The review provides an overview of the approaches, applications, and methods for ester prodrugs. Ester prodrugs are pharmacologically inactive compounds in their original form but become active drugs on biotransformat...The review provides an overview of the approaches, applications, and methods for ester prodrugs. Ester prodrugs are pharmacologically inactive compounds in their original form but become active drugs on biotransformation within the body, which offers advantages concerning the solubility, stability, and targeted delivery of the active drug. Several approaches of ester prodrugs have been reviewed in this review, including simple ester prodrugs, amino acid ester prodrugs, sugar ester prodrugs, lipid ester prodrugs, and polymeric ester prodrugs. This review incorporates in vitro and in vivo methods as well as the characterization of physical and chemical properties for ester prodrugs, cell culture systems, enzymatic assays, and animal models—all of these having a very important bearing on the evaluation of stability, bioavailability, and efficacy for ester prodrugs. While the benefits of using ester prodrugs are significant, there are also disadvantages like instability, poor or variable enzymatic hydrolysis, and toxicity from released promoieties or by-products. This review discusses solutions to the various limitations that include enhancing stability with ionizable promoieties and using physiologically-based pharmacokinetic modeling. The review also highlights the application of ester prodrugs in neurological disorders, such as Parkinson’s disease, and the ongoing efforts to address the critical limitations in treatment efficacy. Future prodrug strategies are poised to advance significantly by harnessing diverse transport mechanisms across the blood-brain barrier and integrating nanotechnology.展开更多
Integrating photodynamic therapy(PDT)with immunosuppression reversal represents a promising synergistic approach to boost cancer immunotherapy.However,the complicated components and cumbersome preparation procedures o...Integrating photodynamic therapy(PDT)with immunosuppression reversal represents a promising synergistic approach to boost cancer immunotherapy.However,the complicated components and cumbersome preparation procedures of the currently developed nano drug delivery systems heavily hinder their further clinical translation.Herein,a reactive oxygen species(ROS)/photo dual-responsive amphipathic prodrug(denoted as PPTN)was designed and synthesized by linking NLG919,an indoleamine-2,3-dioxygenase(IDO)inhibitor,with the photosensitizer protoporphyrin IX(PpIX)by a thioketal moiety,and further modifying with mPEG2k.PPTN could self-assemble into nanoscale unimolecular micelles in aqueous solution without additional excipients,increasing tumor accumulation while effectively addressing the pronounced hydrophobicity challenge of PpIX.Upon light exposure,PPTN generated ROS,not only directly damaging cancer cells,but also trigger the breakage of thioketal bond to accelerate simultaneous release of NLG919.Therefore,PPTN potentially act as a promising ROS/photo dual-responsive carrier-free prodrug delivery system for controllable drug release and specific tumor therapy.Moreover,PPTN induced simultaneous PDT-triggered immunogenic cell death(ICD)effect and specific IDO blockade to boost immune response,exhibiting potent suppression efficacy against primary and distant tumors.Overall,with the superiorities of easily controllable preparation procedures,synchronous drug delivery and ROS/photo dual-responsiveness,such a prodrug unimolecular micelle may represent a promising nanoplatform for photoactivated-immunotherapy.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
Supramolecular prodrug vesicles(H-4⊃B-2@MB)with selective antibacterial activity have been successfully constructed.Specifically,a natural antibiotic prodrug(B-2)with glutathione(GSH)-responsiveness was synthesized.Th...Supramolecular prodrug vesicles(H-4⊃B-2@MB)with selective antibacterial activity have been successfully constructed.Specifically,a natural antibiotic prodrug(B-2)with glutathione(GSH)-responsiveness was synthesized.The hydrophobic interaction between B-2 and a novel water-soluble cavitand with deep cavity(H-4)resulted in the formation of a host-vip complex,which further self-assembled into supramolecular vesicles.The formed vesicles could effectively encapsulate the photosensitizer methylene blue(MB),enabling co-delivery of antibiotics and photosensitizers in the presence of GSH.Moreover,upon excitation at 630 nm,the photosensitizers generate reactive oxygen species(ROS),effectively eradicating E.coli through combined chemo-photodynamic therapy.Considering that GSH is predominantly present in Gram-negative bacteria such as E.coli,this strategy exhibits substantial potential for selectively inhibiting bacteria characterized by high GSH levels to regulate bacterial colony equilibrium.展开更多
Prodrugs need to be converted to active drugs to exert their pharmacological activities.Identifying the direct targets of active drugs is essential to elucidate the pharmacological mechanisms of prodrugs,but remains c...Prodrugs need to be converted to active drugs to exert their pharmacological activities.Identifying the direct targets of active drugs is essential to elucidate the pharmacological mechanisms of prodrugs,but remains challenging,especially for active drugs with low stability.展开更多
Cancer enzymology is a promising filiation of bio-medical sciences. In thepast decades, enzymes, such as GST(glutathione S-transferase) , PKC(protein kinase C) , Topo(DNAtopoisomerases), TK(tyrosine kinase), CD (bacte...Cancer enzymology is a promising filiation of bio-medical sciences. In thepast decades, enzymes, such as GST(glutathione S-transferase) , PKC(protein kinase C) , Topo(DNAtopoisomerases), TK(tyrosine kinase), CD (bacterial cytosine deaminase), CPG2(carboxypeptidase G2) ,and PNP (purine nucleoside phosphorylase), have been known to bear close relations to cancer. Theirspecific expression and influence on the process of tumor initiation, promotion and progressionattract scientists to apply them as a biochemical marker of certain malignant tumor, a predictor ofresponse in cancer chemotherapy; to apply them to drug design, tumor prevention and as adjuvant toradiotherapy or surgery.展开更多
Enzyme prodrug therapies(EPTs)have been intensively explored as attractive approaches to selective activation of systemically administered benign prodrugs by the exogenous enzymes or enzymes expressed at the desired t...Enzyme prodrug therapies(EPTs)have been intensively explored as attractive approaches to selective activation of systemically administered benign prodrugs by the exogenous enzymes or enzymes expressed at the desired target site,thus achieving localized,site-specific therapeutic effect.Many effective strategies(e.g.,antibody-,viral-,gene-,as well as polymer-directed EPT)have been developed for enzyme localization to locally activate systemically administered benign prodrugs.Nevertheless,intrinsic limitations(e.g.,complex intracellular environment and catalyst instability)make the practical application of EPT strategies a task that presents itself as highly challenging.As a promising alternative to natural enzyme,nanozyme has attracted substantial attention since its discovery in 2007,mainly due to the advantages of robust catalytic activity,high stability,low cost,and facile synthesis.Recently,nanozyme-activated prodrug strategies bring a new opportunity for targeted therapy,referred to as nanozyme-activating prodrug therapies.This review focuses on recently reported nanozyme-activated prodrug strategies,aiming to provide some new insights into the potential applications in site-specific drug synthesis.展开更多
The syntheses and preliminary biological evaluation of a potentially bioreductive A-mustard and paclitaxel conjugate prodrug 3 targeting hypoxic tumor tissue are described. Aromatic nitro group was used as the bio-red...The syntheses and preliminary biological evaluation of a potentially bioreductive A-mustard and paclitaxel conjugate prodrug 3 targeting hypoxic tumor tissue are described. Aromatic nitro group was used as the bio-reductive trigger. Generation of paclitaxel occurred after reduction via a subsequent mechanism of ＂cyclization-cyclization-extrusion＂. The prodrug was stable in PBS （pH = 7.4） and released paclitaxel after chemical reduction of the nitro fimctionality. In aerobic cytotoxicity assays, it exhibited diminished cytotoxicity and is a candidate for further biological evaluation.展开更多
To improve the stability and pharmacokinetic properties,prodrugs of L-ddG（L-2＇,3＇-dideoxy-guanosine）and L-D4G （L-2＇,3＇-dihydro-2＇,3＇-dideoxyguanosine）modified with a series of substituted amino groups at C-6...To improve the stability and pharmacokinetic properties,prodrugs of L-ddG（L-2＇,3＇-dideoxy-guanosine）and L-D4G （L-2＇,3＇-dihydro-2＇,3＇-dideoxyguanosine）modified with a series of substituted amino groups at C-6 position of the purine base were designed and synthesized and their anti-HIV activities were evaluated.Compounds 7d and 8g exhibited moderate activity and showed EC_（50）of 42μmol/L and 55μmol/L,respectively.展开更多
Danshensu [3-(3, 4-dihydroxyphenyl) lactic acid, DSS], one of the significant cardioprotective components, is extracted from the root of Salvia miltiorrhiza. In the present study, an ester prodrug of Danshensu(DSS), p...Danshensu [3-(3, 4-dihydroxyphenyl) lactic acid, DSS], one of the significant cardioprotective components, is extracted from the root of Salvia miltiorrhiza. In the present study, an ester prodrug of Danshensu(DSS), palmitoyl Danshensu(PDSS), was synthesized with the aim to improve its oral bioavailability and prolong its half-life. The in vitro experiments were carried out to evaluate the physicochemical properties and stability of PDSS. Although the solubility of PDSS in water was only 0.055 mg·mL^(-1), its solubility in Fa SSIF and Fe SSIF reached 4.68 and 9.08 mg·mL^(-1), respectively. Octanol-water partition coefficient(log P) was increased from-2.48 of DSS to 1.90 of PDSS. PDSS was relatively stable in the aqueous solution in pH range from 5.6 to 7.4. Furthermore, the pharmacokinetics in rats was evaluated after oral administration of PDSS and DSS. AUC and t1/2 of PDSS were enhanced up to 9.8-fold and 2.2-fold, respectively, compared to that of DSS. Cmax was 1.67 ± 0.11 μg·mL^(-1) for PDSS and 0.81 ± 0.06 μg·m L-1 for DSS. Thus, these results demonstrated that PDSS had much higher oral bioavailability and longer circulation time than its parent drug.展开更多
In order to study the hydrolytic characterization of an anti-inflammatory prodrug （ RI-1 ） in vitro, an effective, accurate and reliable method for the simultaneous determination of the prodrug and its two hydrolyti...In order to study the hydrolytic characterization of an anti-inflammatory prodrug （ RI-1 ） in vitro, an effective, accurate and reliable method for the simultaneous determination of the prodrug and its two hydrolytic active compounds is developed using reverse phase high-performance liquid chromatography （RP-HPLC）. The chromatographic separation is performed on an ODS-2 C18 column （250 mm × 4. 6 mm, 5.0 μm particle size） with a simple elution program. The mobile phase is V（ methanol） ： V（0. 1% phosphoric acid solution） =90：10 （adjust pH to 2. 3）. A wavelength of 225 nm and a mobile phase flow rate of 1.0 mL/min are utilized for the quantitative analysis. Excellent linear behaviors over the investigated concentration ranges are observed with values of R2 higher than 0. 999 for all the analytes. The validated method is successfully applied to the simultaneous determination of the prodrug and its active components can be used to detect hydrolytic characterization in vitro.展开更多
Peramivir was a novel and highly potent neuraminidase(NA) inhibitor for the treatment of influenza A and B. However, it exhibited a very low oral bioavailability(only 3%) due to the high polarity(log P of-1.4) and the...Peramivir was a novel and highly potent neuraminidase(NA) inhibitor for the treatment of influenza A and B. However, it exhibited a very low oral bioavailability(only 3%) due to the high polarity(log P of-1.4) and the low membrane permeability across the intestine. To utilize the PEPT1-mediated prodrug strategy to improve the oral absorption and develop the oral alternative, seven amino acid ester prodrugs and seven amino acid amide prodrugs have been synthesized. The permeability of these prodrugs across Caco-2 cells were screened. Peramivr-(CH_2)_2-l-Val and Peramivir-l-Ile were of the highest permeability in ester prodrugs and amide prodrugs, respectively, and then they were selected for further studies. Glycylsarcosine(gly-sar) uptake by Caco-2 could be inbihited by Peramivir-(CH_2)_2-l-Val and Peramivir-l-Ile in a concentration-dependent manner, and the IC 50 was 1.34 ± 0.31 m M and 1.78 ± 0.48 m M, respectively. The direct uptake of Peramivir-(CH_2)_2-l-Val and Peramivirl-Ile in MDCK-PEPT1 cells were significantly higher than in MDCK mock cells, and could be markedly inhibited by gly-sar. The uptake of Peramivir-(CH_2)_2-l-Val and Peramivir-l-Ile(0.01 to 50 m M) in MDCK-hPEPT1 cells conformed to Michaelis–Menten Equation. The oral bioavailability of peramivir was 65.3% and 37.3% after the oral administration of Peramivir-(CH_2)_2-l-Val and Peramivir-l-Ile to rats, respectively. The oral absorption and bioactivation of Peramivir-(CH_2)_2-l-Val was rapid and extensive, and no Peramivir-(CH_2)_2-l-Val was found in plasma. Because the amide bond was relatively stable, Peramivir-l-Ile could not be totally converted to the parent drug in vivo. Peramivir-(CH_2)_2-l-Val with good oral profiles and rapid bioactivation might be a promising prodrug for the further clinic development. The present study also corroborated the idea that the PEPT1-mediated prodrug approach has enormous promise for improving the oral absorption of poorly absorbed drug.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
16 ADT carboxylate esters were prepared by means of esterification and these compounds were expected to increase the bioavailability of 4-hydroxyanehole trithione.In vivo studies showed that ADT concentration of 3a in...16 ADT carboxylate esters were prepared by means of esterification and these compounds were expected to increase the bioavailability of 4-hydroxyanehole trithione.In vivo studies showed that ADT concentration of 3a in plasma was much higher than that of ATT during 120 min.Compound 3a could reach blood peak values of ADT at 660.6 ng/mL which was about 14 times of that by ATT.Additionally,the acute toxicity assay indicated high safety of compound 3a that the maximum tolerated dose was no less than 3.25 g/kg.展开更多
Tumor cells show acidic conditions compared with normal cells,which further inspires scientist to build nanocarrier responsive to tumor microenvironment(TME)for enhancing tumor therapeutic efficacy.Here,we report a pH...Tumor cells show acidic conditions compared with normal cells,which further inspires scientist to build nanocarrier responsive to tumor microenvironment(TME)for enhancing tumor therapeutic efficacy.Here,we report a pH-sensitive and biocompatible polyprodrug based on dextran-doxorubicin(DOX)prodrug(DOXDT)for enhanced chemotherapy.Highdensity DOX component was covalently decorated on the nanocarrier and the drug molecules could be effectively released in the acidic tumor tissue/cells,improving chemotherapy efficacy.Specifically,a dextran-based copolymer was preliminarily prepared by one-step atom transfer radical polymerization(ATRP);then DOX was conjugated on the copolymer component via pH-responsive hydrazone bond.The structure of DOXDT can be well-controlled.The resulting DOXDT was able to further self-assemble into nanoscale micelles with a hydration diameter of about 32.4 nm,which presented excellent micellar stability.Compared to lipid-based drug delivery system,the DOXDT prodrug showed higher drug load capacity up to 23.6%.In addition,excellent stability and smaller size of the nanocarrier contributed to better tissue permeability and tumor suppressive effects in vivo.Hence,this amphipathic DOXDT prodrug is promising in the development of translational DOX formulations,which would be widely applied in cancer therapy.展开更多
Highly water soluble esters of scutellarin with variable molecular weight polyethylene glycol （PEG） were prepared via PEGylation. The physicochemical properties and the stabilities under different conditions were in...Highly water soluble esters of scutellarin with variable molecular weight polyethylene glycol （PEG） were prepared via PEGylation. The physicochemical properties and the stabilities under different conditions were investigated. By PEG modification, the greatly increased water solubility and desirable partition coefficient of scuteUarin were obtained, and the results showed that these conjugates were potential prodrugs for the oral delivery of scuteUarin.展开更多
To improve the therapeutic effect of rhaponticin （RHA）, a folate receptor （FR） targeted RHA prodrug was designed and regioselectively synthesized by utilizing a hydrophilic peptide spacer linked to folic acid （FA...To improve the therapeutic effect of rhaponticin （RHA）, a folate receptor （FR） targeted RHA prodrug was designed and regioselectively synthesized by utilizing a hydrophilic peptide spacer linked to folic acid （FA） via a releasable disulfide linker. A series of biological evaluation was investigated in vitro and in vivo. The positive results of biological investigations warrant further preclinical study before this novel targeted chemotherapeutic is considered for clinical investigation.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
文摘The review provides an overview of the approaches, applications, and methods for ester prodrugs. Ester prodrugs are pharmacologically inactive compounds in their original form but become active drugs on biotransformation within the body, which offers advantages concerning the solubility, stability, and targeted delivery of the active drug. Several approaches of ester prodrugs have been reviewed in this review, including simple ester prodrugs, amino acid ester prodrugs, sugar ester prodrugs, lipid ester prodrugs, and polymeric ester prodrugs. This review incorporates in vitro and in vivo methods as well as the characterization of physical and chemical properties for ester prodrugs, cell culture systems, enzymatic assays, and animal models—all of these having a very important bearing on the evaluation of stability, bioavailability, and efficacy for ester prodrugs. While the benefits of using ester prodrugs are significant, there are also disadvantages like instability, poor or variable enzymatic hydrolysis, and toxicity from released promoieties or by-products. This review discusses solutions to the various limitations that include enhancing stability with ionizable promoieties and using physiologically-based pharmacokinetic modeling. The review also highlights the application of ester prodrugs in neurological disorders, such as Parkinson’s disease, and the ongoing efforts to address the critical limitations in treatment efficacy. Future prodrug strategies are poised to advance significantly by harnessing diverse transport mechanisms across the blood-brain barrier and integrating nanotechnology.
基金supported by the National Natural Science Foundation of China(82373811,82574333,82504683)Natural Science Foundation of Guangdong Province(2024A1515012132).
文摘Integrating photodynamic therapy(PDT)with immunosuppression reversal represents a promising synergistic approach to boost cancer immunotherapy.However,the complicated components and cumbersome preparation procedures of the currently developed nano drug delivery systems heavily hinder their further clinical translation.Herein,a reactive oxygen species(ROS)/photo dual-responsive amphipathic prodrug(denoted as PPTN)was designed and synthesized by linking NLG919,an indoleamine-2,3-dioxygenase(IDO)inhibitor,with the photosensitizer protoporphyrin IX(PpIX)by a thioketal moiety,and further modifying with mPEG2k.PPTN could self-assemble into nanoscale unimolecular micelles in aqueous solution without additional excipients,increasing tumor accumulation while effectively addressing the pronounced hydrophobicity challenge of PpIX.Upon light exposure,PPTN generated ROS,not only directly damaging cancer cells,but also trigger the breakage of thioketal bond to accelerate simultaneous release of NLG919.Therefore,PPTN potentially act as a promising ROS/photo dual-responsive carrier-free prodrug delivery system for controllable drug release and specific tumor therapy.Moreover,PPTN induced simultaneous PDT-triggered immunogenic cell death(ICD)effect and specific IDO blockade to boost immune response,exhibiting potent suppression efficacy against primary and distant tumors.Overall,with the superiorities of easily controllable preparation procedures,synchronous drug delivery and ROS/photo dual-responsiveness,such a prodrug unimolecular micelle may represent a promising nanoplatform for photoactivated-immunotherapy.
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 Natural Science Foundation of China(No.22271154)Natural Science Foundation of Jiangsu Province(No.BK20211179)+3 种基金Innovation Support Program of Jiangsu Province(No.BZ2023055)Fundamental Research Funds for the Central Universities(No.NS2023033)China Postdoctoral Science Foundation(No.2023M731658)Achievement Transformation Project of Qinghai Province(No.2021-SF-145).
文摘Supramolecular prodrug vesicles(H-4⊃B-2@MB)with selective antibacterial activity have been successfully constructed.Specifically,a natural antibiotic prodrug(B-2)with glutathione(GSH)-responsiveness was synthesized.The hydrophobic interaction between B-2 and a novel water-soluble cavitand with deep cavity(H-4)resulted in the formation of a host-vip complex,which further self-assembled into supramolecular vesicles.The formed vesicles could effectively encapsulate the photosensitizer methylene blue(MB),enabling co-delivery of antibiotics and photosensitizers in the presence of GSH.Moreover,upon excitation at 630 nm,the photosensitizers generate reactive oxygen species(ROS),effectively eradicating E.coli through combined chemo-photodynamic therapy.Considering that GSH is predominantly present in Gram-negative bacteria such as E.coli,this strategy exhibits substantial potential for selectively inhibiting bacteria characterized by high GSH levels to regulate bacterial colony equilibrium.
基金support from the National Natural Science Foundation of China(Grant Nos.:U21A20407 and 81973467).
文摘Prodrugs need to be converted to active drugs to exert their pharmacological activities.Identifying the direct targets of active drugs is essential to elucidate the pharmacological mechanisms of prodrugs,but remains challenging,especially for active drugs with low stability.
文摘Cancer enzymology is a promising filiation of bio-medical sciences. In thepast decades, enzymes, such as GST(glutathione S-transferase) , PKC(protein kinase C) , Topo(DNAtopoisomerases), TK(tyrosine kinase), CD (bacterial cytosine deaminase), CPG2(carboxypeptidase G2) ,and PNP (purine nucleoside phosphorylase), have been known to bear close relations to cancer. Theirspecific expression and influence on the process of tumor initiation, promotion and progressionattract scientists to apply them as a biochemical marker of certain malignant tumor, a predictor ofresponse in cancer chemotherapy; to apply them to drug design, tumor prevention and as adjuvant toradiotherapy or surgery.
基金financially supported by the Shandong Provincial Natural Science Foundation of China(No.ZR2021QC088).
文摘Enzyme prodrug therapies(EPTs)have been intensively explored as attractive approaches to selective activation of systemically administered benign prodrugs by the exogenous enzymes or enzymes expressed at the desired target site,thus achieving localized,site-specific therapeutic effect.Many effective strategies(e.g.,antibody-,viral-,gene-,as well as polymer-directed EPT)have been developed for enzyme localization to locally activate systemically administered benign prodrugs.Nevertheless,intrinsic limitations(e.g.,complex intracellular environment and catalyst instability)make the practical application of EPT strategies a task that presents itself as highly challenging.As a promising alternative to natural enzyme,nanozyme has attracted substantial attention since its discovery in 2007,mainly due to the advantages of robust catalytic activity,high stability,low cost,and facile synthesis.Recently,nanozyme-activated prodrug strategies bring a new opportunity for targeted therapy,referred to as nanozyme-activating prodrug therapies.This review focuses on recently reported nanozyme-activated prodrug strategies,aiming to provide some new insights into the potential applications in site-specific drug synthesis.
基金support from the National Natural Science Foundation of China(Grant No.21272154and30672506)Leading Academic Discipline Project of Shanghai Municipal Education Commission(Project No.J50102)EGVM acknowledges the US National Institutes of Health(NCI grant R01CA116804)
文摘The syntheses and preliminary biological evaluation of a potentially bioreductive A-mustard and paclitaxel conjugate prodrug 3 targeting hypoxic tumor tissue are described. Aromatic nitro group was used as the bio-reductive trigger. Generation of paclitaxel occurred after reduction via a subsequent mechanism of ＂cyclization-cyclization-extrusion＂. The prodrug was stable in PBS （pH = 7.4） and released paclitaxel after chemical reduction of the nitro fimctionality. In aerobic cytotoxicity assays, it exhibited diminished cytotoxicity and is a candidate for further biological evaluation.
基金National Natural Science Foundation of China (Grant No.20472006 and 20832001)
文摘To improve the stability and pharmacokinetic properties,prodrugs of L-ddG（L-2＇,3＇-dideoxy-guanosine）and L-D4G （L-2＇,3＇-dihydro-2＇,3＇-dideoxyguanosine）modified with a series of substituted amino groups at C-6 position of the purine base were designed and synthesized and their anti-HIV activities were evaluated.Compounds 7d and 8g exhibited moderate activity and showed EC_（50）of 42μmol/L and 55μmol/L,respectively.
基金supported by the National Natural Science Foundation of China(No.31371014)
文摘Danshensu [3-(3, 4-dihydroxyphenyl) lactic acid, DSS], one of the significant cardioprotective components, is extracted from the root of Salvia miltiorrhiza. In the present study, an ester prodrug of Danshensu(DSS), palmitoyl Danshensu(PDSS), was synthesized with the aim to improve its oral bioavailability and prolong its half-life. The in vitro experiments were carried out to evaluate the physicochemical properties and stability of PDSS. Although the solubility of PDSS in water was only 0.055 mg·mL^(-1), its solubility in Fa SSIF and Fe SSIF reached 4.68 and 9.08 mg·mL^(-1), respectively. Octanol-water partition coefficient(log P) was increased from-2.48 of DSS to 1.90 of PDSS. PDSS was relatively stable in the aqueous solution in pH range from 5.6 to 7.4. Furthermore, the pharmacokinetics in rats was evaluated after oral administration of PDSS and DSS. AUC and t1/2 of PDSS were enhanced up to 9.8-fold and 2.2-fold, respectively, compared to that of DSS. Cmax was 1.67 ± 0.11 μg·mL^(-1) for PDSS and 0.81 ± 0.06 μg·m L-1 for DSS. Thus, these results demonstrated that PDSS had much higher oral bioavailability and longer circulation time than its parent drug.
文摘In order to study the hydrolytic characterization of an anti-inflammatory prodrug （ RI-1 ） in vitro, an effective, accurate and reliable method for the simultaneous determination of the prodrug and its two hydrolytic active compounds is developed using reverse phase high-performance liquid chromatography （RP-HPLC）. The chromatographic separation is performed on an ODS-2 C18 column （250 mm × 4. 6 mm, 5.0 μm particle size） with a simple elution program. The mobile phase is V（ methanol） ： V（0. 1% phosphoric acid solution） =90：10 （adjust pH to 2. 3）. A wavelength of 225 nm and a mobile phase flow rate of 1.0 mL/min are utilized for the quantitative analysis. Excellent linear behaviors over the investigated concentration ranges are observed with values of R2 higher than 0. 999 for all the analytes. The validated method is successfully applied to the simultaneous determination of the prodrug and its active components can be used to detect hydrolytic characterization in vitro.
基金supported by National Natural Science Founda-tion of China(81360485 and 81560577)National Natural Science Foundation of Jiangxi(20132BAB215023)
文摘Peramivir was a novel and highly potent neuraminidase(NA) inhibitor for the treatment of influenza A and B. However, it exhibited a very low oral bioavailability(only 3%) due to the high polarity(log P of-1.4) and the low membrane permeability across the intestine. To utilize the PEPT1-mediated prodrug strategy to improve the oral absorption and develop the oral alternative, seven amino acid ester prodrugs and seven amino acid amide prodrugs have been synthesized. The permeability of these prodrugs across Caco-2 cells were screened. Peramivr-(CH_2)_2-l-Val and Peramivir-l-Ile were of the highest permeability in ester prodrugs and amide prodrugs, respectively, and then they were selected for further studies. Glycylsarcosine(gly-sar) uptake by Caco-2 could be inbihited by Peramivir-(CH_2)_2-l-Val and Peramivir-l-Ile in a concentration-dependent manner, and the IC 50 was 1.34 ± 0.31 m M and 1.78 ± 0.48 m M, respectively. The direct uptake of Peramivir-(CH_2)_2-l-Val and Peramivirl-Ile in MDCK-PEPT1 cells were significantly higher than in MDCK mock cells, and could be markedly inhibited by gly-sar. The uptake of Peramivir-(CH_2)_2-l-Val and Peramivir-l-Ile(0.01 to 50 m M) in MDCK-hPEPT1 cells conformed to Michaelis–Menten Equation. The oral bioavailability of peramivir was 65.3% and 37.3% after the oral administration of Peramivir-(CH_2)_2-l-Val and Peramivir-l-Ile to rats, respectively. The oral absorption and bioactivation of Peramivir-(CH_2)_2-l-Val was rapid and extensive, and no Peramivir-(CH_2)_2-l-Val was found in plasma. Because the amide bond was relatively stable, Peramivir-l-Ile could not be totally converted to the parent drug in vivo. Peramivir-(CH_2)_2-l-Val with good oral profiles and rapid bioactivation might be a promising prodrug for the further clinic development. The present study also corroborated the idea that the PEPT1-mediated prodrug approach has enormous promise for improving the oral absorption of poorly absorbed drug.
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.
文摘16 ADT carboxylate esters were prepared by means of esterification and these compounds were expected to increase the bioavailability of 4-hydroxyanehole trithione.In vivo studies showed that ADT concentration of 3a in plasma was much higher than that of ATT during 120 min.Compound 3a could reach blood peak values of ADT at 660.6 ng/mL which was about 14 times of that by ATT.Additionally,the acute toxicity assay indicated high safety of compound 3a that the maximum tolerated dose was no less than 3.25 g/kg.
基金supported by Science and Technology Project from the Science Technology and Innovation Committee of Shenzhen Municipality(JCYJ20170817170110940 and JCJY20170307163529489)the Sichuan Science and Technology Program(2018JY0392 and 2018GZYZF0008)+1 种基金Sanming Project of Medicine in Shenzhen(SZSM201512033)Shenzhen Public Service Platform of Molecular Medicine in Pediatric Hematology and Oncology。
文摘Tumor cells show acidic conditions compared with normal cells,which further inspires scientist to build nanocarrier responsive to tumor microenvironment(TME)for enhancing tumor therapeutic efficacy.Here,we report a pH-sensitive and biocompatible polyprodrug based on dextran-doxorubicin(DOX)prodrug(DOXDT)for enhanced chemotherapy.Highdensity DOX component was covalently decorated on the nanocarrier and the drug molecules could be effectively released in the acidic tumor tissue/cells,improving chemotherapy efficacy.Specifically,a dextran-based copolymer was preliminarily prepared by one-step atom transfer radical polymerization(ATRP);then DOX was conjugated on the copolymer component via pH-responsive hydrazone bond.The structure of DOXDT can be well-controlled.The resulting DOXDT was able to further self-assemble into nanoscale micelles with a hydration diameter of about 32.4 nm,which presented excellent micellar stability.Compared to lipid-based drug delivery system,the DOXDT prodrug showed higher drug load capacity up to 23.6%.In addition,excellent stability and smaller size of the nanocarrier contributed to better tissue permeability and tumor suppressive effects in vivo.Hence,this amphipathic DOXDT prodrug is promising in the development of translational DOX formulations,which would be widely applied in cancer therapy.
基金supported by the National Natural Science Foundation of China(No.30070935,30271614)
文摘Highly water soluble esters of scutellarin with variable molecular weight polyethylene glycol （PEG） were prepared via PEGylation. The physicochemical properties and the stabilities under different conditions were investigated. By PEG modification, the greatly increased water solubility and desirable partition coefficient of scuteUarin were obtained, and the results showed that these conjugates were potential prodrugs for the oral delivery of scuteUarin.
基金supported by the National Scientific Foundation of China(No81001622)
文摘To improve the therapeutic effect of rhaponticin （RHA）, a folate receptor （FR） targeted RHA prodrug was designed and regioselectively synthesized by utilizing a hydrophilic peptide spacer linked to folic acid （FA） via a releasable disulfide linker. A series of biological evaluation was investigated in vitro and in vivo. The positive results of biological investigations warrant further preclinical study before this novel targeted chemotherapeutic is considered for clinical investigation.
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.
