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Chalcones as Anti-Glioblastoma Stem Cell Agent Alone or as Nanoparticle Formulation Using Carbon Dots as Nanocarrier
Eduardo A Veliz1,2, Anastasiia Kaplina1,3, Sajini D Hettiarachchi1
1Department of Chemistry, University of Miami, 1301 Memorial Drive, Coral Gables, FL 33146, USA.
Abstract:
The current prognosis for glioblastoma is dismal. Treatment-resistant glioblastoma stem cells (GSCs) and the failure of most drugs to reach therapeutic levels within the tumor remain formidable obstacles to successful treatment. Chalcones are aromatic ketones demonstrated to reduce malignant properties in cancers including glioblastoma. Nanomedicines can increase drug accumulation and tumor cell death. Carbon-dots are promising nanocarriers that can be easily functionalized with tumor-targeting ligands and anti-cancer drugs. Therefore, we synthesized a series of 4'-amino chalcones with the rationale that the amino group would serve as a "handle" to facilitate covalent attachment to carbon-dots and tested their cytotoxicity toward GSCs. We generated 31 chalcones (22 4'-amino and 9 4' derivatives) including 5 novel chalcones, and found that 13 had an IC50 below 10 µM in all GSC lines. After confirming that the 4-amino group was not part of the active pharmacophore, chalcones were attached to transferrin-conjugated carbon-dots. These conjugates were significantly more cytotoxic than the free chalcones, with the C-dot-transferrin-2,5, dimethoxy chalcone conjugate inducing up to 100-fold more GSC death. Several of the tested chalcones represent promising lead compounds for the development of novel anti-GSC drugs. Furthermore, designing amino chalcones for carbon-dot mediated drug delivery is a rational and effective methodology.
Insights
Novel amino chalcones show promise for glioblastoma treatment. When attached to carbon-dots, these chalcone-drug conjugates significantly enhanced cancer cell death, offering a new nanomedicine approach.
Area of Science:
- Oncology
- Materials Science
- Pharmacology
Background:
- Glioblastoma (GBM) has a poor prognosis due to treatment-resistant glioblastoma stem cells (GSCs) and poor drug penetration.
- Chalcones, a class of aromatic ketones, exhibit anti-cancer properties, including against glioblastoma.
- Nanomedicine offers a strategy to improve drug delivery and efficacy in tumors.
Purpose of the Study:
- To synthesize and evaluate 4'-amino chalcones for their cytotoxicity against GSCs.
- To develop a carbon-dot (C-dot) based drug delivery system for chalcones.
- To assess the enhanced efficacy of chalcone-loaded C-dots conjugated with transferrin for targeting GSCs.
Main Methods:
- Synthesis of 31 chalcone derivatives, including 22 4'-amino chalcones.
- Cytotoxicity assays to determine the IC50 values against GSC lines.
- Covalent attachment of selected chalcones to transferrin-conjugated carbon-dots.
- Comparative evaluation of the cytotoxicity of free chalcones versus C-dot conjugates.
Main Results:
- Thirteen chalcones demonstrated an IC50 below 10 µM against GSCs.
- The 4-amino group was confirmed not to be essential for chalcone's pharmacophore activity.
- Chalcone-C-dot-transferrin conjugates exhibited significantly higher cytotoxicity compared to free chalcones.
- One conjugate showed up to 100-fold increase in GSC death.
Conclusions:
- Amino chalcones are effective lead compounds for developing new anti-GSC drugs.
- Designing amino chalcones for carbon-dot mediated delivery is a viable and effective strategy for glioblastoma treatment.
- Transferrin-conjugated carbon-dots enhance the therapeutic potential of chalcones against glioblastoma stem cells.
