial Natural Science Foundation(2008085ME147)Anhui University of Technology and Science Graduate Innovation Foundation(2019CX2007).
文摘In coal mining roadway support design,the working resistance of the rock bolt is the key factor affecting its maximum support load.Effective improvement of the working resistance is of great significance to roadway support.Based on the rock bolt’s tensile characteristics and the mining roadway surrounding rock deformation,a mechanical model for calculating the working resistance of the rock bolt was established and solved.Taking the mining roadway of the 17102(3)working face at the Panji No.3 Coal Mine of China as a research site,with a quadrilateral section roadway,the influence of pretension and anchorage length on the working resistance of high-strength and ordinary rock bolts in the middle and corner of the roadway is studied.The results show that when the bolt is in the elastic stage,increasing the pretension and anchorage length can effectively improve the working resistance.When the bolt is in the yield and strain-strengthening stages,increasing the pretension and anchorage length cannot effectively improve the working resistance.The influence of pretension and anchorage length on the ordinary and high-strength bolts is similar.The ordinary bolt’s working resistance is approximately 25 kN less than that of the high-strength bolt.When pretension and anchorage length are considered separately,the best pretensions of the high-strength bolt in the middle of the roadway side and the roadway corner are 41.55 and 104.26 kN,respectively,and the best anchorage lengths are 1.54 and 2.12 m,respectively.The best anchorage length of the ordinary bolt is the same as that of the high-strength bolt,and the best pretension for the ordinary bolt in the middle of the roadway side and at the roadway corner is 33.51 and 85.12 kN,respectively.The research results can provide a theoretical basis for supporting the design of quadrilateral mining roadways.
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financially supported by the National Nature Science Foundation of China (No. 81703451)the China Postdoctoral Science Foundation (No. 2017M611269 and 2018T110233)
文摘Self-nanoemulsifying drug delivery system(SNEDDS) has emerged as a promising platform to improve oral absorption of drugs with poor solubility and low permeability. However,large polarity molecules with insufficient lipid solubility,such as paclitaxel(PTX),would suffer from inferior formulation of SNEDDS due to poor compatibility. Herein,phospholipid-drug complex(PLDC) and SNEDDS were integrated into one system to facilitate oral delivery of PTX. First,PTX was formulated into PLDC in response to its inferior physicochemical properties. Then,the prepared PLDC was further formulated into SNEDDS by integrating these two drug delivery technologies into one system(PLDC-SNEDDS). After PLDC-SNEDDS dispersed in aqueous medium,nanoemulsion was formed immediately with an average particle size of ~30 nm. Furthermore,the nanomulsion of PLDC-SNEDDS showed good colloidal stability in both HCl solution(0.1 mol/l,p H 1.0) and phosphate buffer solution(PBS,p H 6.8). In vivo,PTX-PLDC-SNEDDS showed distinct advantages in terms of oral absorption efficiency,with a3.42-fold and 2.13-fold higher bioavailability than PTX-PLDC and PTX solution,respectively.Our results suggest that the integration of PLDC into SNEDDS could be utilized to facilitate the oral delivery of hydrophobic drugs with large polarity.
基金We acknowledge the financial support for this work provided by the National Natural Science Foundation of China(Grant No.51774010)National Key R&D Program of China(Grant No.2019YF1904304).
文摘The filling mining method is important in realizing the green mining of mineral resources.Aiming at the problems of land resource occupation,environmental pollution,and rational utilization of coal-based solid wastes such as coal gangue,fly ash,and desulfurization gypsum,a new paste filling material was developed with coal gangue,fly ash,and desulfurization gypsum as raw materials.The microstructure of the raw materials was analyzed by XRD and SEM.Combined with the Box-Behnken experimental design,the effect of each component on the fluidity of the filling slurry was analyzed through the response surface analysis.The significance of each component on its bleeding and fluidity was determined,and the optimal ratio of the filling slurry was obtained.Experimental results show that the microcosmic morphology of coal gangue,desulfurization gypsum,and gasification slag presents an irregular block and rough particle surface;the microcosmic morphology of fly ash and bottom slag presents first out spherical or quasi spherical particles.Moreover,obvious sintering traces exist on the surface of the bottom slag.The main crystal mineral of coal gangue and fly ash is SiO_(2),the desulfurization gypsum is composed of Ca(SO_(4))(H_(2)O)and Ca(CO_(3))crystal minerals,the gasification slag is composed of carbon and nitrogen compounds,and the main crystal mineral components in the bottom slag sample are SiO_(2) and Al_(x)Si_(y)O_(z) compounds.The order of significance of each key factor on slurry fluidity is as follows:C(desulfurization gypsum)>D(gasification slag and bottom slag 1:1)>A(coal gangue)>B(fly ash).The order of the significance of each key factor on slurry bleeding is as follows:B(fly ash)>C(desulfurization gypsum)>D(gasification slag and bottom slag 1:1)>A(coal gangue).Considering the material preparation,field application,and other conditions,the mass percentage of each factor content of the new paste filling material is as follows:49.5%coal gangue,8.3%fly ash,4.1%desulfurization gypsum,6.2%gasification slag,and 6.2%bottom slag.
文摘Taibai Mountains,located at the northern foot of the Qinling Mountains,are composed of the Yuan Taibai Mountain(also known as East Taibai Mountain),Aoshan Mountain(also known as West Taibai Mountain)and their connection part.With its complex geographical and climatic conditions,Taibai Mountains are extremely rich in wild plant resources.Based on field investigation,literature review and specimen identification,wild vascular plants resources and their diversity in Taibai Mountains were studied by the sixth Traditional Chinese Medicine(TCM)Resources Scientific Expedition Team of Shenyang Pharmaceutical University.222 species of vascular plants belonging to 163 genera and 63 families were collected during July 2012 in this area,and most of the plants are angiosperms.The families with more species are Liliaceae,Ranunculaceae,Asteraceae,Rosaceae,and Saxifragaceae,and the dominant genus are Aconitum,Sedum,Eleutherococcus,Pedicularis,Polygonatum,and Patrinia.In terms of life form,perennial herbs are the main species,accounting for 72.97%of the total species,with others being some annual(or biennial)herbs,shrubs and lianas.Among all the collected vascular plants,170 species of them are medicinal vascular plants,accounting for 76.58%of the total.Most of the medicinal parts are roots and rhizomes,followed by the whole plants.Finally,on the basis of investigation and study,some suggestions are put forward to strengthen the protection and utilization of plant resources in Taibai Mountains.
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.
文摘In the originally published version of this article,the authors identified inadvertent errors in the preparation of Fig.7A and B.During assembly of the figure,incorrect images from the same batch of raw data were mistakenly selected and duplicated across two separate studies.The figure has now been replaced with the correct images sourced from the same original dataset.
基金financial support from National Natural Science Foundation of China (82272151,82173766,and 82204318)Liaoning Revitalization Talents Program (XLYC2203083)Shenyang Young and Middle-aged Science and Technology Innovation Talent Support Program (RC220389)。
文摘Forming electrostatic nanocomplexes(ENCs)with counter-ions can improve the delivery efficiency of chemotherapy drugs.However,water-soluble chemotherapy drugs like mitoxantrone(MTO),have limited affinity for counter-ions,posing challenges in the creation of stable ENCs.Herein,MTO was connected to fatty alcohols of varying chain lengths(C8,C12,C16)via disulfide bonds,forming hydrophobic prodrugs.We found that conjugating MTO to fatty alcohols significantly improved its affinity for the counter-ion sodium cholesterol sulfate(SCS).Among the designed prodrugs,conjugated to fatty alcohols with longer carbon chain lengths exhibited heightened affinity for SCS,resulting in the formation of more stable ENCs.However,extending the carbon chain also slowed the rate of drug release.Overall,compared with MTO solution,these ENCs demonstrated comparable therapeutic efficacy while causing minimal damage to healthy tissues,especially for MTO-SS-C16 ENCs.Our research provides new insights for constructing stable and safe ENCs for hydrophilic drugs like MTO.
基金the National Key R&D Program of China(No.2022YFE0111600)the National Natural Science Foundation of China(No.82204318)+2 种基金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Dimeric prodrug nanoassemblies(DPNAs)offer great potential in improving the efficacy of chemotherapy.Previously,we developed tetrasulfide bonds as a novel response module and the obtainedγ-4S-2CTX NPs demonstrated superlative self-assembly stability and enhanced anti-tumor efficacy.However,current DPNAs mainly rely on simple PEGylation for surface modification to improve blood circulation,which lacks tumor-selective functionality and limits their further application.To address these limitations,we introduced a new surface modification strategy using RM-1 tumor cell membranes(CMs)to enhance biofunctionality.The initial attempt to use CMs as a single surface modification failed because the affinity of nanocores-CMs remains a problem,which affected the stability of membrane-coated DPNAs.To address this,we used 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N[methoxy(polyethyleneglycol)-2000](DSPE-PEG2k)as an adhesive bridge to improve the affinity between CMs and DPNAs,resulting in a dual-modified formulation termed CM-pDPNAs.This dual modification strategy enhanced CMs binding to DPNAs,enabling precise tumor recognition and internalization,thereby improving tumor elimination efficacy.Furthermore,this approach addressed key challenges associated with current CM-coated nanoparticles(CM-NPs),including complex preparation procedures and poor drug-carrier compatibility.This work elucidates the application of CMs as surface modification modules,paving the way for the next generation of biomimetic prodrug nanoassemblies with superior stability and tumor specficity.
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.
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National Natural Science Foundation of China(No.82204318)Liaoning Revitalization Talents Program(Nos.XLYC22202019,and XLYC2203083)+3 种基金Natural Science Foundation of Henan,Guided Youth Science Fund Project(No.242300420424)Henan Eye Hospital Basic Science Research Program(No.25JCQN004)Key research and development program of Liaoning Province(No.2024JH2/102500061)Youth innovation team of Liaoning Province Department of Education(No.LJ222410163049).
文摘Photodynamic therapy(PDT)employs lasers to activate photosensitizers,generating reactive oxygen species(ROS)for tumor cell destruction.However,the extremely short half-life of ROS and limited diffusion range restrict PDT’s therapeutic efficiency.Recent studies have shown that lysosome-targeted PDT can directly disrupt the“explosive depot”of tumor cells by triggering the release of abundant hydrolases from lysosomes.Nevertheless,existing lysosometargeted strategies rely predominantly on a single protonation mechanism,resulting in low targeted efficiency.To enhance lysosome-targeted bursting,this study adopted a dual-mode recognition strategy,combining“hydrophobic interactionaided fusion”with“charge-directed anchoring”.Specifically,pyropheophorbide-a(PPa)was employed as a model photosensitizer and covalently conjugated with alkyl tertiary amines of varying chain lengths(C1,C4,C8,and C12),yielding lysosome-targeted bursting photosensitizers(PPa1,PPa4,PPa8,and PPa12).Self-assembled nanoparticles(LPPa NPs)were then prepared to facilitate tumor delivery.The objective of this study was to determine the optimal chain length by evaluating the balance among ROS production efficiency,lysosomal targeted capability,and assembly stability of LPPa NPs.Notably,PPa4 NPs demonstrated superior cellular uptake,enhanced ROS generation,and effective lysosometargeted bursting,thereby markedly improving antitumor efficacy.In summary,the dual-mode recognition strategy offered an advanced strategy for enhancing the efficiency of PDT.
基金supported by Science and Technology Major Project of Liaoning(No.2019JH1/10300004,China)the National Natural Science Foundation of China(No.81773656 and 81703451)+2 种基金the Excellent Youth Science Foundation of Liaoning Province(No.2020-YQ-06,China)the China Postdoctoral Science Foundation(No.2020M670794)the Liaoning Revitalization Talents Program(No.XLYC1907129 and XLYC1808017,China)。
文摘Pure drug-assembled nanomedicines(PDANs)are currently under intensive investigation as promising nanoplatforms for cancer therapy.However,poor colloidal stability and less tumor-homing ability remain critical unresolved problems that impede their clinical translation.Herein,we report a core-matched nanoassembly of pyropheophorbide a(PPa)for photodynamic therapy(PDT).Pure PPa molecules are found to self-assemble into nanoparticles(NPs),and an amphiphilic PEG polymer(PPaPEG_(2K))is utilized to achieve core-matched PEGylating modification via the p-p stacking effect and hydrophobic interaction between the PPa core and the PPa-PEG_(2K) shell.Compared to PCL-PEG_(2K) with similar molecular weight,PPa-PEG_(2K) significantly increases the stability,prolongs the systemic circulation and improves the tumor-homing ability and ROS generation efficiency of PPa-nanoassembly.As a result,PPa/PPa-PEG_(2K) NPs exert potent antitumor activity in a 4T1 breast tumor-bearing BALB/c mouse xenograft model.Together,such a core-matched nanoassembly of pure photosensitizer provides a new strategy for the development of imaging-guided theragnostic nanomedicines.
基金supported by the National Natural Science Foundation of China(No.81773656 and 81703451)the Excellent Youth Science Foundation of Liaoning Province(No.2020-YQ-06)+2 种基金the China Postdoctoral Science Foundation(No.2020M670794)the Liaoning Revitalization Talents Program(No.XLYC1907129 and XLYC1808017),Science and Technology Major Project of Liaoning(No.2019JH1/10300004)the National College Students’innovation and entrepreneurship training program(No.201910163200).
文摘Phototherapy has been intensively investigated as a non-invasive cancer treatment option.However,its clinical translation is still impeded by unsatisfactory therapeutic efficacy and severe phototoxicity.To achieve high therapeutic efficiency and high security,a nanoassembly of Forster Resonance Energy Transfer(FRET)photosensitizer pairs is developed on basis of dual-mode photosensitizer co-loading and photocaging strategy.For proof-of-concept,an erythrocyte-camouflaged FRET pair co-assembly of chlorine e6(Ce6,FRET donor)and 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindotricarbocyanine iodide(DiR,FRET acceptor)is investigated for breast cancer treatment.Notably,Ce6 in the nanoassemby is quenched by DiR and could be unlocked for photodynamic therapy(PDT)only when DiR is photobleached by 808-nm laser.As a result,Ce6-caused phototoxicity could be well controlled.Under cascaded laser irradiation(808-660 nm),tumor-localizing temperature rise following laser irradiation on DiR not only induces tumor cell apoptosis but also facilitates the tumor penetration of NPs,relieves tumor hypoxia,and promotes the PDT efficacy of Ce6.Such FRET pair-based nanoassembly provides a new strategy for developing multimodal phototherapy nanomedicines with high efficiency and good security.
