Intensive cancer treatment with drug combination is widely exploited in the clinic but suffers from inconsistent pharmacokinetics among different therapeutic agents.To overcome it,the emerging nanomedicine offers an u...Intensive cancer treatment with drug combination is widely exploited in the clinic but suffers from inconsistent pharmacokinetics among different therapeutic agents.To overcome it,the emerging nanomedicine offers an unparalleled opportunity for encapsulating multiple drugs in a nano-carrier.Herein,a two-step super-assembled strategy was performed to unify the pharmacokinetics of a peptide and a small molecular compound.In this proof-of-concept study,the bioinformatics analysis firstly revealed the potential synergies towards hepatoma therapy for the associative inhibition of exportin 1(XPO1)and ataxia telangiectasia mutated-Rad3-related(ATR),and then a super-assembled nano-pill(gold nano drug carrier loaded AZD6738 and 97110 amino acids of apoptin(AP)(AA@G))was constructed through camouflaging AZD6738(ATR small-molecule inhibitor)-binding human serum albumin onto the AP-Au supramolecular nanoparticle.As expected,both in vitro and in vivo experiment results verified that the AA@G possessed extraordinary biocompatibility and enhanced therapeutic effect through inducing cell cycle arrest,promoting DNA damage and inhibiting DNA repair of hepatoma cell.This work not only provides a co-delivery strategy for intensive liver cancer treatment with the clinical translational potential,but develops a common approach to unify the pharmacokinetics of peptide and small-molecular compounds,thereby extending the scope of drugs for developing the advanced combination therapy.展开更多
Cellular homeostasis crucially relies on the correct nucleocytoplasmic distribution of a vast number of proteins and RNA molecules,which are shuttled in and out of the nucleus by specialized transport receptors.The nu...Cellular homeostasis crucially relies on the correct nucleocytoplasmic distribution of a vast number of proteins and RNA molecules,which are shuttled in and out of the nucleus by specialized transport receptors.The nuclear export receptor XPO1,also called CRM1,mediates the translocation of hundreds of proteins and several classes of RNA to the cytoplasm,and thus regulates critical signaling pathways and cellular functions.The normal function of XPO1 appears to be often disrupted in malignant cells due to gene mutations or,most commonly,aberrant overexpression.Due to its important physiological roles and its frequent alteration in human tumors,XPO1 is a promising target for cancer therapy.XPO1 inhibitors have undergone extensive testing as therapeutic agents in preclinical models of cancer,with promising results.One of these inhibitors,Selinexor,is currently being evaluated in multiple clinical trials of different types of solid tumors and hematological malignancies.Here,we review several key aspects of XPO1 function,as well as the mechanisms that may lead to its alteration in cancer,and provide an update on the status of XPO1 inhibitors being developed as drugs for cancer therapy,including the definitive results of the first clinical trials with Selinexor that have been recently published.展开更多
基金supported by the National Natural Science Foundation of China(Grant Nos.:81272488 and 81602802)the Shaanxi Province Innovation Capacity Support Program(Grant No.:2018TD-002).
文摘Intensive cancer treatment with drug combination is widely exploited in the clinic but suffers from inconsistent pharmacokinetics among different therapeutic agents.To overcome it,the emerging nanomedicine offers an unparalleled opportunity for encapsulating multiple drugs in a nano-carrier.Herein,a two-step super-assembled strategy was performed to unify the pharmacokinetics of a peptide and a small molecular compound.In this proof-of-concept study,the bioinformatics analysis firstly revealed the potential synergies towards hepatoma therapy for the associative inhibition of exportin 1(XPO1)and ataxia telangiectasia mutated-Rad3-related(ATR),and then a super-assembled nano-pill(gold nano drug carrier loaded AZD6738 and 97110 amino acids of apoptin(AP)(AA@G))was constructed through camouflaging AZD6738(ATR small-molecule inhibitor)-binding human serum albumin onto the AP-Au supramolecular nanoparticle.As expected,both in vitro and in vivo experiment results verified that the AA@G possessed extraordinary biocompatibility and enhanced therapeutic effect through inducing cell cycle arrest,promoting DNA damage and inhibiting DNA repair of hepatoma cell.This work not only provides a co-delivery strategy for intensive liver cancer treatment with the clinical translational potential,but develops a common approach to unify the pharmacokinetics of peptide and small-molecular compounds,thereby extending the scope of drugs for developing the advanced combination therapy.
基金We thank our colleagues at the UPV/EHU Dr.Sonia Bañuelos(Dept.of Biochemistry and Molecular Biology),Dr.Gorka Prieto(Dept.of Communication Engineering)and Dr.Asier Fullaondo(Dept.of Genetics,Physical Anthropology and Animal Physiology)for their help in preparing Figures 2 and 3.Supported by grants from the Spanish Government MINECO-FEDER(SAF2014-57743-R)the Basque Country Government(IT634-13)the University of the Basque Country(UFI11/20),as well as a fellowship from the Basque Country Government(to MS)。
文摘Cellular homeostasis crucially relies on the correct nucleocytoplasmic distribution of a vast number of proteins and RNA molecules,which are shuttled in and out of the nucleus by specialized transport receptors.The nuclear export receptor XPO1,also called CRM1,mediates the translocation of hundreds of proteins and several classes of RNA to the cytoplasm,and thus regulates critical signaling pathways and cellular functions.The normal function of XPO1 appears to be often disrupted in malignant cells due to gene mutations or,most commonly,aberrant overexpression.Due to its important physiological roles and its frequent alteration in human tumors,XPO1 is a promising target for cancer therapy.XPO1 inhibitors have undergone extensive testing as therapeutic agents in preclinical models of cancer,with promising results.One of these inhibitors,Selinexor,is currently being evaluated in multiple clinical trials of different types of solid tumors and hematological malignancies.Here,we review several key aspects of XPO1 function,as well as the mechanisms that may lead to its alteration in cancer,and provide an update on the status of XPO1 inhibitors being developed as drugs for cancer therapy,including the definitive results of the first clinical trials with Selinexor that have been recently published.
