Various drug transporters are widely expressed throughout the intestine and play important roles in absorbing nutrients and drugs,thus providing high quality targets for the design of prodrugs or nanoparticles to faci...Various drug transporters are widely expressed throughout the intestine and play important roles in absorbing nutrients and drugs,thus providing high quality targets for the design of prodrugs or nanoparticles to facilitate oral drug delivery.In particular,intestinal carnitine/organic cation transporter 2(OCTN2)and mono-carboxylate transporter protein 1(MCT1)possess high transport capacities and complementary distributions.Therefore,we outline recent developments in transporter-targeted oral drug delivery with regard to the OCTN2 and MCT1 proteins in this review.First,basic information of the two transporters is reviewed,including their topological structures,characteristics and functions,expression and key features of their substrates.Furthermore,progress in transporter-targeting prodrugs and nanoparticles to increase oral drug delivery is discussed,including improvements in the oral absorption of anti-inflammatory drugs,antiepileptic drugs and anticancer drugs.Finally,the potential of a dual transporter-targeting strategy is discussed.展开更多
The purpose of this study was to prepare the oleanolic acid–phospholipid complex (OAPC) and then solidify it employing fumed silica by simple solvent evaporation technique to improve dissolution rate of oleanolic aci...The purpose of this study was to prepare the oleanolic acid–phospholipid complex (OAPC) and then solidify it employing fumed silica by simple solvent evaporation technique to improve dissolution rate of oleanolic acid and oleanolic acid–phospholipid complex. The process of OA-PC was optimized and the type and proportion of fumed silica were studied by dissolution text. The structures of the phospholipid complex and solidified powder were also characterized by differential scanning calorimetry, X-ray diffraction, and scanning electron microscope. In the dissolution tests, OA from solidified powder was further released compared with that from pure OA and OA-PC in different kinds of dissolution media. These results suggest that the method of preparing solidified powder of oleanolic acid–phospholipid complex is suitable for enhancing the dissolution rate of OA and OA-PC.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
Monocarboxylate transporter 1(MCT1)is responsible for oral absorption of short-chain monocarboxylic acids from small intestine,hence,it’s likely to serve as an ideal design target for the development of oral prodrugs...Monocarboxylate transporter 1(MCT1)is responsible for oral absorption of short-chain monocarboxylic acids from small intestine,hence,it’s likely to serve as an ideal design target for the development of oral prodrugs.However,potential application of MCT1 to facilitate the oral delivery is still unclear.Irregular oral absorption,poor permeability and bioavailability greatly limit the oral delivery efficiency of 5-fluorouracil(5-FU).Herein,we design three 5-FU-fatty acid conjugates targeting intestinal MCT1 with different lipophilic linkages.Interestingly,due to high MCT1 affinity and good gastrointestinal stability,5-FUoctanedioic acid monoester prodrug exhibited significant improvement in membrane permeability(13.1-fold)and oral bioavailability(4.1-fold)compared to 5-FU.More surprisingly,stability experiment in intestinal homogenates showed that 5-FU prodrugs could be properly activated to release 5-FU within intestinal cells,which provides an ideal foundation for the improvement of oral bioavailability.In summary,good gastrointestinal stability,high membrane permeability and appropriate intestinal cell bioactivation are the important factors for high-efficiency 5-FU oral prodrugs,and such work provides a good platform for the development of novel oral prodrugs targeting intestinal transporters.展开更多
The therapeutic strategy that gives consideration to the combination of photodynamic therapy and chemotherapy,has emerged as a potential development of effective anti-cancer medicine.Nevertheless,co-delivery of photos...The therapeutic strategy that gives consideration to the combination of photodynamic therapy and chemotherapy,has emerged as a potential development of effective anti-cancer medicine.Nevertheless,co-delivery of photosensitizers(PSs)and chemotherapeutic drugs in traditional carriers still remains great limitations due to low drug loadings and poor biocompatibility.Herein,we have utilized a computer-aided strategy to achieve a desired carrier-free self-delivery of pyropheophorbide a(PPa,a common PS)and podophyllotoxin(PPT,a classical chemotherapeutic drug)for synergistic cancer therapy.First,the computational simulation method identified the similar molecular sizes and rigid molecular structures between two drugs molecules.Based on the molecular docking,the intermolecular interactions were found to includeπ-πstackings,hydrophobic interactions and hydrogen bonds.Next,both drugs could co-assemble into nanoparticles(NPs)via one-step nanoprecipitation method.The various spectral experiments(UV,IR and FL)were conducted to evaluate the formation mechanism of spherical NPs.Moreover,in vitro and in vivo experiments systematically demonstrated that PPT/PPa NPs not only showed better cellular uptake efficiency,stronger cytotoxicity and higher accumulation in tumor sites,but also exhibited synergistic antitumor effect in female BALB/C bearing-4T1 tumor mice.Such a computer-aided design strategy of chem-photodynamic drugs self-delivery systems pave the way for efficient synergistic cancer therapy.展开更多
The non-selective cytotoxicity of toxins limits the clinical relevance of the toxins.In recent years,toxins have been widely used as warheads for antibody-drug conjugates(ADCs)due to their eff-cient killing activity a...The non-selective cytotoxicity of toxins limits the clinical relevance of the toxins.In recent years,toxins have been widely used as warheads for antibody-drug conjugates(ADCs)due to their eff-cient killing activity against various cancer cells.Although ADCs confer certain targeting properties to the toxins,low drug loading capacity,possible immunogenicity,and other drawbacks also limit the po-tential application of ADCs.Recently,non-ADC delivery strategies for toxins have been extensively investigated.To further understand the application of toxins in anti-tumor,this paper provided an over-view of prodrugs,nanodrug delivery systems,and biomimetic drug delivery systems.In addition,toxins and their combination strategies with other therapies were discussed.Finally,the prospect and challenge of toxins in cancertreatmentwerealso summarized.展开更多
Small interfering RNA(siRNA)-based gene silencing has been considered as a potential therapy modality against inflammatory diseases.Nevertheless,the effective delivery of siRNA to desired destination still remains cha...Small interfering RNA(siRNA)-based gene silencing has been considered as a potential therapy modality against inflammatory diseases.Nevertheless,the effective delivery of siRNA to desired destination still remains challenging due to poor stability,high molecular weight and negative charge.Currently,ionizable lipid nanoparticle(LNP)has been extensively used as vector for effective delivery of siRNA.Herein,we report a mannose-modified LNP(M-MC_(3) LNP@TNFα)loading tumor necrosis factorα(TNFα)siRNA for targeting liver macrophages,achieving effectively inhibit acute liver injury.The M-MC_(3) LNP@TNFαnot only increases the internalization of LNP by macrophages,but also enhances the gene silencing efficiency of TNFαin vitro.Additionally,the M-MC_(3) LNP@TNFαexhibits higher accumulation in liver of healthy mice than that of MC_(3) LNP@TNFα(un-modified LNP)owing to the targeting effect of mannose.As expected,the M-MC_(3) LNP@TNFαsignificantly suppresses the expression of TNFαand ameliorates liver damage in acute liver injury model.Such a LNP targeting siRNA delivery holds great potential for the treatment of diseases associated with liver in the future.展开更多
Tumor sentinel lymph node(SLN)metastasis plays a vital role in tumor staging and therapeutic decision-making process.However,precise diagnosis of primary tumors and lymphatic metastases is still hindered by low imagin...Tumor sentinel lymph node(SLN)metastasis plays a vital role in tumor staging and therapeutic decision-making process.However,precise diagnosis of primary tumors and lymphatic metastases is still hindered by low imaging resolution and poor photostability of fluorescent probes.Herein,we report three novel IR820-fatty acid(FA)conjugates(IR-OA,IR-LA,and IR-PA)for precise lymphatic metastasis illumination and primary tumor diagnosis.The IR-FA conjugates are able to non-covalently bound to albumin in vivo,and the fluorescence quantum yield is significantly enhanced after incubation with bovine serum albumin(BSA)in vitro.Moreover,the BSA-IR-FA conjugates display large Stokes shift(>120 nm),dramatically improving in vivo imaging resolution.Among them,IR-PA demonstrates distinct advantage over IR-OA,IR-LA,and IR-maleimide(MAL)(fluorescent probe previously reported by our group)in terms of fluorescence quantum yield,photostability,and imaging resolution.As a result,IR-PA exhibits satisfactory imaging results with high fluorescence intensity and imaging resolution in sentinel lymph node metastasis illumination and primary tumor location.Our findings provide a self-adaptive albumin-binding near-infrared probe conjugate for accurate diagnosis of primary tumors and lymphatic metastases.展开更多
Hypoxia, a salient feature of most solid tumors, confers invasiveness and resistance to the tumor cells. Oxygen-consumption photodynamic therapy(PDT) suffers from the undesirable impediment of local hypoxia in tumors....Hypoxia, a salient feature of most solid tumors, confers invasiveness and resistance to the tumor cells. Oxygen-consumption photodynamic therapy(PDT) suffers from the undesirable impediment of local hypoxia in tumors. Moreover, PDT could further worsen hypoxia. Therefore, developing effective strategies for manipulating hypoxia and improving the effectiveness of PDT has been a focus on antitumor treatment. In this review, the mechanism and relationship of tumor hypoxia and PDT are discussed.Moreover, we highlight recent trends in the field of nanomedicines to modulate hypoxia for enhancing PDT, such as oxygen supply systems, down-regulation of oxygen consumption and hypoxia utilization.Finally, the opportunities and challenges are put forward to facilitate the development and clinical transformation of PDT.展开更多
Substantial progress in the use of chemo-photodynamic nano-drug delivery systems(nanoDDS) for the treatment of the malignant breast cancer has been achieved. The inability to customize precise nanostructures, however,...Substantial progress in the use of chemo-photodynamic nano-drug delivery systems(nanoDDS) for the treatment of the malignant breast cancer has been achieved. The inability to customize precise nanostructures, however, has limited the therapeutic efficacy of the prepared nano-DDS to date. Here,we report a structurally defined tandem-responsive chemo-photosensitive co-nanoassembly to eliminate primary breast tumor and prevent lung metastasis. This both-in-one co-nanoassembly is prepared by assembling a biocompatible photosensitive derivative(pheophorbide-diphenylalanine peptide, PPADA) with a hypoxia-activated camptothecin(CPT) prodrug [(4-nitrophenyl) formate camptothecin, NCPT]. According to computational simulations, the co-assembly nanostructure is not the classical core-shell type, but consists of many small microphase regions. Upon exposure to a 660 nm laser,PPA-DA induce high levels of ROS production to effectively achieve the apoptosis of normoxic cancer cells. Subsequently, the hypoxia-activated N-CPT and CPT spatially penetrate deep into the hypoxic region of the tumor and suppress hypoxia-induced tumor metastasis. Benefiting from the rational design of the chemo-photodynamic both-in-one nano-DDS, these nanomedicines exhibit a promising potential in the inhibition of difficult-to-treat breast tumor metastasis in patients with breast cancer.展开更多
Tumor hypoxia is one of the major factors restricting the photodynamic therapy(PDT)efficacy.To address this problem,we designed an arginine-peptide complex,namely Fluorenylmethoxycarbonyl-Leucine-Leucine-Leucine-Argin...Tumor hypoxia is one of the major factors restricting the photodynamic therapy(PDT)efficacy.To address this problem,we designed an arginine-peptide complex,namely Fluorenylmethoxycarbonyl-Leucine-Leucine-Leucine-Arginine-OH(Fmoc-L_(3)-Arg),which is able to co-assemble with 5,10,15,20-Tetrakis(4-hydroxyphenyl)porphyrin(THPP)into stable nanoparticles(NPs)with uniform and spherical shapes.The THPP/Fomc-L_(3)-Arg NPs were ultra-sensitive to tumorous acidic and oxidative conditions,and could rapidly release photosensitizers in tumor cells.Meanwhile,the co-loaded Fmoc-L_(3)-Arg could efficiently generate nitric oxide(NO),inhibiting mitochondrial cellular respiration and increasing oxygen in tumor cells to support the profound improvement of reactive oxygen species(ROS)yield and PDT efficacy.After intravenous injection,the THPP/Fomc-L_(3)-Arg NPs greatly accumulated at tumor tissue and significantly inhibited tumor growth upon irradiation.In conclusion,such an arginine-peptide complex-based nanoassembly addresses the inevitable problem of hypoxia-induced tumor resistance to PDT.展开更多
Mitochondrial bioenergy plays a vital role in the occurrence and development of cancer.Although strategies to impede mitochondrial energy supply have been rapidly developed,the anticancer efficacy is still far from sa...Mitochondrial bioenergy plays a vital role in the occurrence and development of cancer.Although strategies to impede mitochondrial energy supply have been rapidly developed,the anticancer efficacy is still far from satisfactory,mainly attributed to the hybrid metabolic pathways of mitochondrial oxidative phosphorylation(OXPHOS)and glycolysis.Herein,we construct a cancer cell membrane camouflaged nano-inhibitor,mTPPa-Sy nanoparticle(NP),which co-encapsulates OXPHOS inhibitor(mitochondrial-targeting photosensitizers:TPPa)and glycolysis inhibitor(syrosingopine(Sy))for synergistically blocking the two different energy pathways.The mTPPa-Sy NPs exhibit precision tumor-targeting due to the high affinity between the biomimic membrane and the homotypic cancer cells.Under laser irradiation,the mitochondrial-targeting TPPa,which is synthesized by conjugating pyropheophorbide a(PPa)with triphenylphosphin,produces excessive reactive oxygen species(ROS)and further disrupts the OXPHOS.Interestingly,OXPHOS inhibition reduces O_(2) consumption and improves ROS production,further constructing a closed-loop OXPHOS inhibition system.Moreover,TPPa-initiated OXPHOS inhibition in combination with the Sytriggered glycolysis inhibition results in lethal energy depletion,significantly suppressing tumor growth even after a single treatment.Our findings highlight the necessity and effectiveness of synergetic lethal energy depletion,providing a prospective strategy for efficient cancer therapy.展开更多
Inflammatory bowel disease(IBD)is a chronic and recurrent disease of the gastrointestinal tract,mainly including Crohn's disease(CD)and ulcerative colitis(UC).However,current approaches against IBD do not precisel...Inflammatory bowel disease(IBD)is a chronic and recurrent disease of the gastrointestinal tract,mainly including Crohn's disease(CD)and ulcerative colitis(UC).However,current approaches against IBD do not precisely deliver drugs to the inflammatory site,which leads to life-long medication and serious side effects that can adversely impact patients’adherence.It is necessary to construct optimal drug delivery systems(DDSs)that can target drugs to the region of inflammation,thereby improve therapeutic efficacy and reduce side effects.With the burgeoning development of nanotechnology-based nanomedicines(NMs)and prodrug strategy,remarkable progresses in the treatment of IBD have been made in recent years.Herein,the latest advances are outlined at the intersection of IBD treatment and nanotherapeutics as well as prodrug therapy.First,the pathophysiological microenvironment of inflammatory sites of IBD is introduced in order to rationally design potential NMs and prodrugs.Second,the necessity of NMs for the IBD therapy is elaborated,and the representative nanotherapeutics via passive targeted and active targeted NMs developed to treat the IBD are overviewed.Furthermore,the emerging prodrug-based therapeutics are summarized,including 5-aminosalicylic acid-,amino acid-,and carbohydrate-conjugated prodrugs.Finally,the design considerations and perspectives of these NMs and prodrugs-driven IBD therapeutics in the clinical translation are spotlighted.展开更多
基金This work was financially supported by the Natural Science Foundation of Guangxi Province(Nos.2018JJB140325,2018JJB140377)Guangxi Scientific and Technology Base and Talents of Project(Nos.2018AD19035)+2 种基金Talents Project for Cultivating High-level Talent Teams in the Qi Huang Project of Guangxi University of Chinese Medicine(2018002)the specific subject of the dominant discipline construction of Chinese Pharmacy of Guangxi University of Chinese Medicine,Guang Xi Key Laboratory of Translational Medicine for Treating High-incidence Infectious Diseases with Integrative Medicine and School research projects(no.B170021,2018MS003)Scientific Research Projects of Guangxi University of Chinese Medicine(B170021,2018MS003).
文摘Various drug transporters are widely expressed throughout the intestine and play important roles in absorbing nutrients and drugs,thus providing high quality targets for the design of prodrugs or nanoparticles to facilitate oral drug delivery.In particular,intestinal carnitine/organic cation transporter 2(OCTN2)and mono-carboxylate transporter protein 1(MCT1)possess high transport capacities and complementary distributions.Therefore,we outline recent developments in transporter-targeted oral drug delivery with regard to the OCTN2 and MCT1 proteins in this review.First,basic information of the two transporters is reviewed,including their topological structures,characteristics and functions,expression and key features of their substrates.Furthermore,progress in transporter-targeting prodrugs and nanoparticles to increase oral drug delivery is discussed,including improvements in the oral absorption of anti-inflammatory drugs,antiepileptic drugs and anticancer drugs.Finally,the potential of a dual transporter-targeting strategy is discussed.
文摘The purpose of this study was to prepare the oleanolic acid–phospholipid complex (OAPC) and then solidify it employing fumed silica by simple solvent evaporation technique to improve dissolution rate of oleanolic acid and oleanolic acid–phospholipid complex. The process of OA-PC was optimized and the type and proportion of fumed silica were studied by dissolution text. The structures of the phospholipid complex and solidified powder were also characterized by differential scanning calorimetry, X-ray diffraction, and scanning electron microscope. In the dissolution tests, OA from solidified powder was further released compared with that from pure OA and OA-PC in different kinds of dissolution media. These results suggest that the method of preparing solidified powder of oleanolic acid–phospholipid complex is suitable for enhancing the dissolution rate of OA and OA-PC.
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financially Supported by National Nature Sci-ence Foundation of China(No.81773656,U1608283,81573497)Liaoning Revitalization Talents Program,No XLYC1808017,Key projects of Technology bureau in Shenyang,No18400408Key projects of Liaoning Province Department of Education,No.2017LZD03
文摘Monocarboxylate transporter 1(MCT1)is responsible for oral absorption of short-chain monocarboxylic acids from small intestine,hence,it’s likely to serve as an ideal design target for the development of oral prodrugs.However,potential application of MCT1 to facilitate the oral delivery is still unclear.Irregular oral absorption,poor permeability and bioavailability greatly limit the oral delivery efficiency of 5-fluorouracil(5-FU).Herein,we design three 5-FU-fatty acid conjugates targeting intestinal MCT1 with different lipophilic linkages.Interestingly,due to high MCT1 affinity and good gastrointestinal stability,5-FUoctanedioic acid monoester prodrug exhibited significant improvement in membrane permeability(13.1-fold)and oral bioavailability(4.1-fold)compared to 5-FU.More surprisingly,stability experiment in intestinal homogenates showed that 5-FU prodrugs could be properly activated to release 5-FU within intestinal cells,which provides an ideal foundation for the improvement of oral bioavailability.In summary,good gastrointestinal stability,high membrane permeability and appropriate intestinal cell bioactivation are the important factors for high-efficiency 5-FU oral prodrugs,and such work provides a good platform for the development of novel oral prodrugs targeting intestinal transporters.
基金This work was supported by National Natural Science Foundation of China(nos.81872816,81773656,U1608283)Liaoning Revitalization Talents Program,No XLYC1808017.
文摘The therapeutic strategy that gives consideration to the combination of photodynamic therapy and chemotherapy,has emerged as a potential development of effective anti-cancer medicine.Nevertheless,co-delivery of photosensitizers(PSs)and chemotherapeutic drugs in traditional carriers still remains great limitations due to low drug loadings and poor biocompatibility.Herein,we have utilized a computer-aided strategy to achieve a desired carrier-free self-delivery of pyropheophorbide a(PPa,a common PS)and podophyllotoxin(PPT,a classical chemotherapeutic drug)for synergistic cancer therapy.First,the computational simulation method identified the similar molecular sizes and rigid molecular structures between two drugs molecules.Based on the molecular docking,the intermolecular interactions were found to includeπ-πstackings,hydrophobic interactions and hydrogen bonds.Next,both drugs could co-assemble into nanoparticles(NPs)via one-step nanoprecipitation method.The various spectral experiments(UV,IR and FL)were conducted to evaluate the formation mechanism of spherical NPs.Moreover,in vitro and in vivo experiments systematically demonstrated that PPT/PPa NPs not only showed better cellular uptake efficiency,stronger cytotoxicity and higher accumulation in tumor sites,but also exhibited synergistic antitumor effect in female BALB/C bearing-4T1 tumor mice.Such a computer-aided design strategy of chem-photodynamic drugs self-delivery systems pave the way for efficient synergistic cancer therapy.
基金This work was supported by the National Postdoctoral Foundation of China(No.2023M730375)Liaoning Province Department of Education Project(No.LJKMZ20221365,China)+3 种基金the State Key Laboratory of Natural and Biomimetic Drugs(No.K202215,China)the National Natural Science Foundation of China(No.82173766)Liaoning Province Applied Basic Research Program(No.2022JH2/101300097,China)the Natural Science Foundation of Shandong Province(No.ZR2021QH084,China)。
文摘The non-selective cytotoxicity of toxins limits the clinical relevance of the toxins.In recent years,toxins have been widely used as warheads for antibody-drug conjugates(ADCs)due to their eff-cient killing activity against various cancer cells.Although ADCs confer certain targeting properties to the toxins,low drug loading capacity,possible immunogenicity,and other drawbacks also limit the po-tential application of ADCs.Recently,non-ADC delivery strategies for toxins have been extensively investigated.To further understand the application of toxins in anti-tumor,this paper provided an over-view of prodrugs,nanodrug delivery systems,and biomimetic drug delivery systems.In addition,toxins and their combination strategies with other therapies were discussed.Finally,the prospect and challenge of toxins in cancertreatmentwerealso summarized.
基金financially supported by the National Key R&D Program of China(No.2021YFA0909900).
文摘Small interfering RNA(siRNA)-based gene silencing has been considered as a potential therapy modality against inflammatory diseases.Nevertheless,the effective delivery of siRNA to desired destination still remains challenging due to poor stability,high molecular weight and negative charge.Currently,ionizable lipid nanoparticle(LNP)has been extensively used as vector for effective delivery of siRNA.Herein,we report a mannose-modified LNP(M-MC_(3) LNP@TNFα)loading tumor necrosis factorα(TNFα)siRNA for targeting liver macrophages,achieving effectively inhibit acute liver injury.The M-MC_(3) LNP@TNFαnot only increases the internalization of LNP by macrophages,but also enhances the gene silencing efficiency of TNFαin vitro.Additionally,the M-MC_(3) LNP@TNFαexhibits higher accumulation in liver of healthy mice than that of MC_(3) LNP@TNFα(un-modified LNP)owing to the targeting effect of mannose.As expected,the M-MC_(3) LNP@TNFαsignificantly suppresses the expression of TNFαand ameliorates liver damage in acute liver injury model.Such a LNP targeting siRNA delivery holds great potential for the treatment of diseases associated with liver in the future.
基金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Tumor sentinel lymph node(SLN)metastasis plays a vital role in tumor staging and therapeutic decision-making process.However,precise diagnosis of primary tumors and lymphatic metastases is still hindered by low imaging resolution and poor photostability of fluorescent probes.Herein,we report three novel IR820-fatty acid(FA)conjugates(IR-OA,IR-LA,and IR-PA)for precise lymphatic metastasis illumination and primary tumor diagnosis.The IR-FA conjugates are able to non-covalently bound to albumin in vivo,and the fluorescence quantum yield is significantly enhanced after incubation with bovine serum albumin(BSA)in vitro.Moreover,the BSA-IR-FA conjugates display large Stokes shift(>120 nm),dramatically improving in vivo imaging resolution.Among them,IR-PA demonstrates distinct advantage over IR-OA,IR-LA,and IR-maleimide(MAL)(fluorescent probe previously reported by our group)in terms of fluorescence quantum yield,photostability,and imaging resolution.As a result,IR-PA exhibits satisfactory imaging results with high fluorescence intensity and imaging resolution in sentinel lymph node metastasis illumination and primary tumor location.Our findings provide a self-adaptive albumin-binding near-infrared probe conjugate for accurate diagnosis of primary tumors and lymphatic metastases.
基金financially supported by National Natural Science Foundation of China(Nos.81573371 and U1608283)Liaoning Revitalization Talents Program(No.XLYC1808017,China)+1 种基金Key projects of Technology Bureau in Shenyang(No.18400408,China)Key Projects of Liaoning Province Department of Education(No.2017LZD03,China)
文摘Hypoxia, a salient feature of most solid tumors, confers invasiveness and resistance to the tumor cells. Oxygen-consumption photodynamic therapy(PDT) suffers from the undesirable impediment of local hypoxia in tumors. Moreover, PDT could further worsen hypoxia. Therefore, developing effective strategies for manipulating hypoxia and improving the effectiveness of PDT has been a focus on antitumor treatment. In this review, the mechanism and relationship of tumor hypoxia and PDT are discussed.Moreover, we highlight recent trends in the field of nanomedicines to modulate hypoxia for enhancing PDT, such as oxygen supply systems, down-regulation of oxygen consumption and hypoxia utilization.Finally, the opportunities and challenges are put forward to facilitate the development and clinical transformation of PDT.
基金supported by National Natural Science Foundation of China,Nos.81773656 and U1608283Liaoning Revitalization Talents Program,No.XLYC1808017+2 种基金Key Projects of Technology Bureau in Shenyang,No.18400408Key projects of Liaoning Province Department of Education,No.2017LZD03China Postdoctoral Science Foundation(No.2020M680986)。
文摘Substantial progress in the use of chemo-photodynamic nano-drug delivery systems(nanoDDS) for the treatment of the malignant breast cancer has been achieved. The inability to customize precise nanostructures, however, has limited the therapeutic efficacy of the prepared nano-DDS to date. Here,we report a structurally defined tandem-responsive chemo-photosensitive co-nanoassembly to eliminate primary breast tumor and prevent lung metastasis. This both-in-one co-nanoassembly is prepared by assembling a biocompatible photosensitive derivative(pheophorbide-diphenylalanine peptide, PPADA) with a hypoxia-activated camptothecin(CPT) prodrug [(4-nitrophenyl) formate camptothecin, NCPT]. According to computational simulations, the co-assembly nanostructure is not the classical core-shell type, but consists of many small microphase regions. Upon exposure to a 660 nm laser,PPA-DA induce high levels of ROS production to effectively achieve the apoptosis of normoxic cancer cells. Subsequently, the hypoxia-activated N-CPT and CPT spatially penetrate deep into the hypoxic region of the tumor and suppress hypoxia-induced tumor metastasis. Benefiting from the rational design of the chemo-photodynamic both-in-one nano-DDS, these nanomedicines exhibit a promising potential in the inhibition of difficult-to-treat breast tumor metastasis in patients with breast cancer.
基金supported by the National Natural Science Foundation of China(No.81773656)the Liaoning Revitalization Talents Program(No.XLYC1808017)the Shenyang Youth Science and Technology Innovation Talents Program(No.RC190454).
文摘Tumor hypoxia is one of the major factors restricting the photodynamic therapy(PDT)efficacy.To address this problem,we designed an arginine-peptide complex,namely Fluorenylmethoxycarbonyl-Leucine-Leucine-Leucine-Arginine-OH(Fmoc-L_(3)-Arg),which is able to co-assemble with 5,10,15,20-Tetrakis(4-hydroxyphenyl)porphyrin(THPP)into stable nanoparticles(NPs)with uniform and spherical shapes.The THPP/Fomc-L_(3)-Arg NPs were ultra-sensitive to tumorous acidic and oxidative conditions,and could rapidly release photosensitizers in tumor cells.Meanwhile,the co-loaded Fmoc-L_(3)-Arg could efficiently generate nitric oxide(NO),inhibiting mitochondrial cellular respiration and increasing oxygen in tumor cells to support the profound improvement of reactive oxygen species(ROS)yield and PDT efficacy.After intravenous injection,the THPP/Fomc-L_(3)-Arg NPs greatly accumulated at tumor tissue and significantly inhibited tumor growth upon irradiation.In conclusion,such an arginine-peptide complex-based nanoassembly addresses the inevitable problem of hypoxia-induced tumor resistance to PDT.
基金This work was financially supported by National Natural Science Foundation of China(No.81773656)Liaoning Revitalization Talents Program(No.XLYC1808017)+1 种基金Shenyang Youth Science and Technology Innovation Talents Program(No.RC190454)National Postdoctoral Foundation of China(No.2021M693868).
文摘Mitochondrial bioenergy plays a vital role in the occurrence and development of cancer.Although strategies to impede mitochondrial energy supply have been rapidly developed,the anticancer efficacy is still far from satisfactory,mainly attributed to the hybrid metabolic pathways of mitochondrial oxidative phosphorylation(OXPHOS)and glycolysis.Herein,we construct a cancer cell membrane camouflaged nano-inhibitor,mTPPa-Sy nanoparticle(NP),which co-encapsulates OXPHOS inhibitor(mitochondrial-targeting photosensitizers:TPPa)and glycolysis inhibitor(syrosingopine(Sy))for synergistically blocking the two different energy pathways.The mTPPa-Sy NPs exhibit precision tumor-targeting due to the high affinity between the biomimic membrane and the homotypic cancer cells.Under laser irradiation,the mitochondrial-targeting TPPa,which is synthesized by conjugating pyropheophorbide a(PPa)with triphenylphosphin,produces excessive reactive oxygen species(ROS)and further disrupts the OXPHOS.Interestingly,OXPHOS inhibition reduces O_(2) consumption and improves ROS production,further constructing a closed-loop OXPHOS inhibition system.Moreover,TPPa-initiated OXPHOS inhibition in combination with the Sytriggered glycolysis inhibition results in lethal energy depletion,significantly suppressing tumor growth even after a single treatment.Our findings highlight the necessity and effectiveness of synergetic lethal energy depletion,providing a prospective strategy for efficient cancer therapy.
基金supported by National Key R&D Program of China(No.2021YFA0909900)National Natural Science Foundation of China(No.81773656)+3 种基金Liaoning Revitalization Talents Program(No.XLYC1808017)Shenyang Youth Science and Technology Innovation Talents Program(No.RC190454)China Postdoctoral Science Foundation(No.2020M680986)General Project of Liaoning Provincial Department of Education(Nos.LKZ0927 and LJKQZ2021034)。
文摘Inflammatory bowel disease(IBD)is a chronic and recurrent disease of the gastrointestinal tract,mainly including Crohn's disease(CD)and ulcerative colitis(UC).However,current approaches against IBD do not precisely deliver drugs to the inflammatory site,which leads to life-long medication and serious side effects that can adversely impact patients’adherence.It is necessary to construct optimal drug delivery systems(DDSs)that can target drugs to the region of inflammation,thereby improve therapeutic efficacy and reduce side effects.With the burgeoning development of nanotechnology-based nanomedicines(NMs)and prodrug strategy,remarkable progresses in the treatment of IBD have been made in recent years.Herein,the latest advances are outlined at the intersection of IBD treatment and nanotherapeutics as well as prodrug therapy.First,the pathophysiological microenvironment of inflammatory sites of IBD is introduced in order to rationally design potential NMs and prodrugs.Second,the necessity of NMs for the IBD therapy is elaborated,and the representative nanotherapeutics via passive targeted and active targeted NMs developed to treat the IBD are overviewed.Furthermore,the emerging prodrug-based therapeutics are summarized,including 5-aminosalicylic acid-,amino acid-,and carbohydrate-conjugated prodrugs.Finally,the design considerations and perspectives of these NMs and prodrugs-driven IBD therapeutics in the clinical translation are spotlighted.