Though the development of the diverse hypoxia-activated prodrugs(HAPs)has made great progresses in the last several decades,current cancer therapy based on HAPs still suffers many obstacles,e.g.,poor therapeutic outco...Though the development of the diverse hypoxia-activated prodrugs(HAPs)has made great progresses in the last several decades,current cancer therapy based on HAPs still suffers many obstacles,e.g.,poor therapeutic outcome owing to hard deep reaching to hypoxic region,and the occurrence of metastasis due to hypoxia.Inspired by engineered niches,a novel functional chitosan polymer(CS-FTP)is synthesized for construction of a hydrogel-based bio-niche(CS-FTP-gel)in aiming at remodeling tumor hypoxic microenvironment.The CS-FTP polymers are crosslinked to form a niche-like hydrogel via enzyme-mediated oxygen-consumable dimerization after injected into tumor,in which a HAP(i.e.,AQ4N)could be physically encapsulated,resulting in enhanced tumor hypoxia to facilitate AQ4N-AQ4 toxic transformation for maximizing efficacy of chemotherapy.Furthermore,Pazopanib(PAZ)conjugated onto the CS backbone via ROS-sensitive linker undergoes a stimuli-responsive release behavior to promote antiangiogenesis for tumor starvation,eventually contributing to the inhibition of lung metastasis and synergistic action with AQ4N-based chemotherapy for an orthotopic 4T1 breast tumor model.This study provides a promising strategy for hypoxia-based chemotherapy and demonstrates an encouraging clinical potential for multifunctional hydrogel applicable for antitumor treatment.展开更多
基金National Key Research and Development Program of China(Grant No.2021YFB3801001)National Natural Science Foundation of China(Grant Nos.32030061)+2 种基金Key Program for Basic Research of Shanghai(Grant No.19JC1415600,21JC1406000)All the animal experiments were performed with the approval of the Fudan University Experimental Animal Centeranimal biomedical research authorization numbered is 2020-Cancer hospital-JS220.
文摘Though the development of the diverse hypoxia-activated prodrugs(HAPs)has made great progresses in the last several decades,current cancer therapy based on HAPs still suffers many obstacles,e.g.,poor therapeutic outcome owing to hard deep reaching to hypoxic region,and the occurrence of metastasis due to hypoxia.Inspired by engineered niches,a novel functional chitosan polymer(CS-FTP)is synthesized for construction of a hydrogel-based bio-niche(CS-FTP-gel)in aiming at remodeling tumor hypoxic microenvironment.The CS-FTP polymers are crosslinked to form a niche-like hydrogel via enzyme-mediated oxygen-consumable dimerization after injected into tumor,in which a HAP(i.e.,AQ4N)could be physically encapsulated,resulting in enhanced tumor hypoxia to facilitate AQ4N-AQ4 toxic transformation for maximizing efficacy of chemotherapy.Furthermore,Pazopanib(PAZ)conjugated onto the CS backbone via ROS-sensitive linker undergoes a stimuli-responsive release behavior to promote antiangiogenesis for tumor starvation,eventually contributing to the inhibition of lung metastasis and synergistic action with AQ4N-based chemotherapy for an orthotopic 4T1 breast tumor model.This study provides a promising strategy for hypoxia-based chemotherapy and demonstrates an encouraging clinical potential for multifunctional hydrogel applicable for antitumor treatment.
