Tumor microenvironment-responsive drug self-delivery systems utilize tumor microenvironment-responsive chemical bonds to link anti-tumor drugs,exploiting the hydrophilic and hydrophobic properties of different drugs t...Tumor microenvironment-responsive drug self-delivery systems utilize tumor microenvironment-responsive chemical bonds to link anti-tumor drugs,exploiting the hydrophilic and hydrophobic properties of different drugs to form amphiphilic prodrug molecules with self-assembly characteristics.Upon stimulation by specific factors in the tumor microenvironment,these amphiphilic prodrug molecules can release drugs at precise sites within the tumor.These strategies significantly increase the drug concentration at the tumor site while effectively reducing the damage of anti-cancer drugs to normal tissues.Owing to the advanced delivery strategies such as synergistic administration and controlled drug release,tumor microenvironment-responsive drug self-delivery systems hold great potential for treating malignant tumors with multidrug resistance(MDR).At the same time,the stimulus-reactivity of metal complexes provides an important opportunity to design site-specific prodrugs that can maximize therapeutic efficacy while minimizing adverse side effects of metal drugs.This innovative drug design complements the tumor microenvironment-responsive self-delivery system,providing more feasible therapeutic strategies and possibilities in the field of cancer therapy and drug delivery.This work provides a comprehensive review of recent advancements in drug self-delivery systems,offering insights into their potential applications in cancer therapy and MDR reversal.展开更多
The diversity,complexity,heterogeneity,and drug resistance of tumors make it challenging to meet the clinical needs of a single apoptosis-inducing chemotherapy.The combination of apoptosis and ferroptosis is expected ...The diversity,complexity,heterogeneity,and drug resistance of tumors make it challenging to meet the clinical needs of a single apoptosis-inducing chemotherapy.The combination of apoptosis and ferroptosis is expected to address the side effects of chemotherapy and enhance therapeutic efficacy.Here,an amphiphilic pH-responsive doxorubicin(DOX)and ferrocene(Fc)-containing copolyprodrug(P(ADH-DOXFc)-PEG)was designed with high DOX and Fc content of 66.5%and 0.58 mmol/g by a facile polycondensation for combining chemotherapy with ferroptosis in cancer treatment.A drug self-delivery system(DSDS)with an average hydrodynamic diameter(D_(h))of 135 nm can be easily obtained via self-assembly with the polyprodrug blocks as the hydrophobic core and PEG as the hydrophilic brush.The cumulative DOX release reached 72.7%in the simulated tumor intracellular acidic microenvironment within 56 h,whereas the premature drug leakage was only 6.2%in the simulated normal physiological medium.The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT)assay results indicated an IC_(50)of 8.2μg/mL,exhibiting enhanced anti-tumor efficacy and a successful combination of apoptosis and ferroptosis,with a combination index(CI)of 0.88.展开更多
Numerous efforts have been devoted to altering the dynamic covalent linkers between the drug structural units in polyprodrugs from the viewpoint of molecular structure;however,the effect of their aggregation states ha...Numerous efforts have been devoted to altering the dynamic covalent linkers between the drug structural units in polyprodrugs from the viewpoint of molecular structure;however,the effect of their aggregation states has not yet been explored.Here,the effect of aggregation states on the in vitro drug release and cytotoxicity was investigated using a pH/glutathione(GSH)co-triggered degradable doxorubicin(DOX)-based polyprodrug(PDOX)as a model,which was synthesized by the facile polymerization of a pH/GSH dual-triggered dimeric prodrug(DDOX_(ss))and 2,2-dimethoxypropane(DMP)by forming acid-labile ketal bond.Owing to the pH/GSH dual-triggered disulfide/α-amide and acid-labile ketal linkers between the DOX structural units,the resultant PDOX exhibited excellent pH/GSH co-triggered DOX release.With a similar diameter,the PDOX-NPs1 nanomedicines via fast precipitation showed faster DOX release than PDOX-NPs2 via slow self-assembly,regardless of their polymerization degree(DP).The effect of aggregation states is expected to be a secondary strategy for a more desired tumor intracellular microenvironment-responsive drug delivery for tumor chemotherapy,in addition to the molecular structures of polyprodrugs as drug self-delivery systems(DSDSs).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
Metastasis is closely related to the high mortality of cancer patients,which is regulated by multiple signaling pathways.Hence,multiphase blocking of this biological process is beneficial for cancer treatments.Herein,...Metastasis is closely related to the high mortality of cancer patients,which is regulated by multiple signaling pathways.Hence,multiphase blocking of this biological process is beneficial for cancer treatments.Herein,we establish a multifunctional self-delivering system by synthesizing D-α-tocopheryl succinates(TOS)-conjugated chondroitin sulfate(CS)(CT NPs),which both serve as nanocarrier and antimetastatic agent that affects different phases of the metastatic cascade.TOS as the hydrophobic segment of CT NPs can inhibit the secretion of matrix metalloproteinase-9,while the hydrophilic segment CS targets B16F10 cells through CD44 receptors and reduces the interaction between tumor cells and platelets.The results show that CT NPs are able to inhibit metastasis successfully both in vitro and in vivo by interfering the multiphase of the metastatic cascade.Following encapsulating chemotherapeutic drug doxorubicin(DOX),the obtained micelles CT/DOX efficiently suppress both primary-tumor growth and metastases in B16F10 bearing mice.As a result,the rationally designed multifunctional NPs composing of biocompatible materials provide excellent therapeutic effects on solid tumors and metastases。展开更多
A mixed drug self-delivery system(DSDS)with high drug content(>50%)was developed to regulate pHtriggered drug release,based on two doxorubicin(DOX)-DOX dimmers:D-DOX_(ADH) and D-DOX_(car) conjugated with acid-labil...A mixed drug self-delivery system(DSDS)with high drug content(>50%)was developed to regulate pHtriggered drug release,based on two doxorubicin(DOX)-DOX dimmers:D-DOX_(ADH) and D-DOX_(car) conjugated with acid-labile dynamic covalent bonds(hydrazone and carbamate,respectively)and stabilized with PEGylated D-DOX_(ADH)(D-DOX_(ADH)-PEG).Owing to the different stability of the dynamic covalent bonds in the two dimers and the noncovalent interaction between them,pH-triggered drug release could be easily regulated by adjusting the feeding ratios of the two DOX-DOX dimers in the mixed DSDS.Similar in vitro cellular toxicity was achieved with the mixed DSDS nanoparticles prepared with different feeding ratios.The mixed DSDS nanoparticles had a similar DOX content and diameter but different drug releasing rates.The MTT assays revealed that a high anti-tumor efficacy could be achieved with the slowrelease mixed DSDS nanoparticles.展开更多
Hepatocellular carcinoma(HCC)is the most common primary liver cancer with a poor prognosis.Chemotherapy is one of the first-line clinical therapeutic strategies for HCC.Still,the effectiveness of chemotherapy is hampe...Hepatocellular carcinoma(HCC)is the most common primary liver cancer with a poor prognosis.Chemotherapy is one of the first-line clinical therapeutic strategies for HCC.Still,the effectiveness of chemotherapy is hampered by the tumor immunosuppressive microenvironment and drug resistance caused by insufficient delivery.Herein,we developed a metal-drug self-delivery nanomedicine(FDAH)to improve the chemo/chemodynamic therapeutic efficacy of HCC.The core of FDAH is an iron-based nanoparticle chelated with two clinical drugs,Doxorubicin(DOX)and Plerixafor(AMD3100).Additionally,the nanomedicine is externally modified with a hyaluronic acid(HA)shell,which can prolong the circulation time of the nanoparticles in the bloodstream after intravenous administration.After entering the bloodstream,the nanomedicine reaches the tumor tissue through the EPR effect and is phagocytosed by the tumor cells via HA/CD44-specific interaction.Iron ion-mediated chemodynamic therapy is mediated by the Fenton reaction to generate ROS,causing an imbalance of redox homeostasis within the tumor cells and enhancing the sensitivity of tumor cells to DOX.In addition,AMD3100 intervenes in the CXCL12/CXCR4 axis to influence the infiltration level of immune cells and promote DOX chemotherapy in tumor cells.This work suggests that alleviating immunosuppression via a metal-drug self-delivery system of the CXCR4 inhibitor can effectively improve the DOX chemotherapy and iron ions-mediated chemodynamic therapy.展开更多
A novel self-delivered prodrug system was fabricated for tumor-targeting therapy. In this nanosystem, the Arg-Gly-Asp-Ser （RGDS） tetrapeptide was used to improve the therapeutic index to integrin-overexpressing tumo...A novel self-delivered prodrug system was fabricated for tumor-targeting therapy. In this nanosystem, the Arg-Gly-Asp-Ser （RGDS） tetrapeptide was used to improve the therapeutic index to integrin-overexpressing tumor cells. The antitumorous drug camptothecin was further appended to the ε-amino group of lysine by 20-O-succinyl linkage and controllably released via hydrolytic cleavage. Prodrug molecules self-assembled into fibrillar nano-architectures and achieved the capability of self-delivery after being injected subcutaneously into mice. Introduction of hydrophobic myristic add favored the self-assembly and enhanced the cellular internalization of the prodrugs. In vitro and in vivo studies demonstrated that the self-assembled nanofibers could effectively target integrin- overexpressing tumorous cells and inhibit tumor growth via RGD-mediated specific targeting. Therefore, the traditional idea that fibrillar structures hold low therapeutic efficacy due to poor cell uptake can be challenged.展开更多
Prodrug self-delivery carriers with targeting that specifically responded to tumor microenvironments have good potential to improve the application dilemma of approved clinical therapeutic drugs(systemic distribution ...Prodrug self-delivery carriers with targeting that specifically responded to tumor microenvironments have good potential to improve the application dilemma of approved clinical therapeutic drugs(systemic distribution and side effects).It's noted the conversion of gemcitabine(GEM)to inactive ingredients under the action of cytidine deaminase(CDA)during metabolism in vivo limits its clinical effect.A high level of reactive oxygen species(ROS)results in a high level of oxidative stress in tumor cells,which changes the expression of CDA and optimizes the metabolism of GEM in vivo and overcome drug resistance.In this study,the ROS responsive and ROS self-supplied prodrug of artemisia(ART)-thioacetal bond(TK)-GEM was synthesized and self-vectors based on ART-TK-GEM(TK@FA NPs)was prepared by using nano precipitation.ROS responsive characteristics ensure specific release of prodrugs in tumor cells with high level of ROS thereby reducing side effects on normal cells and tissues.The endogenous ROS and newly generated ROS by ART can reduce the expression of CDA and optimizes the metabolism of GEM,and the accumulated ROS can also induce apoptosis of tumor cells,realizing synergistic anti-tumor effect of chemical drugs and traditional Chinese medicines.This paper proposes a simple method by using clinically approved drugs to improve the insufficient effect of existing chemotherapy and overcome resistance,which has potential to appropriately shorten the drug development cycle and accelerate the clinical investigation of drugs.展开更多
Glioblastoma(GBM) remains a formidable challenge in oncology.Chemodynamic therapy(CDT) that triggers tumor cell death by reactive oxygen species(ROS) could open up a new door for GBM treatment.Herein,we report a novel...Glioblastoma(GBM) remains a formidable challenge in oncology.Chemodynamic therapy(CDT) that triggers tumor cell death by reactive oxygen species(ROS) could open up a new door for GBM treatment.Herein,we report a novel CDT nanoagent.Hemoglobin(Hb)and glucose oxidase(GOx) were employed as powerful CDT catalysts.Instead of encapsulating the proteins in drug delivery nanocarriers,we formulate multimeric superstructures as self-delivery entities by crosslinking techniques.Red blood cell(RBC) membranes are camouflaged on the protein superstructures to promote the delivery across blood-brain barrier.The as-prepared RBC@Hb@GOx nanoparticles(NPs) offer superior biocompatibility,simplified structure,and high accumulation at the tumor site.We successfully demonstrated that the NPs could efficiently produce toxic ROS to kill U87 MG cancer cells in vitro and inhibit the growth of GBM tumor in vivo,suggesting that the new CDT nanoagent holds great promise for treating GBM.展开更多
Herein, we designed a dual-response shape transformation and charge reversal strategy with chemo-photodynamic therapy to improve the blood circulation time, tumor penetration and retention,which finally enhanced the a...Herein, we designed a dual-response shape transformation and charge reversal strategy with chemo-photodynamic therapy to improve the blood circulation time, tumor penetration and retention,which finally enhanced the anti-tumor effect. In the system, hydrophobic photosensitizer chlorin e6(Ce6), hydrophilic chemotherapeutic drug berberrubine(BBR) and matrix metalloproteinase-2(MMP-2) response peptide(PLGVRKLVFF) were coupled by linkers to form a linear triblock molecule BBR-PLGVRKLVFF-Ce6(BPC), which can self-assemble into nanoparticles. Then, positively charged BPC and polyethylene glycol-histidine(PEG-His) were mixed to form PEG-His@BPC with negative surface charge and long blood circulation time. Due to the acidic tumor microenvironment, the PEG shell was detached from PEG-His@BPC attributing to protonation of the histidine, which achieved charge reversal, size reduction and enhanced tumor penetration. At the same time, enzyme cutting site was exposed, and the spherical nanoparticles could transform into nanofibers following the enzymolysis by MMP-2, while BBR was released to kill tumors by inducing apoptosis. Compared with original nanoparticles, the nanofibers with photosensitizer Ce6 retained within tumor site for a longer time. Collectively,we provided a good example to fully use the intrinsic properties of different drugs and linkers to construct tumor microenvironment-responsive charge reversal and shape transformable nanoparticles with synergistic antitumor effect.展开更多
基金supported by the National Natural Science Foundation of China(No.21907059)Shandong Province Chinese Medicine Science and Technology Development Project(No.M-2022258)+1 种基金the Young Scientist Development Foundation of Shandong First Medical University(No.202201-002)the Academic Promotion Program of Shandong First Medical University(Nos.2019LJ003 and 2019QL011).
文摘Tumor microenvironment-responsive drug self-delivery systems utilize tumor microenvironment-responsive chemical bonds to link anti-tumor drugs,exploiting the hydrophilic and hydrophobic properties of different drugs to form amphiphilic prodrug molecules with self-assembly characteristics.Upon stimulation by specific factors in the tumor microenvironment,these amphiphilic prodrug molecules can release drugs at precise sites within the tumor.These strategies significantly increase the drug concentration at the tumor site while effectively reducing the damage of anti-cancer drugs to normal tissues.Owing to the advanced delivery strategies such as synergistic administration and controlled drug release,tumor microenvironment-responsive drug self-delivery systems hold great potential for treating malignant tumors with multidrug resistance(MDR).At the same time,the stimulus-reactivity of metal complexes provides an important opportunity to design site-specific prodrugs that can maximize therapeutic efficacy while minimizing adverse side effects of metal drugs.This innovative drug design complements the tumor microenvironment-responsive self-delivery system,providing more feasible therapeutic strategies and possibilities in the field of cancer therapy and drug delivery.This work provides a comprehensive review of recent advancements in drug self-delivery systems,offering insights into their potential applications in cancer therapy and MDR reversal.
文摘The diversity,complexity,heterogeneity,and drug resistance of tumors make it challenging to meet the clinical needs of a single apoptosis-inducing chemotherapy.The combination of apoptosis and ferroptosis is expected to address the side effects of chemotherapy and enhance therapeutic efficacy.Here,an amphiphilic pH-responsive doxorubicin(DOX)and ferrocene(Fc)-containing copolyprodrug(P(ADH-DOXFc)-PEG)was designed with high DOX and Fc content of 66.5%and 0.58 mmol/g by a facile polycondensation for combining chemotherapy with ferroptosis in cancer treatment.A drug self-delivery system(DSDS)with an average hydrodynamic diameter(D_(h))of 135 nm can be easily obtained via self-assembly with the polyprodrug blocks as the hydrophobic core and PEG as the hydrophilic brush.The cumulative DOX release reached 72.7%in the simulated tumor intracellular acidic microenvironment within 56 h,whereas the premature drug leakage was only 6.2%in the simulated normal physiological medium.The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT)assay results indicated an IC_(50)of 8.2μg/mL,exhibiting enhanced anti-tumor efficacy and a successful combination of apoptosis and ferroptosis,with a combination index(CI)of 0.88.
文摘Numerous efforts have been devoted to altering the dynamic covalent linkers between the drug structural units in polyprodrugs from the viewpoint of molecular structure;however,the effect of their aggregation states has not yet been explored.Here,the effect of aggregation states on the in vitro drug release and cytotoxicity was investigated using a pH/glutathione(GSH)co-triggered degradable doxorubicin(DOX)-based polyprodrug(PDOX)as a model,which was synthesized by the facile polymerization of a pH/GSH dual-triggered dimeric prodrug(DDOX_(ss))and 2,2-dimethoxypropane(DMP)by forming acid-labile ketal bond.Owing to the pH/GSH dual-triggered disulfide/α-amide and acid-labile ketal linkers between the DOX structural units,the resultant PDOX exhibited excellent pH/GSH co-triggered DOX release.With a similar diameter,the PDOX-NPs1 nanomedicines via fast precipitation showed faster DOX release than PDOX-NPs2 via slow self-assembly,regardless of their polymerization degree(DP).The effect of aggregation states is expected to be a secondary strategy for a more desired tumor intracellular microenvironment-responsive drug delivery for tumor chemotherapy,in addition to the molecular structures of polyprodrugs as drug self-delivery systems(DSDSs).
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supported by Major Projects of the National Natural Science Foundation of China(81974499)Sichuan Science and Technology Program(2018RZ0136)Sichuan Veterinary Medicine and Drug innovation Group of China Agricultural Research System(SCCXTD-2020-18).
文摘Metastasis is closely related to the high mortality of cancer patients,which is regulated by multiple signaling pathways.Hence,multiphase blocking of this biological process is beneficial for cancer treatments.Herein,we establish a multifunctional self-delivering system by synthesizing D-α-tocopheryl succinates(TOS)-conjugated chondroitin sulfate(CS)(CT NPs),which both serve as nanocarrier and antimetastatic agent that affects different phases of the metastatic cascade.TOS as the hydrophobic segment of CT NPs can inhibit the secretion of matrix metalloproteinase-9,while the hydrophilic segment CS targets B16F10 cells through CD44 receptors and reduces the interaction between tumor cells and platelets.The results show that CT NPs are able to inhibit metastasis successfully both in vitro and in vivo by interfering the multiphase of the metastatic cascade.Following encapsulating chemotherapeutic drug doxorubicin(DOX),the obtained micelles CT/DOX efficiently suppress both primary-tumor growth and metastases in B16F10 bearing mice.As a result,the rationally designed multifunctional NPs composing of biocompatible materials provide excellent therapeutic effects on solid tumors and metastases。
文摘A mixed drug self-delivery system(DSDS)with high drug content(>50%)was developed to regulate pHtriggered drug release,based on two doxorubicin(DOX)-DOX dimmers:D-DOX_(ADH) and D-DOX_(car) conjugated with acid-labile dynamic covalent bonds(hydrazone and carbamate,respectively)and stabilized with PEGylated D-DOX_(ADH)(D-DOX_(ADH)-PEG).Owing to the different stability of the dynamic covalent bonds in the two dimers and the noncovalent interaction between them,pH-triggered drug release could be easily regulated by adjusting the feeding ratios of the two DOX-DOX dimers in the mixed DSDS.Similar in vitro cellular toxicity was achieved with the mixed DSDS nanoparticles prepared with different feeding ratios.The mixed DSDS nanoparticles had a similar DOX content and diameter but different drug releasing rates.The MTT assays revealed that a high anti-tumor efficacy could be achieved with the slowrelease mixed DSDS nanoparticles.
基金supported by the Beijing Natural Science Foundation(L248075)the National Natural Science Foundation of China(32171370)+2 种基金the Guangdong Basic and Applied Basic Research Foundation(2022A1515140073 and 2022A1515010415)the Scientific and Technological Innovation Project of China Academy of Chinese Medical Sciences(CI2023C012YL)the Science and Technology Program of Guangzhou(2023A03J0493).
文摘Hepatocellular carcinoma(HCC)is the most common primary liver cancer with a poor prognosis.Chemotherapy is one of the first-line clinical therapeutic strategies for HCC.Still,the effectiveness of chemotherapy is hampered by the tumor immunosuppressive microenvironment and drug resistance caused by insufficient delivery.Herein,we developed a metal-drug self-delivery nanomedicine(FDAH)to improve the chemo/chemodynamic therapeutic efficacy of HCC.The core of FDAH is an iron-based nanoparticle chelated with two clinical drugs,Doxorubicin(DOX)and Plerixafor(AMD3100).Additionally,the nanomedicine is externally modified with a hyaluronic acid(HA)shell,which can prolong the circulation time of the nanoparticles in the bloodstream after intravenous administration.After entering the bloodstream,the nanomedicine reaches the tumor tissue through the EPR effect and is phagocytosed by the tumor cells via HA/CD44-specific interaction.Iron ion-mediated chemodynamic therapy is mediated by the Fenton reaction to generate ROS,causing an imbalance of redox homeostasis within the tumor cells and enhancing the sensitivity of tumor cells to DOX.In addition,AMD3100 intervenes in the CXCL12/CXCR4 axis to influence the infiltration level of immune cells and promote DOX chemotherapy in tumor cells.This work suggests that alleviating immunosuppression via a metal-drug self-delivery system of the CXCR4 inhibitor can effectively improve the DOX chemotherapy and iron ions-mediated chemodynamic therapy.
基金This work was supported by the National Natural Science Foundation of China （Nos. 51125014, 51503227 and 51233003） and Natural Science Foundation of Hubei Province of China （Nos. 2014CFB696 and 2013CFA003）.
文摘A novel self-delivered prodrug system was fabricated for tumor-targeting therapy. In this nanosystem, the Arg-Gly-Asp-Ser （RGDS） tetrapeptide was used to improve the therapeutic index to integrin-overexpressing tumor cells. The antitumorous drug camptothecin was further appended to the ε-amino group of lysine by 20-O-succinyl linkage and controllably released via hydrolytic cleavage. Prodrug molecules self-assembled into fibrillar nano-architectures and achieved the capability of self-delivery after being injected subcutaneously into mice. Introduction of hydrophobic myristic add favored the self-assembly and enhanced the cellular internalization of the prodrugs. In vitro and in vivo studies demonstrated that the self-assembled nanofibers could effectively target integrin- overexpressing tumorous cells and inhibit tumor growth via RGD-mediated specific targeting. Therefore, the traditional idea that fibrillar structures hold low therapeutic efficacy due to poor cell uptake can be challenged.
基金financial support from Guangdong Nature Resource Center(GDNRC,No.(2020)037)Natural Science Foundation of Guangdong Province(Nos.22019A1515011498,2019A1515011619)。
文摘Prodrug self-delivery carriers with targeting that specifically responded to tumor microenvironments have good potential to improve the application dilemma of approved clinical therapeutic drugs(systemic distribution and side effects).It's noted the conversion of gemcitabine(GEM)to inactive ingredients under the action of cytidine deaminase(CDA)during metabolism in vivo limits its clinical effect.A high level of reactive oxygen species(ROS)results in a high level of oxidative stress in tumor cells,which changes the expression of CDA and optimizes the metabolism of GEM in vivo and overcome drug resistance.In this study,the ROS responsive and ROS self-supplied prodrug of artemisia(ART)-thioacetal bond(TK)-GEM was synthesized and self-vectors based on ART-TK-GEM(TK@FA NPs)was prepared by using nano precipitation.ROS responsive characteristics ensure specific release of prodrugs in tumor cells with high level of ROS thereby reducing side effects on normal cells and tissues.The endogenous ROS and newly generated ROS by ART can reduce the expression of CDA and optimizes the metabolism of GEM,and the accumulated ROS can also induce apoptosis of tumor cells,realizing synergistic anti-tumor effect of chemical drugs and traditional Chinese medicines.This paper proposes a simple method by using clinically approved drugs to improve the insufficient effect of existing chemotherapy and overcome resistance,which has potential to appropriately shorten the drug development cycle and accelerate the clinical investigation of drugs.
基金supported by the Villum Fonden, Denmark, Project No. 13153the China Scholarship Council (CSC) for its generous support。
文摘Glioblastoma(GBM) remains a formidable challenge in oncology.Chemodynamic therapy(CDT) that triggers tumor cell death by reactive oxygen species(ROS) could open up a new door for GBM treatment.Herein,we report a novel CDT nanoagent.Hemoglobin(Hb)and glucose oxidase(GOx) were employed as powerful CDT catalysts.Instead of encapsulating the proteins in drug delivery nanocarriers,we formulate multimeric superstructures as self-delivery entities by crosslinking techniques.Red blood cell(RBC) membranes are camouflaged on the protein superstructures to promote the delivery across blood-brain barrier.The as-prepared RBC@Hb@GOx nanoparticles(NPs) offer superior biocompatibility,simplified structure,and high accumulation at the tumor site.We successfully demonstrated that the NPs could efficiently produce toxic ROS to kill U87 MG cancer cells in vitro and inhibit the growth of GBM tumor in vivo,suggesting that the new CDT nanoagent holds great promise for treating GBM.
基金supported by National Natural Science Foundation of China (82173762)111 Project (B18035,China)+1 种基金the Key Research and Development Program of Science and Technology Department of Sichuan Province (2022JDJQ0050,2022YFS0334)the Open Research Fund of Chengdu University of Traditional Chinese Medicine State Key Laboratory of Characteristic Chinese Medicine Resources in Southwest China。
文摘Herein, we designed a dual-response shape transformation and charge reversal strategy with chemo-photodynamic therapy to improve the blood circulation time, tumor penetration and retention,which finally enhanced the anti-tumor effect. In the system, hydrophobic photosensitizer chlorin e6(Ce6), hydrophilic chemotherapeutic drug berberrubine(BBR) and matrix metalloproteinase-2(MMP-2) response peptide(PLGVRKLVFF) were coupled by linkers to form a linear triblock molecule BBR-PLGVRKLVFF-Ce6(BPC), which can self-assemble into nanoparticles. Then, positively charged BPC and polyethylene glycol-histidine(PEG-His) were mixed to form PEG-His@BPC with negative surface charge and long blood circulation time. Due to the acidic tumor microenvironment, the PEG shell was detached from PEG-His@BPC attributing to protonation of the histidine, which achieved charge reversal, size reduction and enhanced tumor penetration. At the same time, enzyme cutting site was exposed, and the spherical nanoparticles could transform into nanofibers following the enzymolysis by MMP-2, while BBR was released to kill tumors by inducing apoptosis. Compared with original nanoparticles, the nanofibers with photosensitizer Ce6 retained within tumor site for a longer time. Collectively,we provided a good example to fully use the intrinsic properties of different drugs and linkers to construct tumor microenvironment-responsive charge reversal and shape transformable nanoparticles with synergistic antitumor effect.
