Acute myeloid leukaemia(AML)is characterized mainly by an increase in the number of myeloid cells in the bone marrow and a decrease in the number of mature cells;AML accounts for 28%of leukaemia cases,and it has a fiv...Acute myeloid leukaemia(AML)is characterized mainly by an increase in the number of myeloid cells in the bone marrow and a decrease in the number of mature cells;AML accounts for 28%of leukaemia cases,and it has a five-year survival rate of only30.5%[1].The prognosis of AML patients is mostly poor,and drug resistance eventually emerges with the long-term use of chemotherapy or targeted therapy;this drug resistance represents a daunting challenge in the management of AML[2,3].展开更多
Aptamers serve as unique targeting ligands,making aptamer-drug conjugates(ApDCs)an attractive strategy for targeted cancer therapy.This study performs a comprehensive evaluation from rodents to non-human primates(NHP)...Aptamers serve as unique targeting ligands,making aptamer-drug conjugates(ApDCs)an attractive strategy for targeted cancer therapy.This study performs a comprehensive evaluation from rodents to non-human primates(NHP)of a protein tyrosine kinase 7(PTK7)-targeted ApDC(Sgc8c-M)made by conjugating the potent antimitotic agent monomethyl auristatin E(MMAE)to the classic PTK7 aptamer Sgc8c.Efficacy studies in various cancer types with PTK7 overexpression showed that Sgc8c-M effectively induces sustained tumor regression in cell line-derived and patient-derived xenografts,outperforming unconjugated MMAE,the chemotherapy drug paclitaxel,and a PTK7-targeted antibody-drug conjugate.Pharmacokinetic(PK)studies in mice revealed that Sgc8c-M leads to rapid accumulation and sustained MMAE levels in tumors,along with fast clearance from plasma and normal tissues.Further study in rats confirmed rapid clearance across most organs and revealed that over 75%of MMAE was excreted through urine and feces within 24 h.Toxicokinetic(TK)assessments indicated comparable systemic drug exposure without accumulation for repeated doses compared to single administration.Toxicity evaluations showed that the therapeutic dose with high efficacy was safe and that the toxicity resulting from extremely high doses could be reversibly controlled.Encouraged by these findings,we evaluated PK/TK profiles and safety of Sgc8c-M in cynomolgus monkeys.Similar to PK/TK profiles observed in rats,Sgc8c-M demonstrated good dose-dependent drug exposure.It was,moreover,well tolerated in monkeys with no obvious accumulation following multiple administrations.These findings highlight the potential of Sgc8c-M as an effective antitumor agent and provide useful insights for the clinical translation of emerging ApDCs.展开更多
Gene therapy,a revolutionary approach to treating genetic disorders,aims to introduce functional genes into cells to correct genetic defects.Liposomes,artificial lipid vesicles,have emerged as promising nonviral vecto...Gene therapy,a revolutionary approach to treating genetic disorders,aims to introduce functional genes into cells to correct genetic defects.Liposomes,artificial lipid vesicles,have emerged as promising nonviral vectors for gene delivery.Owing to their biocompatibility,versatility,and ability to encapsulate various therapeutic molecules,liposomes are ideal candidates for gene therapy.This review explores the principles of liposome-based gene therapy,including composition,mechanisms of action,and applications.We discuss the challenges and limitations of liposome-mediated gene delivery and ongoing research efforts to improve their efficacy and safety.In conclusion,liposomes offer a promising avenue for developing effective and safe gene therapies for various genetic diseases.展开更多
基金supported by the National Natural Science Foundation of China(81673466,81821005,32322048,22225702,92153302,32471497,82404655,and 82273951)Guangdong High-level New R&D Institute(2019B090904008)+8 种基金Guangdong High-level Innovative Research Institute(2021B0909050003)Science and Technology Commission of Shanghai Municipality(18431907100 and 19430750100)the National Key Research and Development Program of China(2020YFE0202200)Program of Shanghai Academic Research Leader(2XD1420900)Shanghai Rising-Star Program(22QA1411100)the Youth Innovation Promotion Association(CAS2021276)the support of the Sanofi scholarship program,Shandong Laboratory Program(SYS202205)Taishan Scholars Program(tstp0648)Innovative Research Team of High-level Local Universities in Shanghai,and Shanghai Science and Technology Development Funds(24YF2755300)。
文摘Acute myeloid leukaemia(AML)is characterized mainly by an increase in the number of myeloid cells in the bone marrow and a decrease in the number of mature cells;AML accounts for 28%of leukaemia cases,and it has a five-year survival rate of only30.5%[1].The prognosis of AML patients is mostly poor,and drug resistance eventually emerges with the long-term use of chemotherapy or targeted therapy;this drug resistance represents a daunting challenge in the management of AML[2,3].
基金funded by the National Key Research and Development Program of China(2023YFC3405100)the“Pioneer”and“Leading Goose”R&D Program of Zhejiang(2023SDYXS0001 and 2025C01109)+2 种基金the Zhejiang Provincial Natural Science Foundation of China(LDQ24B020002 and LDQ23B050001)the National Natural Science Foundation of China(No.22104132)the Zhejiang Province“Kunpeng Action”Program.
文摘Aptamers serve as unique targeting ligands,making aptamer-drug conjugates(ApDCs)an attractive strategy for targeted cancer therapy.This study performs a comprehensive evaluation from rodents to non-human primates(NHP)of a protein tyrosine kinase 7(PTK7)-targeted ApDC(Sgc8c-M)made by conjugating the potent antimitotic agent monomethyl auristatin E(MMAE)to the classic PTK7 aptamer Sgc8c.Efficacy studies in various cancer types with PTK7 overexpression showed that Sgc8c-M effectively induces sustained tumor regression in cell line-derived and patient-derived xenografts,outperforming unconjugated MMAE,the chemotherapy drug paclitaxel,and a PTK7-targeted antibody-drug conjugate.Pharmacokinetic(PK)studies in mice revealed that Sgc8c-M leads to rapid accumulation and sustained MMAE levels in tumors,along with fast clearance from plasma and normal tissues.Further study in rats confirmed rapid clearance across most organs and revealed that over 75%of MMAE was excreted through urine and feces within 24 h.Toxicokinetic(TK)assessments indicated comparable systemic drug exposure without accumulation for repeated doses compared to single administration.Toxicity evaluations showed that the therapeutic dose with high efficacy was safe and that the toxicity resulting from extremely high doses could be reversibly controlled.Encouraged by these findings,we evaluated PK/TK profiles and safety of Sgc8c-M in cynomolgus monkeys.Similar to PK/TK profiles observed in rats,Sgc8c-M demonstrated good dose-dependent drug exposure.It was,moreover,well tolerated in monkeys with no obvious accumulation following multiple administrations.These findings highlight the potential of Sgc8c-M as an effective antitumor agent and provide useful insights for the clinical translation of emerging ApDCs.
基金supported by the SEEDgrant(2023/0298)sanctioned by GITAM(deemed tobe University),Vishakhapatnam,Andhra Pradesh。
文摘Gene therapy,a revolutionary approach to treating genetic disorders,aims to introduce functional genes into cells to correct genetic defects.Liposomes,artificial lipid vesicles,have emerged as promising nonviral vectors for gene delivery.Owing to their biocompatibility,versatility,and ability to encapsulate various therapeutic molecules,liposomes are ideal candidates for gene therapy.This review explores the principles of liposome-based gene therapy,including composition,mechanisms of action,and applications.We discuss the challenges and limitations of liposome-mediated gene delivery and ongoing research efforts to improve their efficacy and safety.In conclusion,liposomes offer a promising avenue for developing effective and safe gene therapies for various genetic diseases.
