Gliomas are the most common intracranial tumors with poor survival and high mortality.Furthermore,the clinical efficacy of current drugs is still not ideal;despite the development of several therapeutic drugs over the...Gliomas are the most common intracranial tumors with poor survival and high mortality.Furthermore,the clinical efficacy of current drugs is still not ideal;despite the development of several therapeutic drugs over the past decades and tumor progression or recurrence is inevitable in many patients.RNAibased therapy presents a novel disease-related gene targeting therapy,including otherwise undruggable genes,and generates therapeutic options.However,the therapeutic effect of siRNA is hindered by multiple biological barriers,primarily the blood-brain barrier(BBB).A glycoprotein-derived peptide-mediated delivery system is the preferred option to resolve this phenomenon.RDP,a polypeptide composed of 15 amino acids derived from rabies virus glycoprotein(RVG),possesses an N-type acetylcholine receptor(nAChR)-binding efficiency similar to that of RVG29.Given its lower cost and small particle size when used as a ligand,RDP should be extensively evaluated.First,we verified the brain-targeting efficacyy of RDP at the cellular and animal levels and further explored the possibility of using the RDP-oligoarginine peptide(designated RDP-5R)as a bio-safe vehicle to deliver therapeutic siRNA into glioma cells in vitro and in vivo.The polypeptide carrier possesses a diblock design composed of oligoarginine for binding siRNA through electrostatic interactions and RDP for cascade BBB-and glioma cell-targeting.The results indicated that RDP-R5/siRNA nanoparticles exhibited stable and suitable physicochemical properties for in vivo application,desirable glioma-targeting effects,and therapeutic efficiency.As a novel and efficient polypeptide carrier,RDP-based polypeptides hold great promise as a noninvasive,safe,and efficient treatment for various brain diseases.展开更多
Embolization that deliberately blocks target blood vessels through the delivery of embolic agents has emerged as a preferred therapy for various vascular-related diseases.Although various embolic materials are availab...Embolization that deliberately blocks target blood vessels through the delivery of embolic agents has emerged as a preferred therapy for various vascular-related diseases.Although various embolic materials are available in clinical practice,including solid and liquid embolic agents,their effectiveness remains limited in target vessels with broad size ranges and complex architectures.These limitations pose challenges in achieving controlled and durable embolization at target sites.To address these issues,we develop an advanced physically/chemically dual-crosslinked hydrogel(DC-gel)composed of thermosensitive poly(ethylene glycol)-poly(D-amino acid)copolymers and triethoxysilane-capped 4-arm poly(ethylene glycol)macromolecule crosslinkers,which exhibits superior injectability and high mechanical strength.The physically-crosslinked network is formed by a sol-gel transition mediated by thermosensitive copolymers,which ensures catheter injectability while being robust enough to retain DC-gel at the injected region.Subsequently,the controlled in-situ chemical-crosslinking mediated by macromolecule crosslinkers provides additional mechanical strength for durable vascular embolization.Furthermore,an oily contrast agent with an ultrahigh iodine amount(>60 wt%)is developed and incorporated into DC-gel to endow it with long-lasting imaging capabilities for real-time and post-operative visualization.In vivo experiments conducted on rabbit artery,vein and tumor models confirm that our DC-gel system achieves persistent embolization without recanalization or non-target embolization,which stems from its superior mechanical stability and long-term persistence obtained by the dual crosslinking strategy plus a moderate fibroinflammatory response induced by the poly(D-amino acid)component.Overall,DC-gel represents a highly promising embolic material that addresses current limitations in embolization therapy,offering enhanced controllability,durability,and imaging capabilities for clinical applications.展开更多
基金supported by CAMS Innovation Fund for Medical Sciences(No.2021-I2M-1-026,China).
文摘Gliomas are the most common intracranial tumors with poor survival and high mortality.Furthermore,the clinical efficacy of current drugs is still not ideal;despite the development of several therapeutic drugs over the past decades and tumor progression or recurrence is inevitable in many patients.RNAibased therapy presents a novel disease-related gene targeting therapy,including otherwise undruggable genes,and generates therapeutic options.However,the therapeutic effect of siRNA is hindered by multiple biological barriers,primarily the blood-brain barrier(BBB).A glycoprotein-derived peptide-mediated delivery system is the preferred option to resolve this phenomenon.RDP,a polypeptide composed of 15 amino acids derived from rabies virus glycoprotein(RVG),possesses an N-type acetylcholine receptor(nAChR)-binding efficiency similar to that of RVG29.Given its lower cost and small particle size when used as a ligand,RDP should be extensively evaluated.First,we verified the brain-targeting efficacyy of RDP at the cellular and animal levels and further explored the possibility of using the RDP-oligoarginine peptide(designated RDP-5R)as a bio-safe vehicle to deliver therapeutic siRNA into glioma cells in vitro and in vivo.The polypeptide carrier possesses a diblock design composed of oligoarginine for binding siRNA through electrostatic interactions and RDP for cascade BBB-and glioma cell-targeting.The results indicated that RDP-R5/siRNA nanoparticles exhibited stable and suitable physicochemical properties for in vivo application,desirable glioma-targeting effects,and therapeutic efficiency.As a novel and efficient polypeptide carrier,RDP-based polypeptides hold great promise as a noninvasive,safe,and efficient treatment for various brain diseases.
基金supported by the Natural Science Foundation of Shanghai(grant no.23ZR1406800)the National Natural Science Foundation of China(grant no.22475052)Special Project for Emerging Interdisciplinary Research in the Health Industry of the Shanghai Municipal Health Commission(grant no.2022JC030).
文摘Embolization that deliberately blocks target blood vessels through the delivery of embolic agents has emerged as a preferred therapy for various vascular-related diseases.Although various embolic materials are available in clinical practice,including solid and liquid embolic agents,their effectiveness remains limited in target vessels with broad size ranges and complex architectures.These limitations pose challenges in achieving controlled and durable embolization at target sites.To address these issues,we develop an advanced physically/chemically dual-crosslinked hydrogel(DC-gel)composed of thermosensitive poly(ethylene glycol)-poly(D-amino acid)copolymers and triethoxysilane-capped 4-arm poly(ethylene glycol)macromolecule crosslinkers,which exhibits superior injectability and high mechanical strength.The physically-crosslinked network is formed by a sol-gel transition mediated by thermosensitive copolymers,which ensures catheter injectability while being robust enough to retain DC-gel at the injected region.Subsequently,the controlled in-situ chemical-crosslinking mediated by macromolecule crosslinkers provides additional mechanical strength for durable vascular embolization.Furthermore,an oily contrast agent with an ultrahigh iodine amount(>60 wt%)is developed and incorporated into DC-gel to endow it with long-lasting imaging capabilities for real-time and post-operative visualization.In vivo experiments conducted on rabbit artery,vein and tumor models confirm that our DC-gel system achieves persistent embolization without recanalization or non-target embolization,which stems from its superior mechanical stability and long-term persistence obtained by the dual crosslinking strategy plus a moderate fibroinflammatory response induced by the poly(D-amino acid)component.Overall,DC-gel represents a highly promising embolic material that addresses current limitations in embolization therapy,offering enhanced controllability,durability,and imaging capabilities for clinical applications.
