Tumor blockade therapy inhibits tumor progression by cutting off essential supplies of nutrients,oxygen,and biomolecules from the surrounding microenvironments.Inspired by natural processes,tumor biomineralization has...Tumor blockade therapy inhibits tumor progression by cutting off essential supplies of nutrients,oxygen,and biomolecules from the surrounding microenvironments.Inspired by natural processes,tumor biomineralization has evolved due to its biocompatibility,self-reinforcing capability,and penetrationindependent mechanism.However,the selective induction of tumor biomineralization using synthetic tools presents a significant challenge.Herein,a metabolic glycoengineering-assistant tumor biomineralization strategy was developed.Specifically,the azido group(N_(3))was introduced onto the cytomembrane by incubating tumor cells with glycose analog Ac4ManNAz.In addition,a bisphosphonate-containing polymer,dibenzocyclooctyne-poly(ethylene glycol)-alendronate(DBCO-PEG-ALN,DBPA)was synthesized,which attached to the tumor cell surface via"click chemistry"reaction between DBCO and N_(3).Subsequently,the bisphosphonate group on the cell surface chelated with positively charged ions in the microenvironments,triggering a consecutive process of biomineralization.This physical barrier significantly reduced tumor cell viability and mobility in a calcium ion concentration-dependent manner,suggesting its potential as an effective anti-tumor strategy for in vivo applications.展开更多
Increasing evidence indicates that sialic acid plays an important role during nerve regeneration. Sialic acids can be modified in vitro as well as in vivo using metabolic oligosaccharide engineering of the N-awl side ...Increasing evidence indicates that sialic acid plays an important role during nerve regeneration. Sialic acids can be modified in vitro as well as in vivo using metabolic oligosaccharide engineering of the N-awl side chain. N-Propionylmannosamine （ManNProp） increases neurite outgrowth and accelerates the reestablishment of functional synapses in vitro. We investigated the influence of systemic ManNProp application using a specific in vivo mouse model. Using mice expressing axonal fluorescent proteins, we quantified the extension of regenerating axons, the number of regenerating axons, the number of arborising axons and the number of branches per axon 5 days after injury. Sciatic nerves from non-expressing mice were grafted into those expressing yellow fluorescent protein. We began a twice-daily intraperitoneal application of either peracetylated ManNProp （200 mg/kg） or saline solution 5 days before injury, and continued it until nerve harvest （5 days after transection）. ManNProp significantly increased the mean distance of axonal regeneration （2.49 mm vs. 1.53 mm; P 〈 0.005） and the number of arborizing axons （21% vs. 16%; P = 0.008） 5 days after sciatic nerve grafting. ManNProp did not affect the number of regenerating axons or the number of branches per arborizing axon. The biochemical glycoengineering of the N-acyl side chain of sialic acid might be a promising approach for improving peripheral nerve regeneration.展开更多
Tumor-associated carbohydrate antigens(TACAs) are attractive targets for vaccine development. In this context, we described a strategy combining artificial TACA and glycoengineering for cancer vaccine development. A 2...Tumor-associated carbohydrate antigens(TACAs) are attractive targets for vaccine development. In this context, we described a strategy combining artificial TACA and glycoengineering for cancer vaccine development. A 2,4-ditrophenyl(DNP)-modified GM3 intermediate was synthesized chemoenzymatically and conjugated to keyhole limpet hemocyanin(KLH), and the resulting bioconjugate was tested for its potential as a vaccine candidate. Mice immunological studies revealed that the DNP-modified GM3(GM3-NHDNP) analog elicited strong and rapid immune responses by recruiting anti-DNP antibodies to facilitate the targeted delivery of the vaccine construct to antigen processing cells(APCs). Moreover, the endogenously produced anti-DNP antibodies, together with the elicited antibodies against GM3-NHDNP, may synergistically promote tumor binding and cancer cell death when the cancer cell surfaces are glycoengineered to express the GM3-NHDNP antigen.展开更多
We report the design and development of aβ-glucuronidase(β-Glu)-responsive ManNAz derivative,Glu-AAM,for tumor-selective metabolic glycoengineering.Glu-AAM enables specific labeling of tumor cell surface sialoglycan...We report the design and development of aβ-glucuronidase(β-Glu)-responsive ManNAz derivative,Glu-AAM,for tumor-selective metabolic glycoengineering.Glu-AAM enables specific labeling of tumor cell surface sialoglycans in the presence of overexpressedβ-Glu in cancer cells,including breast,leukemia,and colorectal cancer cells.We demonstrate the high selectivity and efficiency of Glu-AAM-mediated metabolic glycoengineering across multiple cancer cell lines.Furthermore,we synthesized multivalent antibody-recruiting molecules(DBCO-Rha)that can be covalently attached to the azido-modified tumor cell surface,leading to potent antibody-dependent cellular phagocytosis and complement-dependent cytotoxicity.The octameric DBCO-Rha8 construct exhibited the most effective immune response.This integrated strategy ofβ-Glu-responsive metabolic glycoengineering and antibody-recruiting immunotherapy provides a promising platform for targeted cancer therapies and expands the toolbox of metabolic glycoengineering for cancer immunotherapy.展开更多
Glycosylation of the Fc region of IgG has a profound impact on the safety and clinical efficacy of therapeutic antibodies. While the biantennary complex.type oligosaccharide attached to Asn297 of the Fc is essen- tial...Glycosylation of the Fc region of IgG has a profound impact on the safety and clinical efficacy of therapeutic antibodies. While the biantennary complex.type oligosaccharide attached to Asn297 of the Fc is essen- tial for antibody effector functions, fucose and outer-arm sugars attached to the core heptasaccharide that gen- erate structural heterogeneity （glycoforms） exhibit unique biological activities. Hence, efficient and quan- titative glycan analysis techniques have been increas- ingly important for the development and quality control of therapeutic antibodies, and g｜ycan profiles of the Fc are recognized as critical quality attributes. In the past decade our understanding of the influence of glycosy- lation on the structure/function of IgG-Fc has grown rapidly through X-ray crystallographic and nuclear magnetic resonance studies, which provides possibili- ties for the design of novel antibody therapeutics. Fur- thermore, the chemoenzymatic glycoengineering approach using endoglycosidase-based glycosyn- thases may facilitate the development of homogeneous IgG glycoforms with desirable functionality as next- generation therapeutic antibodies. Thus, the Fc glycans are fertile ground for the improvement of the safety,functionality, and efficacy of therapeutic IgG antibodies in the era of precision medicine.展开更多
Benefiting from the advantage of taking place in biological environments without interfering with an innate biochemical process,the bioorthogonal reaction that commonly contains the“bond formation”and“bond cleavage...Benefiting from the advantage of taking place in biological environments without interfering with an innate biochemical process,the bioorthogonal reaction that commonly contains the“bond formation”and“bond cleavage”system has been widely used in targeted therapy for a variety of tumors.Herein,several prominent cases based on the bioorthogonal reaction that tailoring the metabolic glycoengineering tactics to modified cells for cancer immunotherapy,and the innovative tactics for reducing the metal ions’toxic and side effects with microneedle patches will be highlighted.Based on these applications,the complexities,potential pitfalls,and opportunities of bioorthogonal chemistry in future cancer therapy will be evaluated.展开更多
基金supported by the National Natural Science Foundation of China(Nos.U23A20591 and 52273158)the Science and Technology Development Program of Jilin Province(Nos.20240101002JJ and 20210504001GH).
文摘Tumor blockade therapy inhibits tumor progression by cutting off essential supplies of nutrients,oxygen,and biomolecules from the surrounding microenvironments.Inspired by natural processes,tumor biomineralization has evolved due to its biocompatibility,self-reinforcing capability,and penetrationindependent mechanism.However,the selective induction of tumor biomineralization using synthetic tools presents a significant challenge.Herein,a metabolic glycoengineering-assistant tumor biomineralization strategy was developed.Specifically,the azido group(N_(3))was introduced onto the cytomembrane by incubating tumor cells with glycose analog Ac4ManNAz.In addition,a bisphosphonate-containing polymer,dibenzocyclooctyne-poly(ethylene glycol)-alendronate(DBCO-PEG-ALN,DBPA)was synthesized,which attached to the tumor cell surface via"click chemistry"reaction between DBCO and N_(3).Subsequently,the bisphosphonate group on the cell surface chelated with positively charged ions in the microenvironments,triggering a consecutive process of biomineralization.This physical barrier significantly reduced tumor cell viability and mobility in a calcium ion concentration-dependent manner,suggesting its potential as an effective anti-tumor strategy for in vivo applications.
文摘Increasing evidence indicates that sialic acid plays an important role during nerve regeneration. Sialic acids can be modified in vitro as well as in vivo using metabolic oligosaccharide engineering of the N-awl side chain. N-Propionylmannosamine （ManNProp） increases neurite outgrowth and accelerates the reestablishment of functional synapses in vitro. We investigated the influence of systemic ManNProp application using a specific in vivo mouse model. Using mice expressing axonal fluorescent proteins, we quantified the extension of regenerating axons, the number of regenerating axons, the number of arborising axons and the number of branches per axon 5 days after injury. Sciatic nerves from non-expressing mice were grafted into those expressing yellow fluorescent protein. We began a twice-daily intraperitoneal application of either peracetylated ManNProp （200 mg/kg） or saline solution 5 days before injury, and continued it until nerve harvest （5 days after transection）. ManNProp significantly increased the mean distance of axonal regeneration （2.49 mm vs. 1.53 mm; P 〈 0.005） and the number of arborizing axons （21% vs. 16%; P = 0.008） 5 days after sciatic nerve grafting. ManNProp did not affect the number of regenerating axons or the number of branches per arborizing axon. The biochemical glycoengineering of the N-acyl side chain of sialic acid might be a promising approach for improving peripheral nerve regeneration.
基金supported by the National Natural Science Foundation of China (Nos. 21907038, 32000904)the Natural Science Foundation of Jiangsu Province (No. BK20200601, China)+4 种基金the National Postdoctoral Program for Innovative Talents of China (No. BX20200153)the Health and Family Planning Commission of Wuxi, China (No. Z202005)the Social Development Key Project of Jiangsu Province (No. BE2019632, China)partly supported by the 111 Project (No. 111-2-06, China)the National First-class Discipline Program of Food Science and Technology (No. JUFSTR20180101, China)。
文摘Tumor-associated carbohydrate antigens(TACAs) are attractive targets for vaccine development. In this context, we described a strategy combining artificial TACA and glycoengineering for cancer vaccine development. A 2,4-ditrophenyl(DNP)-modified GM3 intermediate was synthesized chemoenzymatically and conjugated to keyhole limpet hemocyanin(KLH), and the resulting bioconjugate was tested for its potential as a vaccine candidate. Mice immunological studies revealed that the DNP-modified GM3(GM3-NHDNP) analog elicited strong and rapid immune responses by recruiting anti-DNP antibodies to facilitate the targeted delivery of the vaccine construct to antigen processing cells(APCs). Moreover, the endogenously produced anti-DNP antibodies, together with the elicited antibodies against GM3-NHDNP, may synergistically promote tumor binding and cancer cell death when the cancer cell surfaces are glycoengineered to express the GM3-NHDNP antigen.
基金supported by the National Natural Science Foundation of China(No.22177040)partly funded by the Fundamental Research Funds for the Central Universities(No.JUSRP123037)the 111 Project(No.111-2-06).
文摘We report the design and development of aβ-glucuronidase(β-Glu)-responsive ManNAz derivative,Glu-AAM,for tumor-selective metabolic glycoengineering.Glu-AAM enables specific labeling of tumor cell surface sialoglycans in the presence of overexpressedβ-Glu in cancer cells,including breast,leukemia,and colorectal cancer cells.We demonstrate the high selectivity and efficiency of Glu-AAM-mediated metabolic glycoengineering across multiple cancer cell lines.Furthermore,we synthesized multivalent antibody-recruiting molecules(DBCO-Rha)that can be covalently attached to the azido-modified tumor cell surface,leading to potent antibody-dependent cellular phagocytosis and complement-dependent cytotoxicity.The octameric DBCO-Rha8 construct exhibited the most effective immune response.This integrated strategy ofβ-Glu-responsive metabolic glycoengineering and antibody-recruiting immunotherapy provides a promising platform for targeted cancer therapies and expands the toolbox of metabolic glycoengineering for cancer immunotherapy.
文摘Glycosylation of the Fc region of IgG has a profound impact on the safety and clinical efficacy of therapeutic antibodies. While the biantennary complex.type oligosaccharide attached to Asn297 of the Fc is essen- tial for antibody effector functions, fucose and outer-arm sugars attached to the core heptasaccharide that gen- erate structural heterogeneity （glycoforms） exhibit unique biological activities. Hence, efficient and quan- titative glycan analysis techniques have been increas- ingly important for the development and quality control of therapeutic antibodies, and g｜ycan profiles of the Fc are recognized as critical quality attributes. In the past decade our understanding of the influence of glycosy- lation on the structure/function of IgG-Fc has grown rapidly through X-ray crystallographic and nuclear magnetic resonance studies, which provides possibili- ties for the design of novel antibody therapeutics. Fur- thermore, the chemoenzymatic glycoengineering approach using endoglycosidase-based glycosyn- thases may facilitate the development of homogeneous IgG glycoforms with desirable functionality as next- generation therapeutic antibodies. Thus, the Fc glycans are fertile ground for the improvement of the safety,functionality, and efficacy of therapeutic IgG antibodies in the era of precision medicine.
基金supported by the Major State Basic Research Development Program of China (Grant No.2017YFA0205201)the National Natural Science Foundation of China (Grant Nos.81925019 and U1705281).
文摘Benefiting from the advantage of taking place in biological environments without interfering with an innate biochemical process,the bioorthogonal reaction that commonly contains the“bond formation”and“bond cleavage”system has been widely used in targeted therapy for a variety of tumors.Herein,several prominent cases based on the bioorthogonal reaction that tailoring the metabolic glycoengineering tactics to modified cells for cancer immunotherapy,and the innovative tactics for reducing the metal ions’toxic and side effects with microneedle patches will be highlighted.Based on these applications,the complexities,potential pitfalls,and opportunities of bioorthogonal chemistry in future cancer therapy will be evaluated.
