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Anti-nucleolin aptamer-guided anticancer activity of AS1411-Chalcone conjugate in breast cancer
Vijay Murali Ravi Mythili1, Vasanth Kanth Thasma Loganathbabu2, Kumaran Kasinathan2
1Integrated Genetics and Molecular Oncology Group, Department of Genetic Engineering, Faculty of Engineering and Technology, SRM Institute of Science and Technology, SRM Nagar, Potheri, Chengalpattu Dt, Tamil Nadu, 603203, India; Center for Biotechnology Education, Krieger School of Arts and Sciences, Johns Hopkins University, Baltimore, Maryland, USA.
Abstract:
The DNA aptamer AS1411 is a 26-nucleotide, guanine-rich oligonucleotide with high specificity for nucleolin-a multifunctional protein overexpressed on the surface of many cancer cells and involved in key processes such as proliferation and apoptosis. By selectively binding nucleolin, AS1411 serves as an ideal targeting ligand for delivering therapeutic agents. Chalcone, a naturally occurring flavonoid with documented anticancer activity, induces apoptosis and inhibits tumor growth; however, its clinical utility is limited by nonspecific cytotoxicity. In this study, we synthesized a novel aptamer-drug conjugate by covalently linking chalcone to AS1411, thereby leveraging the aptamer's targeting ability to enhance drug delivery specifically to cancer cells. Comprehensive characterization using UV-visible spectroscopy, FTIR, and zeta potential analysis confirmed successful conjugation and favorable physicochemical properties. In vitro assays revealed that the AS1411-chalcone conjugate significantly improved anticancer efficacy in MCF-7 breast cancer cells by reducing the IC50 from 96.6 μg/mL (free chalcone) to 74.4 μg/mL and by achieving a 50 % reduction in colony formation. Moreover, the conjugate exhibited reduced cytotoxicity toward normal HDF cells and induced cell cycle arrest and apoptotic cell death selectively in cancer cells. These findings highlight the potential of AS1411-mediated chalcone delivery as a targeted therapeutic strategy that enhances drug potency while minimizing off-target effects.
Insights
This study developed a novel DNA aptamer-drug conjugate (AS1411-chalcone) for targeted cancer therapy. The conjugate enhances anticancer efficacy and reduces toxicity by delivering the drug specifically to cancer cells.
Area of Science:
- Biochemistry
- Molecular Biology
- Nanotechnology
Background:
- The DNA aptamer AS1411 targets nucleolin, a protein overexpressed in many cancers.
- Chalcone exhibits anticancer properties but suffers from nonspecific cytotoxicity.
- Targeted drug delivery systems are crucial for improving cancer therapy efficacy and reducing side effects.
Purpose of the Study:
- To synthesize and characterize a novel aptamer-drug conjugate by linking AS1411 with chalcone.
- To evaluate the in vitro anticancer efficacy and selectivity of the AS1411-chalcone conjugate.
- To investigate the conjugate's effects on cancer cell cycle progression and apoptosis.
Main Methods:
- Covalent conjugation of AS1411 and chalcone.
- Physicochemical characterization using UV-visible spectroscopy, FTIR, and zeta potential analysis.
- In vitro anticancer assays on MCF-7 breast cancer cells and normal human dermal fibroblasts (HDFs).
Main Results:
- Successful synthesis of the AS1411-chalcone conjugate with favorable physicochemical properties.
- The conjugate demonstrated significantly enhanced anticancer efficacy in MCF-7 cells (lower IC50) compared to free chalcone.
- The AS1411-chalcone conjugate showed reduced cytotoxicity in normal HDF cells and induced selective cancer cell cycle arrest and apoptosis.
Conclusions:
- The AS1411-chalcone conjugate represents a promising targeted therapeutic strategy for cancer.
- Aptamer-drug conjugates can enhance drug potency and minimize off-target effects.
- This approach holds potential for developing more effective and safer cancer treatments.
