Exosome is an excellent vesicle for in vivo delivery of therapeutics,including RNAi and chemical drugs.The extremely high efficiency in cancer regression can partly be attributed to its fusion mechanism in delivering ...Exosome is an excellent vesicle for in vivo delivery of therapeutics,including RNAi and chemical drugs.The extremely high efficiency in cancer regression can partly be attributed to its fusion mechanism in delivering therapeutics to cytosol without endosome trapping.However,being composed of a lipidbilayer membrane without specific recognition capacity for aimed-cells,the entry into nonspecific cells can lead to potential side-effects and toxicity.Applying engineering approaches for targeting-capacity to deliver therapeutics to specific cells is desirable.Techniques with chemical modification in vitro and genetic engineering in cells have been reported to decorate exosomes with targeting ligands.RNA nanoparticles have been used to harbor tumor-specific ligands displayed on exosome surface.The negative charge reduces nonspecific binding to vital cells with negatively charged lipid-membrane due to the electrostatic repulsion,thus lowering the side-effect and toxicity.In this review,we focus on the uniqueness of RNA nanoparticles for exosome surface display of chemical ligands,small peptides or RNA aptamers,for specific cancer targeting to deliver anticancer therapeutics,highlighting recent advances in targeted delivery of siRNA and miRNA that overcomes the previous RNAi delivery roadblocks.Proper understanding of exosome engineering with RNA nanotechnology promises efficient therapies for a wide range of cancer subtypes.展开更多
DNA topoisomerase IIα(170 kDa,TOP2α/170)induces transient DNA double-strand breaks in proliferating cells to resolve DNA topological entanglements during chromosome condensation,replication,and segregation.Therefore...DNA topoisomerase IIα(170 kDa,TOP2α/170)induces transient DNA double-strand breaks in proliferating cells to resolve DNA topological entanglements during chromosome condensation,replication,and segregation.Therefore,TOP2α/170 is a prominent target for anticancer drugs whose clinical efficacy is often compromised due to chemoresistance.Although many resistance mechanisms have been defined,acquired resistance of human cancer cell lines to TOP2αinterfacial inhibitors/poisons is frequently associated with a reduction of Top2α/170 expression levels.Recent studies by our laboratory,in conjunction with earlier findings by other investigators,support the hypothesis that a major mechanism of acquired resistance to TOP2α-targeted drugs is due to alternative RNA processing/splicing.Specifically,several TOP2αmRNA splice variants have been reported which retain introns and are translated into truncated TOP2αisoforms lacking nuclear localization sequences and subsequent dysregulated nuclear-cytoplasmic disposition.In addition,intron retention can lead to truncated isoforms that lack both nuclear localization sequences and the active site tyrosine(Tyr805)necessary for forming enzyme-DNA covalent complexes and inducing DNA damage in the presence of TOP2α-targeted drugs.Ultimately,these truncated TOP2αisoforms result in decreased drug activity against TOP2αin the nucleus and manifest drug resistance.Therefore,the complete characterization of the mechanism(s)regulating the alternative RNA processing of TOP2αpre-mRNA may result in new strategies to circumvent acquired drug resistance.Additionally,novel TOP2αsplice variants and truncated TOP2αisoforms may be useful as biomarkers for drug resistance,prognosis,and/or direct future TOP2α-targeted therapies.展开更多
基金supported in part by NIH grants U01CA207946 and R01EB019036 to Peixuan Guo and NIH grant R01CA257961 to Dan Shu and Daniel W.Binzelfunded by the CM Chen Foundationsupported in part by Grant P30CA016058,National Cancer Institute,Bethesda,MD。
文摘Exosome is an excellent vesicle for in vivo delivery of therapeutics,including RNAi and chemical drugs.The extremely high efficiency in cancer regression can partly be attributed to its fusion mechanism in delivering therapeutics to cytosol without endosome trapping.However,being composed of a lipidbilayer membrane without specific recognition capacity for aimed-cells,the entry into nonspecific cells can lead to potential side-effects and toxicity.Applying engineering approaches for targeting-capacity to deliver therapeutics to specific cells is desirable.Techniques with chemical modification in vitro and genetic engineering in cells have been reported to decorate exosomes with targeting ligands.RNA nanoparticles have been used to harbor tumor-specific ligands displayed on exosome surface.The negative charge reduces nonspecific binding to vital cells with negatively charged lipid-membrane due to the electrostatic repulsion,thus lowering the side-effect and toxicity.In this review,we focus on the uniqueness of RNA nanoparticles for exosome surface display of chemical ligands,small peptides or RNA aptamers,for specific cancer targeting to deliver anticancer therapeutics,highlighting recent advances in targeted delivery of siRNA and miRNA that overcomes the previous RNAi delivery roadblocks.Proper understanding of exosome engineering with RNA nanotechnology promises efficient therapies for a wide range of cancer subtypes.
基金This work was supported by the National Institutes of Health National Cancer Institute(Grant R01 CA226906-01A1).
文摘DNA topoisomerase IIα(170 kDa,TOP2α/170)induces transient DNA double-strand breaks in proliferating cells to resolve DNA topological entanglements during chromosome condensation,replication,and segregation.Therefore,TOP2α/170 is a prominent target for anticancer drugs whose clinical efficacy is often compromised due to chemoresistance.Although many resistance mechanisms have been defined,acquired resistance of human cancer cell lines to TOP2αinterfacial inhibitors/poisons is frequently associated with a reduction of Top2α/170 expression levels.Recent studies by our laboratory,in conjunction with earlier findings by other investigators,support the hypothesis that a major mechanism of acquired resistance to TOP2α-targeted drugs is due to alternative RNA processing/splicing.Specifically,several TOP2αmRNA splice variants have been reported which retain introns and are translated into truncated TOP2αisoforms lacking nuclear localization sequences and subsequent dysregulated nuclear-cytoplasmic disposition.In addition,intron retention can lead to truncated isoforms that lack both nuclear localization sequences and the active site tyrosine(Tyr805)necessary for forming enzyme-DNA covalent complexes and inducing DNA damage in the presence of TOP2α-targeted drugs.Ultimately,these truncated TOP2αisoforms result in decreased drug activity against TOP2αin the nucleus and manifest drug resistance.Therefore,the complete characterization of the mechanism(s)regulating the alternative RNA processing of TOP2αpre-mRNA may result in new strategies to circumvent acquired drug resistance.Additionally,novel TOP2αsplice variants and truncated TOP2αisoforms may be useful as biomarkers for drug resistance,prognosis,and/or direct future TOP2α-targeted therapies.
