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Combinatorial Inhibition of Cell Surface Receptors Using Dual Aptamer-Functionalized Nanoconstructs for Cancer
Hyojin Lee1, Tae Hee Kim1, Daechan Park2
1Center for Biomaterials, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea.
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.
Insights
This study introduces a dual-targeting strategy using bispecific nanocarriers to combat cancer by simultaneously targeting c-Met and nucleolin receptors. This novel approach enhances anti-cancer efficacy and overcomes limitations of single-target therapies.
Area of Science:
- Biotechnology
- Nanomedicine
- Cancer Therapeutics
Background:
- Membrane receptors overexpressed in disease are therapeutic targets.
- Single-targeting strategies often suffer from poor efficacy, resistance, and toxicity.
Purpose of the Study:
- To develop a dual-targeting strategy to enhance anti-cancer efficacy.
- To investigate the therapeutic potential of targeting the interaction between c-Met and nucleolin receptors.
Main Methods:
- Designed bispecific nanocarriers densely grafted with anti-c-Met and anti-nucleolin aptamers.
- Investigated the synergistic proximity interactions between therapeutics and dual receptor targets.
- Assessed the impact on cellular functions, cell cycle, and anti-cancer efficacy.
Main Results:
- Demonstrated a novel interaction between c-Met and nucleolin.
- Bispecific nanocarriers increased local aptamer concentration and induced receptor clustering.
- Simultaneous targeting inhibited receptor functions and enhanced anti-cancer efficacy by altering the cell cycle.
Conclusions:
- Dual-targeting via nanoconstruct-mediated receptor interaction offers a promising strategy for effective combinatorial cancer treatment.
- This approach overcomes limitations of single-targeting therapies.
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