Targeted drug delivery coupled with rapid drug release in cytoplasm is a powerful strategy to enhance efficacy and reduce off-target effects of anti-cancer drugs. Herein, we describe a dual-functional mixed micellar s...Targeted drug delivery coupled with rapid drug release in cytoplasm is a powerful strategy to enhance efficacy and reduce off-target effects of anti-cancer drugs. Herein, we describe a dual-functional mixed micellar system consisting of a pH-responsive copolymer D-α-tocopheryl polyethylene glycol 1000-block- poly-（β-amino ester） （TPGS-b-PBAE, TP） and AS1411 aptamer （Apt） decorated TPGS polymer （Apt-TPGS）, which recognizes the over-expressed nucleolin on the plasma membrane of cancer cells. The anti-cancer drug paclitaxel （PTX） was encapsulated in the Apt-mixed micelles, and these drug-loaded micelles had a suitable particle size and zeta potential of 116.3 nm ± 12.4 nm and -26.2 mV ±4.2 mV, respectively. PTX/Apt-mixed micelles were stable at pH 7.4, but they dissociated and quickly released the encapsulated PTX in a weakly acidic environment （pH 5.5）. Compared with non-Apt modified mixed micelles, more Apt-modified mixed micelles were internalized in SKOV3 ovarian cancer cells, whereas no significant difference in cellular uptake was observed in normal cells （LO2 cells）. The enhanced transmembrane ability of Apt-modified mixed micelles was achieved through Apt-nucleolin interaction. With a synergistic effect of cancer cell recognition and pH-sensitive drug release, we observed significantly increased cytotoxicity and G2/M phase arrest against SKOV3 cells by PTX/ Apt-mixed micelles. Intravenous administration of PTX/Apt-mixed micelles for 16 days significantly increased tumor accumulation of PTX, inhibited tumor growth, and reduced myelosuppression on tumor-bearing mice compared with free PTX injection. Therefore, this dual-functional Apt-mixed micellar system is a promising drug delivery system for targeted cancer therapy.展开更多
An operationally simple and efficient method for the synthesis of a wide range of alkylated nucleotides under mild conditions was developed. This improved method furnishes alkylated nucleotides fi＇om both single nucl...An operationally simple and efficient method for the synthesis of a wide range of alkylated nucleotides under mild conditions was developed. This improved method furnishes alkylated nucleotides fi＇om both single nucleotides and oligonucleotides, and were prepared in high yields of 81% to 91%. Alkyl modified aptamer AS1411s were synthesized using this method and the biological activity screening results demonstrated that alkylation at the 1^st P-S site on yielded stronger target protein binding capacity, greater growth suppression effects against K562 and HL-60 cell lines, and improved serum stability, as compared with AS1411. This modified aptamer may be useful in tumor detection and treatment.展开更多
The combination of photothermal therapywith chemotherapy has gradually developed into promising cancer therapy.Here,a synergistic photothermal-chemotherapy nanoplatform based on polydopamine(PDA)-coated gold nanoparti...The combination of photothermal therapywith chemotherapy has gradually developed into promising cancer therapy.Here,a synergistic photothermal-chemotherapy nanoplatform based on polydopamine(PDA)-coated gold nanoparticles(AuNPs)were facilely achieved via the in situ polymerization of dopamine(DA)on the surface of AuNPs.This nanoplatform exhibited augmented photothermal conversion efficiency and enhanced colloidal stability in comparison with uncoated PDA shell AuNPs.The i-motif DNA nanostructure was assembled on PDA-coated AuNPs,which could be transformed into a C-quadruplex structure under an acidic environment,showing a characteristic pH response.The PDA shell served as a linker between the AuNPs and the i-motif DNA nanostructure.To enhance the specific cellular uptake,the AS1411 aptamer was introduced to the DNA nanostructure employed as a targeting ligand.In addition,Dox-loaded NPs(DAu@PDA-AS141)showed the pH/photothermal-responsive release of Dox.The photothermal effect of DAu@PDA-AS141 elicited excellent photothermal performance and efficient cancer cell inhibition under 808 nm near-infrared(NIR)irradiation.Overall,these results demonstrate that the DAu@PDA-AS141 nanoplatform shows great potential in synergistic photothermal-chemotherapy.展开更多
BCL-2 gene as well as its products is recognized as a promising target for the molecular targeted therapy of tumors.However,due to certain defense measures of tumor cells,the therapeutic effect based on the gene silen...BCL-2 gene as well as its products is recognized as a promising target for the molecular targeted therapy of tumors.However,due to certain defense measures of tumor cells,the therapeutic effect based on the gene silencing of BCL-2 is greatly reduced.Here we fabricate a smart response nucleic acid therapeutic that could silence the gene effectively through a dual-targeted and cascade-enhanced strategy.In brief,nano-graphene oxide(GO),working as a nano-carrier,is loaded with a well-designed DNAzyme,which can target and silence the BCL-2 mRNA.Furthermore,upon binding with the BCL-2 mRNA,the enzymatic activity of the DNAzyme can be initiated,cutting a substrate oligonucleotide to produce an anti-nucleolin aptamer AS1411.Nucleolin,a nucleolar phosphoprotein,is known as a stabilizer of BCL-2 mRNA.Via binding and inactivating the nucleolin,AS1411 can destabilize BCL-2 mRNA.By this means of simultaneously targeting mRNA and its stabilizer in an integrated system,effective silencing of the BCL-2 gene of tumor cells is achieved at both the cellular and in vivo levels.After being dosed with this nucleic acid therapeutic and without any chemotherapeutics,apoptosis of tumor cells at the cellular level and apparent shrinkage of tumors in vivo are observed.By labeling a molecular beacon on the substrate of DNAzyme,visualization of the enzymatic activity as well as the tumor in vivo can be also achieved.Our work presents a pure bio-therapeutic strategy that has positive implications for enhancing tumor treatment and avoiding side effects of chemotherapeutics.展开更多
Here we report a dual-functionalized electrochemical substrate to trigger cancer cells release based on the supramolecular interaction between β-cyclodextrin （β-CD） and Fc on clinical trial II aptamer AS1411 funct...Here we report a dual-functionalized electrochemical substrate to trigger cancer cells release based on the supramolecular interaction between β-cyclodextrin （β-CD） and Fc on clinical trial II aptamer AS1411 functionalized graphene platform. On one hand, the host-guest interaction can be reversible electrochemically controlled to realize cancer cells capture/release, and 1-adamantylamine binding can further amplify this surface change by competing interaction with β-CD. On the other hand, the AS1411 aptamer and its complementary DNA （cDNA） also can be used as a switchable anchor for cell adhesion. Our work gives an example for label-free, multi-functionalized triggered cell release based on aptamer and β-CD/graphene-modified surface and this multi-ways for cell catch-and-release on graphene modified surface also provides their potential biomedical application.展开更多
Selective occlusion of tumor vasculature has proven to be an effective strategy for cancer therapy.Among vascular coagulation agents,the extracellular domain of coagulation-inducing protein tissue factor,truncated tis...Selective occlusion of tumor vasculature has proven to be an effective strategy for cancer therapy.Among vascular coagulation agents,the extracellular domain of coagulation-inducing protein tissue factor,truncated tissue factor(tTF),is the most widely used.Since the truncated protein exhibits no coagulation activity and is rapidly cleared in the circulation,free tTF cannot be used for cancer treatment on its own but must be combined with other moieties.We here developed a novel,tumor-specific tTF delivery system through coupling tTF with the DNA aptamer,AS1411,which selectively binds to nucleolin receptors overexpressing on the surface of tumor vascular endothelial cells and is specifically cytotoxic to target cells.Systemic administration of the tTF-AS1411 conjugates into tumor-bearing animals induced intravascular thrombosis solely in tumors,thus reducing tumor blood supply and inducing tumor necrosis without apparent side effects.This conjugate represents a uniquely attractive candidate for the clinical translation of vessel occlusion agent for cancer therapy.展开更多
文摘Targeted drug delivery coupled with rapid drug release in cytoplasm is a powerful strategy to enhance efficacy and reduce off-target effects of anti-cancer drugs. Herein, we describe a dual-functional mixed micellar system consisting of a pH-responsive copolymer D-α-tocopheryl polyethylene glycol 1000-block- poly-（β-amino ester） （TPGS-b-PBAE, TP） and AS1411 aptamer （Apt） decorated TPGS polymer （Apt-TPGS）, which recognizes the over-expressed nucleolin on the plasma membrane of cancer cells. The anti-cancer drug paclitaxel （PTX） was encapsulated in the Apt-mixed micelles, and these drug-loaded micelles had a suitable particle size and zeta potential of 116.3 nm ± 12.4 nm and -26.2 mV ±4.2 mV, respectively. PTX/Apt-mixed micelles were stable at pH 7.4, but they dissociated and quickly released the encapsulated PTX in a weakly acidic environment （pH 5.5）. Compared with non-Apt modified mixed micelles, more Apt-modified mixed micelles were internalized in SKOV3 ovarian cancer cells, whereas no significant difference in cellular uptake was observed in normal cells （LO2 cells）. The enhanced transmembrane ability of Apt-modified mixed micelles was achieved through Apt-nucleolin interaction. With a synergistic effect of cancer cell recognition and pH-sensitive drug release, we observed significantly increased cytotoxicity and G2/M phase arrest against SKOV3 cells by PTX/ Apt-mixed micelles. Intravenous administration of PTX/Apt-mixed micelles for 16 days significantly increased tumor accumulation of PTX, inhibited tumor growth, and reduced myelosuppression on tumor-bearing mice compared with free PTX injection. Therefore, this dual-functional Apt-mixed micellar system is a promising drug delivery system for targeted cancer therapy.
基金the Ministry of Science and Technology of China(Grant No.2012CB720604)National Natural Science Foundation of China(Grant No.21332010)
文摘An operationally simple and efficient method for the synthesis of a wide range of alkylated nucleotides under mild conditions was developed. This improved method furnishes alkylated nucleotides fi＇om both single nucleotides and oligonucleotides, and were prepared in high yields of 81% to 91%. Alkyl modified aptamer AS1411s were synthesized using this method and the biological activity screening results demonstrated that alkylation at the 1^st P-S site on yielded stronger target protein binding capacity, greater growth suppression effects against K562 and HL-60 cell lines, and improved serum stability, as compared with AS1411. This modified aptamer may be useful in tumor detection and treatment.
基金This work was financially supported by National Natural Sciences Foundation of China(31971308 and 82102767)National S&T Major Project(2019ZX09301-147)+1 种基金Sichuan Science and Technology Program(2021YFS0081)Luzhou Science and Technology Plan(2018CDLZ-10).
文摘The combination of photothermal therapywith chemotherapy has gradually developed into promising cancer therapy.Here,a synergistic photothermal-chemotherapy nanoplatform based on polydopamine(PDA)-coated gold nanoparticles(AuNPs)were facilely achieved via the in situ polymerization of dopamine(DA)on the surface of AuNPs.This nanoplatform exhibited augmented photothermal conversion efficiency and enhanced colloidal stability in comparison with uncoated PDA shell AuNPs.The i-motif DNA nanostructure was assembled on PDA-coated AuNPs,which could be transformed into a C-quadruplex structure under an acidic environment,showing a characteristic pH response.The PDA shell served as a linker between the AuNPs and the i-motif DNA nanostructure.To enhance the specific cellular uptake,the AS1411 aptamer was introduced to the DNA nanostructure employed as a targeting ligand.In addition,Dox-loaded NPs(DAu@PDA-AS141)showed the pH/photothermal-responsive release of Dox.The photothermal effect of DAu@PDA-AS141 elicited excellent photothermal performance and efficient cancer cell inhibition under 808 nm near-infrared(NIR)irradiation.Overall,these results demonstrate that the DAu@PDA-AS141 nanoplatform shows great potential in synergistic photothermal-chemotherapy.
基金This work was supported by the National Natural Science Foundation of China(No.21575088)the Natural Science Foundation of Shanghai(No.19ZR1474200).
文摘BCL-2 gene as well as its products is recognized as a promising target for the molecular targeted therapy of tumors.However,due to certain defense measures of tumor cells,the therapeutic effect based on the gene silencing of BCL-2 is greatly reduced.Here we fabricate a smart response nucleic acid therapeutic that could silence the gene effectively through a dual-targeted and cascade-enhanced strategy.In brief,nano-graphene oxide(GO),working as a nano-carrier,is loaded with a well-designed DNAzyme,which can target and silence the BCL-2 mRNA.Furthermore,upon binding with the BCL-2 mRNA,the enzymatic activity of the DNAzyme can be initiated,cutting a substrate oligonucleotide to produce an anti-nucleolin aptamer AS1411.Nucleolin,a nucleolar phosphoprotein,is known as a stabilizer of BCL-2 mRNA.Via binding and inactivating the nucleolin,AS1411 can destabilize BCL-2 mRNA.By this means of simultaneously targeting mRNA and its stabilizer in an integrated system,effective silencing of the BCL-2 gene of tumor cells is achieved at both the cellular and in vivo levels.After being dosed with this nucleic acid therapeutic and without any chemotherapeutics,apoptosis of tumor cells at the cellular level and apparent shrinkage of tumors in vivo are observed.By labeling a molecular beacon on the substrate of DNAzyme,visualization of the enzymatic activity as well as the tumor in vivo can be also achieved.Our work presents a pure bio-therapeutic strategy that has positive implications for enhancing tumor treatment and avoiding side effects of chemotherapeutics.
文摘Here we report a dual-functionalized electrochemical substrate to trigger cancer cells release based on the supramolecular interaction between β-cyclodextrin （β-CD） and Fc on clinical trial II aptamer AS1411 functionalized graphene platform. On one hand, the host-guest interaction can be reversible electrochemically controlled to realize cancer cells capture/release, and 1-adamantylamine binding can further amplify this surface change by competing interaction with β-CD. On the other hand, the AS1411 aptamer and its complementary DNA （cDNA） also can be used as a switchable anchor for cell adhesion. Our work gives an example for label-free, multi-functionalized triggered cell release based on aptamer and β-CD/graphene-modified surface and this multi-ways for cell catch-and-release on graphene modified surface also provides their potential biomedical application.
基金supported by grants from the National R&D Program of China(2018YFE0205300,2018YFA0208900)the National Natural Science Foundation of China(81871489,91859118,31730032,31700870,31470969,31661130152)+2 种基金the National Distinguished Young Scientist program(31325010,China)the K.C.Wong Education Foundation(GJTD-2018-03,China)the Beijing Municipal Natural Science Foundation(7182126,China)
文摘Selective occlusion of tumor vasculature has proven to be an effective strategy for cancer therapy.Among vascular coagulation agents,the extracellular domain of coagulation-inducing protein tissue factor,truncated tissue factor(tTF),is the most widely used.Since the truncated protein exhibits no coagulation activity and is rapidly cleared in the circulation,free tTF cannot be used for cancer treatment on its own but must be combined with other moieties.We here developed a novel,tumor-specific tTF delivery system through coupling tTF with the DNA aptamer,AS1411,which selectively binds to nucleolin receptors overexpressing on the surface of tumor vascular endothelial cells and is specifically cytotoxic to target cells.Systemic administration of the tTF-AS1411 conjugates into tumor-bearing animals induced intravascular thrombosis solely in tumors,thus reducing tumor blood supply and inducing tumor necrosis without apparent side effects.This conjugate represents a uniquely attractive candidate for the clinical translation of vessel occlusion agent for cancer therapy.
