Abstract
Membrane receptors overexpressed in diseased states are considered novel therapeutic targets. However, the single targeting approach faces several fundamental issues, such as poor efficacy, resistance, and toxicity. Here, we report a dual-targeting strategy to enhance anti-cancer efficacy via synergistic proximity interactions between therapeutics and two receptor proteins. Importantly, we report the first finding of an interaction between c-Met and nucleolin and demonstrate the therapeutic value of targeting the interaction between them. Bispecific nanocarriers densely grafted with anti-c-Met and -nucleolin aptamer increased the local concentration of aptamers at the target sites, in addition to inducing target receptor clustering. It was also demonstrated that the simultaneous targeting of c-Met and nucleolin inhibited the cellular functions of the receptors and increased anti-cancer efficacy by altering the cell cycle. Our findings pave the way for the development of an effective combinatorial treatment based on nanoconstruct-mediated interaction between receptors.
Highlights
The treatment of many malignant diseases through the use of combinatorial drug therapies has recently attracted the attention of physicians and scientists [1,2,3,4]
As c-Met and nucleolin are often overexpressed in cancer cells, apt AuNS targeting either c-Met or nucleolin tends to recognize surface receptors
We performed a series of additional experiments with HER2, another receptor tyrosine kinases (RTKs) member, using the anti-HER2 aptamer to identify any forceful combination of targeting receptors
Summary
The treatment of many malignant diseases through the use of combinatorial drug therapies has recently attracted the attention of physicians and scientists [1,2,3,4]. Nucleolin (NCL) on the cell surface is a novel cancer target molecule for tumor therapy, due to its abundance on the surface and prominence in various cancer cells, including gastric, breast, lung, and prostate cancers [5,6,7] In this context, anti-cancer drugs, such as immunogens, peptides, and aptamers (apts), have been intensively investigated for anti-NCL therapy [8,9,10]. AS1411 faces some fundamental limitations, including a short circulatory half-life, unexpected immune responses, and insufficient anti-cancer outcomes These drawbacks have been mitigated using a variety of methods, such as by modifying the aptamer, conjugating the aptamer with a nanocarrier, or utilizing combinatorial treatment with other anti-cancer reagents [7]
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