1. Aptamer functionalized hypoxia-potentiating agent and hypoxia-inducible factor inhibitor combined with hypoxia-activated prodrug for enhanced tumor therapy.
- Author
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Ma Y, Zhang H, Shen X, Yang X, Deng Y, Tian Y, Chen Z, Pan Y, Luo H, Zhong C, Yu S, Lu A, Zhang B, Tang T, and Zhang G
- Subjects
- Animals, Humans, Female, Mice, Cell Line, Tumor, Xenograft Model Antitumor Assays, Mice, Nude, Mice, Inbred BALB C, Anthraquinones, Prodrugs pharmacology, Triple Negative Breast Neoplasms drug therapy, Triple Negative Breast Neoplasms metabolism, Triple Negative Breast Neoplasms pathology, Aptamers, Nucleotide pharmacology, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Hypoxia-Inducible Factor 1, alpha Subunit genetics, Hypoxia-Inducible Factor 1, alpha Subunit antagonists & inhibitors
- Abstract
Triple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer. Hypoxia-activated prodrugs (HAPs) have shown promise as potential therapeutic agents for TNBC. While increasing hypoxia levels may promote the HAP activation, it raises concerns regarding HIF1α-dependent drug resistance. It is desirable to develop a targeted approach that enhances tumor hypoxia for HAP activation without promoting HIF1α-dependent drug resistance in TNBC treatment. Herein, we proposed a multi-responsive carrier-free self-assembled nanomedicine named AQ4N@CA4T1ASO. This nanomedicine first targeted tumors by the TNBC-targeting aptamers (T1), and then disassembled in the reductive and acidic conditions within tumors. The released Combretastatin 4 (CA4) could exacerbate hypoxia, thereby promoting the conversion of inactive Banoxantrone (AQ4N) to its active form, AQ4. Simultaneously, the released antisense oligonucleotide (ASO) could attenuate hypoxia-induced HIF1α mRNA expression, thereby sensitizing the tumor to chemotherapy. Overall, this smart nanomedicine represents a profound targeted therapy strategy, combining "hypoxia-potentiating, hypoxia-activated, chemo-sensitization" approaches for TNBC treatment. In vivo study demonstrated significant suppression of tumor growth, highlighting the promising potential of this nanomedicine for future clinical translation., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2024
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