Multi-drug resistant cancer cells with over-expression of Bcl2 anti-apoptotic proteins can be effectively killed by transfecting them with Nur77 transcription factor(pNur77).Previous attempts are generally therapeutic...Multi-drug resistant cancer cells with over-expression of Bcl2 anti-apoptotic proteins can be effectively killed by transfecting them with Nur77 transcription factor(pNur77).Previous attempts are generally therapeutically unsatisfactory due to low sustained gene expression and are further disadvantaged by their multi-component designs requiring complicated preparation.Herein,we designed a single cationic amphiphilic copolymer from branched poly(ethylenimine)(PEI-25k),the gold standard non-viral vector,that functions simultaneously as the non-viral vector and hydrogel forming polymeric matrix.Our single-component hydrogel gene delivery platform is highly facile to prepare as it only requires co-dissolution of the copolymer with pNur77 to form a homogeneous sol.Due to the high cationic charge density of PEI-25k,this PEIbased copolymer effectively complexes a high payload of the plasmid.Subsequently,the copolymer's thermogelling ability enables it to spontaneously selfassemble into a hydrogel depot by simply being warmed to physiological temperatures upon intra-tumoral injection.Leveraging upon the high transfection efficiency of PEI-25k,this PEI-based thermogel achieved prolonged localized release of pNur77 with high transfection efficiency.This leads to successful tumor size reduction and suppressed tumor reoccurrence in mouse models with low systemic cytotoxicity.We believe this single-component cationic thermogel non-viral gene delivery platform is highly attractive for gene therapy.展开更多
CONSPECTUS:Temperature responsive supramolecular hydrogels,also known as thermogels,are produced by the self-assembly of amphiphilic copolymers in solution following temperature stimulus.They are a class of high calib...CONSPECTUS:Temperature responsive supramolecular hydrogels,also known as thermogels,are produced by the self-assembly of amphiphilic copolymers in solution following temperature stimulus.They are a class of high caliber novel materials possessing highly attractive properties such as injectability,ability to undergo temperature controlled reversible sol−gel phase transitions,high biocompatibility,and tunable biodegradability.Much research vigor has been dedicated to designing advanced amphiphilic copolymers and investigating their molecular interactions in order to enhance the properties of the thermogelling systems and expand the scope of their applications.As such,thermogelling systems have since become well established in the field of sustained localized drug or protein delivery and have also been demonstrated as high potential materials for niche applications such as threedimensional cell culture,wound healing patches,and vitreous endotamponades.Recent developments saw the advent of thermogelling systems with advanced biomedical applications ranging from enhanced cancer therapy to radiology imaging to tissue engineering,and these are usually achieved by the conjugating of biologically relevant molecules such as drugs and peptides to the thermogel copolymer or by incorporating nanoparticles into the thermogel systems.New developments in this field see a shift away from employing traditional synthetic polymers such as polypropylene glycol(PPG)and poly(lactic-co-glycolic acid)(PLGA)to utilizing more advanced nature-derived bioactive molecules and also introducing chiral moieties in the thermogelling copolymer backbone.展开更多
基金Agency for Science,Technology and ResearchIAF-PP grant,Grant/Award Number:H20c6a0033+1 种基金National Research Foundation Singapore,Grant/Award Number:NRF-NRFI07-2021-0003Natural Science Foundation of China,Grant/Award Number:82173750。
文摘Multi-drug resistant cancer cells with over-expression of Bcl2 anti-apoptotic proteins can be effectively killed by transfecting them with Nur77 transcription factor(pNur77).Previous attempts are generally therapeutically unsatisfactory due to low sustained gene expression and are further disadvantaged by their multi-component designs requiring complicated preparation.Herein,we designed a single cationic amphiphilic copolymer from branched poly(ethylenimine)(PEI-25k),the gold standard non-viral vector,that functions simultaneously as the non-viral vector and hydrogel forming polymeric matrix.Our single-component hydrogel gene delivery platform is highly facile to prepare as it only requires co-dissolution of the copolymer with pNur77 to form a homogeneous sol.Due to the high cationic charge density of PEI-25k,this PEIbased copolymer effectively complexes a high payload of the plasmid.Subsequently,the copolymer's thermogelling ability enables it to spontaneously selfassemble into a hydrogel depot by simply being warmed to physiological temperatures upon intra-tumoral injection.Leveraging upon the high transfection efficiency of PEI-25k,this PEI-based thermogel achieved prolonged localized release of pNur77 with high transfection efficiency.This leads to successful tumor size reduction and suppressed tumor reoccurrence in mouse models with low systemic cytotoxicity.We believe this single-component cationic thermogel non-viral gene delivery platform is highly attractive for gene therapy.
基金This work was supported by an IAF-PP(HMBS Domain)grant H17/01/a0/013(OrBID):OculaR Biomaterials and Device.
文摘CONSPECTUS:Temperature responsive supramolecular hydrogels,also known as thermogels,are produced by the self-assembly of amphiphilic copolymers in solution following temperature stimulus.They are a class of high caliber novel materials possessing highly attractive properties such as injectability,ability to undergo temperature controlled reversible sol−gel phase transitions,high biocompatibility,and tunable biodegradability.Much research vigor has been dedicated to designing advanced amphiphilic copolymers and investigating their molecular interactions in order to enhance the properties of the thermogelling systems and expand the scope of their applications.As such,thermogelling systems have since become well established in the field of sustained localized drug or protein delivery and have also been demonstrated as high potential materials for niche applications such as threedimensional cell culture,wound healing patches,and vitreous endotamponades.Recent developments saw the advent of thermogelling systems with advanced biomedical applications ranging from enhanced cancer therapy to radiology imaging to tissue engineering,and these are usually achieved by the conjugating of biologically relevant molecules such as drugs and peptides to the thermogel copolymer or by incorporating nanoparticles into the thermogel systems.New developments in this field see a shift away from employing traditional synthetic polymers such as polypropylene glycol(PPG)and poly(lactic-co-glycolic acid)(PLGA)to utilizing more advanced nature-derived bioactive molecules and also introducing chiral moieties in the thermogelling copolymer backbone.
