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Combretastatin A4 Nanodrug‐Induced MMP9 Amplification Boosts Tumor‐Selective Release of Doxorubicin Prodrug
Author(s) -
Jiang Jian,
Shen Na,
Ci Tianyuan,
Tang Zhaohui,
Gu Zhen,
Li Gao,
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.201904278
Subject(s) - prodrug , mmp9 , doxorubicin , pharmacology , matrix metalloproteinase , cancer research , materials science , chemistry , chemotherapy , medicine , downregulation and upregulation , biochemistry , gene
Tumor‐associated enzyme‐activated prodrugs can potentially improve the selectivity of chemotherapeutics. However, the paucity of tumor‐associated enzymes which are essential for prodrug activation usually limits the antitumor potency. A cooperative strategy that utilizes combretastatin A4 nanodrug (CA4‐NPs) and matrix metalloproteinase 9 (MMP9)‐activated doxorubicin prodrug (MMP9‐DOX‐NPs) is developed. CA4 is a typical vascular disrupting agent that can selectively disrupt immature tumor blood vessels and exacerbate the tumor hypoxia state. After treatment with CA4‐NPs, MMP9 expression can be significantly enhanced by 5.6‐fold in treated tumors, which further boosts tumor‐selective active drug release of MMP9‐DOX‐NPs by 3.7‐fold in an orthotopic 4T1 mammary adenocarcinoma mouse model. The sequential delivery of CA4‐NPs and MMP9‐DOX‐NPs exhibits enhanced antitumor efficacy with reduced systemic toxicity compared with the noncooperative controls.