Peptide-drug conjugates(PDCs)are drug delivery systems consisting of a drug covalently coupled to a multifunctional peptide via a cleavable linker.As an emerging prodrug strategy,PDCs not only preserve the function an...Peptide-drug conjugates(PDCs)are drug delivery systems consisting of a drug covalently coupled to a multifunctional peptide via a cleavable linker.As an emerging prodrug strategy,PDCs not only preserve the function and bioactivity of the peptides but also release the drugs responsively with the cleavable property of the linkers.Given the ability to significantly improve the circulation stability and targeting of drugs in vivo and reduce the toxic side effects of drugs,PDCs have already been extensively applied in drug delivery.Herein,we review the types and mechanisms of peptides,linkers and drugs used to construct PDCs,and summarize the clinical applications and challenges of PDC drugs.展开更多
Peptide-drug conjugates(PDCs) composed of peptide, spacer and drug have gained extensive attention in the field of drug delivery owing to its precise control over the drug payload and architecture. However,the achieve...Peptide-drug conjugates(PDCs) composed of peptide, spacer and drug have gained extensive attention in the field of drug delivery owing to its precise control over the drug payload and architecture. However,the achievement of controllable and rapid drug release at targeted site by PDCs is still a great challenge for pharmaceutist. Herein, we introduced the histidine residue into PDCs to generate a supramolecular hydrogel via a p H-trigger strategy, which exhibited an autocatalytic effect to precisely tune drug release from PDCs hydrogel. Using indomethacin(Idm) as model drug, various PDCs(Y(Idm)EEH, Y(Idm)EEK and Y(Idm)EER) were synthesized and their self-assembling properties were investigated in terms of critical aggregation concentration(CAC), transmission electron microscopy(TEM) and rheometer. Introduction of histidine residue into PDCs presented a robust catalytic activity on the ester hydrolysis of p-nitrophenyl acetate in aqueous solution, as well conferred the autocatalytic capacity to hydrolyze the PDCs into active parent drug(Idm). Overall, we reported an autocatalytic activity of histidine residue to precisely tune drug release from PDCs hydrogels.展开更多
Melittin,a classical antimicrobial peptide,is a highly potent antitumor agent.However,its significant toxicity seriously hampers its application in tumor therapy.In this study,we developed novel melittin analogs with ...Melittin,a classical antimicrobial peptide,is a highly potent antitumor agent.However,its significant toxicity seriously hampers its application in tumor therapy.In this study,we developed novel melittin analogs with pH-responsive,cell-penetrating and membranelytic activities by replacing arginine and lysine with histidine.After conjugation with camptothecin(CPT),CPT-AAM-1 and CPT-AAM-2 were capable of killing tumor cells by releasing CPT at low concentrations and disrupting cell membranes at high concentrations under acidic conditions.Notably,we found that the C-terminus of the melittin analogs was more suitable for drug conjugation than the N-terminus.CPT-AAM-1 significantly suppressed melanoma growth in vivo with relatively low toxicity.Collectively,the present study demonstrates that the development of antitumor drugs based on pH-responsive antimicrobial peptide-drug conjugates is a promising strategy.展开更多
As a representative chemotherapeutic drug,docetaxel(DTX)has been used for breast cancer treatment for decades.However,the poor solubility of DTX limits its efficacy,and the DTX based therapy increases the metastasis r...As a representative chemotherapeutic drug,docetaxel(DTX)has been used for breast cancer treatment for decades.However,the poor solubility of DTX limits its efficacy,and the DTX based therapy increases the metastasis risk due to the upregulation of C-X-C chemokine receptor type 4(CXCR4)expression during the treatment.Herein,we conjugated CXCR4 antagonist peptide(CTCE)with DTX(termed CTCE-DTX)as an anti-metastasis agent to treat breast cancer.CTCE-DTX could selfassemble to nanoparticles,targeting CXCR4-upregulated metastatic tumor cells and enhancing the DTX efficacy.Thus,the CTCE-DTX NPs achieved promising efficacy on inhibiting both bonespecific metastasis and lung metastasis of triple-negative breast cancer.Our work provided a rational strategy on designing peptide-drug conjugates with synergistic anti-tumor efficacy.展开更多
Engineering of smart building molecules is key basis in designing intelligent drug delivery systems.As an emerging sophisticated delivery system strategy,the powerful functions of peptide drug conjugates(PDCs)are attr...Engineering of smart building molecules is key basis in designing intelligent drug delivery systems.As an emerging sophisticated delivery system strategy,the powerful functions of peptide drug conjugates(PDCs)are attributed to a smart linker and multifunctional peptide domain.Peptides exhibit a wide range of functions and properties,including easy chemical synthesis and versatile modification,tunable biocompatibility,diversified self-assembled nanostructures,specific recognition/binding,and deep penetration of the cell membrane/extracellular matrix.In addition,various types of linkers enable PDCs to release drugs responsively according to the disease microen-vironment or treatment needs.Owing to these inherent advantages,PDCs have been widely explored for drug delivery.Herein,the latest developments in functional peptides and linkers commonly used to construct smart PDCs are reviewed.The purpose is to bring widespread attention to PDC design strategies and their contribution to fighting various diseases,as well as to provide guidance for research on intelligent PDC drug delivery systems.展开更多
基金supported by grants from CAMS Innovation Fund for Medical Sciences(CIFMS,China)(2021-I2M-1-026)。
文摘Peptide-drug conjugates(PDCs)are drug delivery systems consisting of a drug covalently coupled to a multifunctional peptide via a cleavable linker.As an emerging prodrug strategy,PDCs not only preserve the function and bioactivity of the peptides but also release the drugs responsively with the cleavable property of the linkers.Given the ability to significantly improve the circulation stability and targeting of drugs in vivo and reduce the toxic side effects of drugs,PDCs have already been extensively applied in drug delivery.Herein,we review the types and mechanisms of peptides,linkers and drugs used to construct PDCs,and summarize the clinical applications and challenges of PDC drugs.
基金financially supported by the Natural Science Foundation of Zhejiang Province(No.LY20H180012)。
文摘Peptide-drug conjugates(PDCs) composed of peptide, spacer and drug have gained extensive attention in the field of drug delivery owing to its precise control over the drug payload and architecture. However,the achievement of controllable and rapid drug release at targeted site by PDCs is still a great challenge for pharmaceutist. Herein, we introduced the histidine residue into PDCs to generate a supramolecular hydrogel via a p H-trigger strategy, which exhibited an autocatalytic effect to precisely tune drug release from PDCs hydrogel. Using indomethacin(Idm) as model drug, various PDCs(Y(Idm)EEH, Y(Idm)EEK and Y(Idm)EER) were synthesized and their self-assembling properties were investigated in terms of critical aggregation concentration(CAC), transmission electron microscopy(TEM) and rheometer. Introduction of histidine residue into PDCs presented a robust catalytic activity on the ester hydrolysis of p-nitrophenyl acetate in aqueous solution, as well conferred the autocatalytic capacity to hydrolyze the PDCs into active parent drug(Idm). Overall, we reported an autocatalytic activity of histidine residue to precisely tune drug release from PDCs hydrogels.
基金supported by the grants from the National Natural Science Foundation of China(Nos.81773566 and 21602092)Innovation Project of Medicine and Health Science and Technology of Chinese Academy of Medical Sciences(2019-I2M-5-074)+1 种基金the Funds for Fundamental Research Creative Groups of Gansu Province(No.20JR5RA310)the Fundamental Research Funds for the Central Universities(No.lzujbky-2021-38).
文摘Melittin,a classical antimicrobial peptide,is a highly potent antitumor agent.However,its significant toxicity seriously hampers its application in tumor therapy.In this study,we developed novel melittin analogs with pH-responsive,cell-penetrating and membranelytic activities by replacing arginine and lysine with histidine.After conjugation with camptothecin(CPT),CPT-AAM-1 and CPT-AAM-2 were capable of killing tumor cells by releasing CPT at low concentrations and disrupting cell membranes at high concentrations under acidic conditions.Notably,we found that the C-terminus of the melittin analogs was more suitable for drug conjugation than the N-terminus.CPT-AAM-1 significantly suppressed melanoma growth in vivo with relatively low toxicity.Collectively,the present study demonstrates that the development of antitumor drugs based on pH-responsive antimicrobial peptide-drug conjugates is a promising strategy.
基金sponsored by the National Natural Science Foundation of China(52173120,21877023,32271391)the Youth Innovation Promotion Association CAS(2021018,China)+1 种基金the Beijing Natural Science Foundation(L222015,China)the Beijing Nova Program(20220484233,China)。
文摘As a representative chemotherapeutic drug,docetaxel(DTX)has been used for breast cancer treatment for decades.However,the poor solubility of DTX limits its efficacy,and the DTX based therapy increases the metastasis risk due to the upregulation of C-X-C chemokine receptor type 4(CXCR4)expression during the treatment.Herein,we conjugated CXCR4 antagonist peptide(CTCE)with DTX(termed CTCE-DTX)as an anti-metastasis agent to treat breast cancer.CTCE-DTX could selfassemble to nanoparticles,targeting CXCR4-upregulated metastatic tumor cells and enhancing the DTX efficacy.Thus,the CTCE-DTX NPs achieved promising efficacy on inhibiting both bonespecific metastasis and lung metastasis of triple-negative breast cancer.Our work provided a rational strategy on designing peptide-drug conjugates with synergistic anti-tumor efficacy.
基金supported by National Natural Science Foundation of China(No.82173992,81773662,81973488,81804100)National Key R&D program of China(2018YFC1706905)Postgraduate Research&Practice Innovation Program of Jiangsu Province(KYCX_201491).
文摘Engineering of smart building molecules is key basis in designing intelligent drug delivery systems.As an emerging sophisticated delivery system strategy,the powerful functions of peptide drug conjugates(PDCs)are attributed to a smart linker and multifunctional peptide domain.Peptides exhibit a wide range of functions and properties,including easy chemical synthesis and versatile modification,tunable biocompatibility,diversified self-assembled nanostructures,specific recognition/binding,and deep penetration of the cell membrane/extracellular matrix.In addition,various types of linkers enable PDCs to release drugs responsively according to the disease microen-vironment or treatment needs.Owing to these inherent advantages,PDCs have been widely explored for drug delivery.Herein,the latest developments in functional peptides and linkers commonly used to construct smart PDCs are reviewed.The purpose is to bring widespread attention to PDC design strategies and their contribution to fighting various diseases,as well as to provide guidance for research on intelligent PDC drug delivery systems.
