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Selectively Potentiating Hypoxia Levels by Combretastatin A4 Nanomedicine: Toward Highly Enhanced Hypoxia‐Activated Prodrug Tirapazamine Therapy for Metastatic Tumors
Author(s) -
Yang Shengcai,
Tang Zhaohui,
Hu Chenyang,
Zhang Dawei,
Shen Na,
Yu Haiyang,
Chen Xuesi
Publication year - 2019
Publication title -
advanced materials
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 10.707
H-Index - 527
eISSN - 1521-4095
pISSN - 0935-9648
DOI - 10.1002/adma.201805955
Subject(s) - tirapazamine , tumor hypoxia , nanomedicine , prodrug , hypoxia (environmental) , cancer research , ethylene glycol , combretastatin , materials science , combination therapy , misonidazole , pharmacology , medicine , radiation therapy , chemistry , cytotoxicity , nanotechnology , oxygen , in vitro , nanoparticle , biochemistry , organic chemistry , biology , microtubule , tubulin , microbiology and biotechnology
Hypoxia‐activated prodrugs (HAPs) have the potential to selectively kill hypoxic cells and convert tumor hypoxia from a problem to a selective treatment advantage. However, HAPs are unsuccessful in most clinical trials owing to inadequate hypoxia within the treated tumors, as implied by a further substudy of a phase II clinical trial. Here, a novel strategy for the combination of HAPs plus vascular disrupting agent (VDA) nanomedicine for efficacious solid tumor therapy is developed. An effective VDA nanomedicine of poly( l ‐glutamic acid)‐ graft ‐methoxy poly(ethylene glycol)/combretastatin A4 (CA4‐NPs) is prepared and can selectively enhance tumor hypoxia and boost a typical HAP tirapazamine (TPZ) therapy against metastatic 4T1 breast tumors. After treatment with the combination of TPZ plus CA4‐NPs, complete tumor reduction is observed in 4T1 xenograft mice (initial tumor volume is 180 mm 3 ), and significant tumor shrinkage and antimetastatic effects are observed in challenging large tumors with initial volume of 500 mm 3 . The report here highlights the potential of using a combination of HAPs plus VDA nanomedicine in solid tumor therapy.