The disulfide bond plays a crucial role in the design of anti-tumor prodrugs due to its exceptional tumor-specific redox responsiveness. However, premature breaking of disulfide bonds is triggered by small amounts of ...The disulfide bond plays a crucial role in the design of anti-tumor prodrugs due to its exceptional tumor-specific redox responsiveness. However, premature breaking of disulfide bonds is triggered by small amounts of reducing substances (e.g., ascorbic acid, glutathione, uric acid and tea polyphenols) in the systemic circulation. This may lead to toxicity, particularly in oral prodrugs that require more frequent and high-dose treatments. Fine-tuning the activation kinetics of these prodrugs is a promising prospect for more efficient on-target cancer therapies. In this study, disulfide, steric disulfide, and ester bonds were used to bridge cabazitaxel (CTX) to an intestinal lymph vessel-directed triglyceride (TG) module. Then, synthetic prodrugs were efficiently incorporated into self-nanoemulsifying drug delivery system (corn oil and Maisine CC were used as the oil phase and Cremophor EL as the surfactant). All three prodrugs had excellent gastric stability and intestinal permeability. The oral bioavailability of the disulfide bond-based prodrugs (CTX-(C)S-(C)S-TG and CTX-S-S-TG) was 11.5- and 19.1-fold higher than that of the CTX solution, respectively, demonstrating good oral delivery efficiency. However, the excessive reduction sensitivity of the disulfide bond resulted in lower plasma stability and safety of CTX-S-S-TG than that of CTX-(C)S-(C)S-TG. Moreover, introducing steric hindrance into disulfide bonds could also modulate drug release and cytotoxicity, significantly improving the anti-tumor activity even compared to that of intravenous CTX solution at half dosage while minimizing off-target adverse effects. Our findings provide insights into the design and fine-tuning of different disulfide bond-based linkers, which may help identify oral prodrugs with more potent therapeutic efficacy and safety for cancer therapy.展开更多
Currently commercial fixed-concomitant three agents have multiple problems such as multiple dosing administration,poor efficacy and side effects.Once-daily fixed-combination timolol-netarsudil-latanoprost ophthalmic s...Currently commercial fixed-concomitant three agents have multiple problems such as multiple dosing administration,poor efficacy and side effects.Once-daily fixed-combination timolol-netarsudil-latanoprost ophthalmic solution(FC-TNL)has the ability to treat glaucoma by lowering the intraocular pressure(IOP)with great efficacy and improving patient compliance.However,the commercialized netarsudil dimesylate precipitated when the p H of the solution was above 5.4,or when maleic acid,the salt of commercial timolol maleate,was mixed with netarsudil dimesylate.Consequently,the homologous salt engineering strategy was used to make netarsudil dimesylate soluble in p H 4.8–5.2 solution by synthesizing timolol mesylate.Next,the morphology of timolol mesylate was observed by scanning electron microscopy,differential scanning calorimetry,thermogravimetric analysis,and powder X-ray diffraction.The prepared FC-TNL showed good stability during refrigeration storage.Additionally,FC-TNL exerted no influence on the intraocular penetration of each active compounds in the pharmacokinetic study.Importantly,oncedaily FC-TNL exerted potent IOP-lowering effect and protective effect on retinal ganglion cells.The FC-TNL was stable,safe and effective,being a promising glaucoma therapeutic.展开更多
Small-molecule prodrug nanoassemblies have emerged as efficient antitumor drug delivery systems.However,in the case of camptothecins-based prodrug nanoassemblies,linear aliphatic side chain modification often results ...Small-molecule prodrug nanoassemblies have emerged as efficient antitumor drug delivery systems.However,in the case of camptothecins-based prodrug nanoassemblies,linear aliphatic side chain modification often results in rod-shaped or irregularly shaped nanoassemblies,which are highly unfavorable for sterilization through filtration,and may cause capillary blockage upon intravenous injection.The rational design of camptothecins-based prodrug nanoassemblies remains a challenge.Herein,we propose that branched aliphatic alcohol(BAA)functionalization could fine-tune the structure-tolerance-antitumor efficacy axis of prodrug nanoassemblies.Correspondingly,four SN38-BAA prodrugs were synthesized by conjugating 7-ethyl-10-hydroxycamptothecin(SN38)with BAAs of varying lengths via a tumor redox-responsive disulfide bond,which self-assemble into uniform spherical nanoparticles.The length of BAA was found to significant impact the multiple drug delivery process,including colloidal stability,drug release profiles and pharmacokinetics.Overall,SN38-C21 NPs(SN38-11-heneicosanol nanoparticles),featuring the longest BAA,showcased multiple therapeutic advantages,ultimately culminating the optimal antitumor efficacy and tolerance.The findings underscore the potential of BAA functionalization in strengthening the therapeutic outcomes of prodrug nanoassemblies,and provide valuable insights for developing translational camptothecins-based nanomedicines.展开更多
Erratum to Nano Research 2022,15(10):9092-9104 https://doi.org/10.1007/s12274-022-4544-7 Figure 9 was unfortunately mistakenly typeset.This error did not affect any of the conclusions from the published paper.
The unique characteristics of the tumor microenvironment(TME)could be exploited to develop antitumor nanomedicine strategies.However,in many cases,the actual therapeutic effect is far from reaching our expectations du...The unique characteristics of the tumor microenvironment(TME)could be exploited to develop antitumor nanomedicine strategies.However,in many cases,the actual therapeutic effect is far from reaching our expectations due to the notable tumor heterogeneity.Given the amplified characteristics of TME regulated by vascular disrupting agents(VDAs),nanomedicines may achieve unexpected improved efficacy.Herein,we fabricate platelet membrane-fusogenic liposomes(PML/DP&PPa),namely“platesomes”,which actively load the hypoxia-activated pro-prodrug DMG-PR104A(DP)and physically encapsulate the photosensitizer pyropheophorbide a(PPa).Considering the different stages of tumor vascular collapse and shutdown induced by a VDA combretastatin-A4 phosphate(CA4P),PML/DP&PPa is injected 3 h after intraperitoneal administration of CA4P.First,CA4P-mediated tumor hemorrhage amplifies the enhanced permeation and retention(EPR)effect,and the platesome-biological targeting further promotes the tumor accumulation of PML/DP&PPa.Besides,CA4P-induced vascular occlusion inhibits oxygen supply,followed by photodynamic therapy-caused acute tumor hypoxia.This prolonged extreme hypoxia contributes to the complete activation of DP and then high inhibitory effect on tumor growth and metastasis.Thus,such a combining strategy of artificially-regulated TME and bio-inspired platesomes pronouncedly improves tumor drug delivery and boosts tumor hypoxia-selective activation,and provides a preferable solution to high-efficiency cancer therapy.展开更多
The reduction-responsive disulfide bonds have been widely used as bioactive linkages to facilitate a rapid release of anticancer drugs into tumor cells.However,the activation can be hindered by the kinetics of the thi...The reduction-responsive disulfide bonds have been widely used as bioactive linkages to facilitate a rapid release of anticancer drugs into tumor cells.However,the activation can be hindered by the kinetics of the thiol-disulfide exchange reactions.Supplementing with an additional reductant is a promising strategy to further boost drug release.Herein,inspired by the specific absorption mechanism of triglyceride fat,structured lipid-mimetic oral prodrugs of 7-ethyl-10-hydroxycamptothecin(SN38)were designed to improve intestinal permeability and bypass the first-pass effect.SN38 prodrugs were prepared into lipid formulations that could self-emulsify into nano-sized particles after entering the gastrointestinal tract.Surprisingly,we found that the oral bioavailability of the prodrug lipid formulation could be up to 2.69-fold higher than that of the parent SN38,indicating an effective oral delivery.In addition,the reduction-responsive disulfide bond was used as a linker,and ascorbic acid(ASC)was coadministrated to further promote the efficient release of SN38 from the prodrug.ASC enhanced the oral antitumor effect of the reduction-responsive oral prodrug and exhibited good safety.In summary,the combination of a structured lipid-mimetic prodrug and ASC was firstly demonstrated to boost the oral chemotherapy effect of the difficult-for-oral chemotherapeutics.展开更多
基金supported by National Natural Science Foundation of China(No.82173766,82104109)Natural Science Foundation of Liaoning Province(2022-BS158)+1 种基金Liaoning Province Applied Basic Research Program(No.2022JH2/101300097)National Key R&D Program of China(No.2022YFE0111600).
文摘The disulfide bond plays a crucial role in the design of anti-tumor prodrugs due to its exceptional tumor-specific redox responsiveness. However, premature breaking of disulfide bonds is triggered by small amounts of reducing substances (e.g., ascorbic acid, glutathione, uric acid and tea polyphenols) in the systemic circulation. This may lead to toxicity, particularly in oral prodrugs that require more frequent and high-dose treatments. Fine-tuning the activation kinetics of these prodrugs is a promising prospect for more efficient on-target cancer therapies. In this study, disulfide, steric disulfide, and ester bonds were used to bridge cabazitaxel (CTX) to an intestinal lymph vessel-directed triglyceride (TG) module. Then, synthetic prodrugs were efficiently incorporated into self-nanoemulsifying drug delivery system (corn oil and Maisine CC were used as the oil phase and Cremophor EL as the surfactant). All three prodrugs had excellent gastric stability and intestinal permeability. The oral bioavailability of the disulfide bond-based prodrugs (CTX-(C)S-(C)S-TG and CTX-S-S-TG) was 11.5- and 19.1-fold higher than that of the CTX solution, respectively, demonstrating good oral delivery efficiency. However, the excessive reduction sensitivity of the disulfide bond resulted in lower plasma stability and safety of CTX-S-S-TG than that of CTX-(C)S-(C)S-TG. Moreover, introducing steric hindrance into disulfide bonds could also modulate drug release and cytotoxicity, significantly improving the anti-tumor activity even compared to that of intravenous CTX solution at half dosage while minimizing off-target adverse effects. Our findings provide insights into the design and fine-tuning of different disulfide bond-based linkers, which may help identify oral prodrugs with more potent therapeutic efficacy and safety for cancer therapy.
基金financially supported by the Liao Ning Revitalization Talents Program(XLYC1902061)。
文摘Currently commercial fixed-concomitant three agents have multiple problems such as multiple dosing administration,poor efficacy and side effects.Once-daily fixed-combination timolol-netarsudil-latanoprost ophthalmic solution(FC-TNL)has the ability to treat glaucoma by lowering the intraocular pressure(IOP)with great efficacy and improving patient compliance.However,the commercialized netarsudil dimesylate precipitated when the p H of the solution was above 5.4,or when maleic acid,the salt of commercial timolol maleate,was mixed with netarsudil dimesylate.Consequently,the homologous salt engineering strategy was used to make netarsudil dimesylate soluble in p H 4.8–5.2 solution by synthesizing timolol mesylate.Next,the morphology of timolol mesylate was observed by scanning electron microscopy,differential scanning calorimetry,thermogravimetric analysis,and powder X-ray diffraction.The prepared FC-TNL showed good stability during refrigeration storage.Additionally,FC-TNL exerted no influence on the intraocular penetration of each active compounds in the pharmacokinetic study.Importantly,oncedaily FC-TNL exerted potent IOP-lowering effect and protective effect on retinal ganglion cells.The FC-TNL was stable,safe and effective,being a promising glaucoma therapeutic.
基金supported by National Natural Science Foundation of China(Nos.82272151,82204318 and 82173766)Doctoral Scientific Research Staring Foundation of Liaoning Province(No.2021-BS-130)+1 种基金General Program of Department of Education of Liaoning Province(No.LJKZ0953)Shenyang Young and Middle-aged Science and Technology Innovation Talent Support Program(No.RC220389).
文摘Small-molecule prodrug nanoassemblies have emerged as efficient antitumor drug delivery systems.However,in the case of camptothecins-based prodrug nanoassemblies,linear aliphatic side chain modification often results in rod-shaped or irregularly shaped nanoassemblies,which are highly unfavorable for sterilization through filtration,and may cause capillary blockage upon intravenous injection.The rational design of camptothecins-based prodrug nanoassemblies remains a challenge.Herein,we propose that branched aliphatic alcohol(BAA)functionalization could fine-tune the structure-tolerance-antitumor efficacy axis of prodrug nanoassemblies.Correspondingly,four SN38-BAA prodrugs were synthesized by conjugating 7-ethyl-10-hydroxycamptothecin(SN38)with BAAs of varying lengths via a tumor redox-responsive disulfide bond,which self-assemble into uniform spherical nanoparticles.The length of BAA was found to significant impact the multiple drug delivery process,including colloidal stability,drug release profiles and pharmacokinetics.Overall,SN38-C21 NPs(SN38-11-heneicosanol nanoparticles),featuring the longest BAA,showcased multiple therapeutic advantages,ultimately culminating the optimal antitumor efficacy and tolerance.The findings underscore the potential of BAA functionalization in strengthening the therapeutic outcomes of prodrug nanoassemblies,and provide valuable insights for developing translational camptothecins-based nanomedicines.
文摘Erratum to Nano Research 2022,15(10):9092-9104 https://doi.org/10.1007/s12274-022-4544-7 Figure 9 was unfortunately mistakenly typeset.This error did not affect any of the conclusions from the published paper.
基金financially supported by the National Natural Science Foundation of China(No.81773656)Liaoning Revitalization Talents Program(No.XLYC1808017,China)+1 种基金Shenyang Youth Science and Technology Innovation Talents Program(No.RC190454,China)College Student Innovation and Entrepreneurship Training Program of Shenyang Pharmaceutical University(No.X202010163141,China)。
文摘The unique characteristics of the tumor microenvironment(TME)could be exploited to develop antitumor nanomedicine strategies.However,in many cases,the actual therapeutic effect is far from reaching our expectations due to the notable tumor heterogeneity.Given the amplified characteristics of TME regulated by vascular disrupting agents(VDAs),nanomedicines may achieve unexpected improved efficacy.Herein,we fabricate platelet membrane-fusogenic liposomes(PML/DP&PPa),namely“platesomes”,which actively load the hypoxia-activated pro-prodrug DMG-PR104A(DP)and physically encapsulate the photosensitizer pyropheophorbide a(PPa).Considering the different stages of tumor vascular collapse and shutdown induced by a VDA combretastatin-A4 phosphate(CA4P),PML/DP&PPa is injected 3 h after intraperitoneal administration of CA4P.First,CA4P-mediated tumor hemorrhage amplifies the enhanced permeation and retention(EPR)effect,and the platesome-biological targeting further promotes the tumor accumulation of PML/DP&PPa.Besides,CA4P-induced vascular occlusion inhibits oxygen supply,followed by photodynamic therapy-caused acute tumor hypoxia.This prolonged extreme hypoxia contributes to the complete activation of DP and then high inhibitory effect on tumor growth and metastasis.Thus,such a combining strategy of artificially-regulated TME and bio-inspired platesomes pronouncedly improves tumor drug delivery and boosts tumor hypoxia-selective activation,and provides a preferable solution to high-efficiency cancer therapy.
基金supported by the National Key Research and Development Program of China(No.2021YFA0909900)the National Natural Science Foundation of China(Nos.82073777,82104109,and 82173766).
文摘The reduction-responsive disulfide bonds have been widely used as bioactive linkages to facilitate a rapid release of anticancer drugs into tumor cells.However,the activation can be hindered by the kinetics of the thiol-disulfide exchange reactions.Supplementing with an additional reductant is a promising strategy to further boost drug release.Herein,inspired by the specific absorption mechanism of triglyceride fat,structured lipid-mimetic oral prodrugs of 7-ethyl-10-hydroxycamptothecin(SN38)were designed to improve intestinal permeability and bypass the first-pass effect.SN38 prodrugs were prepared into lipid formulations that could self-emulsify into nano-sized particles after entering the gastrointestinal tract.Surprisingly,we found that the oral bioavailability of the prodrug lipid formulation could be up to 2.69-fold higher than that of the parent SN38,indicating an effective oral delivery.In addition,the reduction-responsive disulfide bond was used as a linker,and ascorbic acid(ASC)was coadministrated to further promote the efficient release of SN38 from the prodrug.ASC enhanced the oral antitumor effect of the reduction-responsive oral prodrug and exhibited good safety.In summary,the combination of a structured lipid-mimetic prodrug and ASC was firstly demonstrated to boost the oral chemotherapy effect of the difficult-for-oral chemotherapeutics.