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WZB117 Decorated Metformin-Carboxymethyl Chitosan Nanoparticles for Targeting Breast Cancer Metabolism
Anindita De1, Ashish Wadhwani2, Sauraj1
1College of Pharmacy, Gachon Institute of Pharmaceutical Science, Gachon University, Incheon 21936, Republic of Korea.
Abstract:
The "Warburg effect" provides a novel method for treating cancer cell metabolism. Overexpression of glucose transporter 1 (GLUT1), activation of AMP-activated protein kinase (AMPK), and downregulation of mammalian target of rapamycin (mTOR) have been identified as biomarkers of abnormal cancer cell metabolism. Metformin (MET) is an effective therapy for breast cancer (BC), but its efficacy is largely reliant on the concentration of glucose at the tumor site. We propose a WZB117 (a GLUT1 inhibitor)-OCMC (O-carboxymethyl-chitosan)-MET combo strategy for simultaneous GLUT1 and mTOR targeting for alteration of BC metabolism. WZB117 conjugated polymeric nanoparticles were 225.67 ± 11.5 nm in size, with a PDI of 0.113 ± 0.16, and an encapsulation of 72.78 6.4%. OCMC pH-dependently and selectively releases MET at the tumor site. MET targets the mTOR pathway in cancer cells, and WZB117 targets BCL2 to alter GLUT1 at the cancer site. WZB117-OCMC-MET overcomes the limitations of MET monotherapy by targeting mTOR and BCL2 synergistically. WZB117-OCMC-MET activates AMPK and suppresses mTOR in a Western blot experiment, indicating growth-inhibitory and apoptotic characteristics. AO/EB and the cell cycle enhance cellular internalization as compared to MET alone. WZB117-OCMC-MET affects cancer cells' metabolism and is a promising BC therapeutic strategy.
Insights
This study introduces a novel combination therapy using WZB117 and Metformin (MET) delivered via nanoparticles to target breast cancer metabolism. This approach synergistically inhibits cancer growth by targeting glucose transporter 1 (GLUT1) and mTOR pathways.
Area of Science:
- Biochemistry
- Oncology
- Nanotechnology
Background:
- The Warburg effect highlights altered cancer cell metabolism, with biomarkers including glucose transporter 1 (GLUT1) overexpression and dysregulated AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) pathways.
- Metformin (MET) shows efficacy in breast cancer (BC) treatment, but its effectiveness is limited by tumor glucose levels.
Purpose of the Study:
- To develop a combination therapy targeting both GLUT1 and mTOR pathways for enhanced breast cancer treatment.
- To overcome the limitations of metformin monotherapy by creating a synergistic drug delivery system.
Main Methods:
- Conjugation of WZB117 (a GLUT1 inhibitor) with O-carboxymethyl-chitosan (OCMC) to create pH-dependent nanoparticles for selective MET release.
- Characterization of nanoparticle size, polydispersity index (PDI), and encapsulation efficiency.
- Evaluation of the combination therapy's effect on AMPK activation, mTOR suppression, cell cycle, and apoptosis via Western blot and AO/EB staining.
Main Results:
- WZB117-conjugated OCMC nanoparticles demonstrated optimal size (225.67 ± 11.5 nm) and encapsulation (72.78 ± 6.4%).
- The OCMC carrier facilitated pH-dependent, tumor-site-specific release of MET.
- Western blot analysis confirmed that WZB117-OCMC-MET activated AMPK and suppressed mTOR, exhibiting growth-inhibitory and apoptotic effects.
- Enhanced cellular internalization and anti-cancer effects were observed compared to MET monotherapy.
Conclusions:
- The WZB117-OCMC-MET combination strategy offers a synergistic approach to target breast cancer metabolism by simultaneously inhibiting GLUT1 and mTOR.
- This novel nanoparticle-based therapy demonstrates significant potential as a promising therapeutic strategy for breast cancer treatment.
