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Chondroitin/Lactoferrin-dual functionalized pterostilbene-solid lipid nanoparticles as targeted breast cancer therapy
Sara Aly1, Amal H El-Kamel1, Eman Sheta2
1Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt.
Abstract:
Breast cancer remains the leading cause of cancer-associated mortality in women. Research investigating novel therapeutic approaches is thus crucial, including phytotherapeutics. Pterostilbene (PTS) is a phytochemical agent with promising efficacy against breast cancer. Poor solubility, low bioavailability and chemical instability are major drawbacks compromising PTS functionality. Herein, novel PTS-loaded solid lipid nanoparticles (PTS-SLNs) were fabricated using the ultrasonication technique. Dual-functionalization with lactoferrin (Lf) and chondroitin-sulfate (CS; CS/Lf/PTS-SLNs) was adopted as active-targeting approach. CS/Lf/PTS-SLNs demonstrated nanoparticle-size (223.42 ± 18.71 nm), low PDI (0.33 ± 0.017), acceptable zeta potential (-11.85 ± 0.07 mV) and controlled release (72.93 ± 2.93% after 24 h). In vitro studies on triple-negative MDA-MB-231 revealed prominent cytotoxicity of CS/Lf/PTS-SLNs (2.63-fold IC50 reduction), higher anti-migratory effect and cellular uptake relative to PTS-solution. The in vivo anti-tumor efficacy in an orthotopic cancer model verified the superiority of CS/Lf/PTS-SLNs; achieving 2.4-fold decrease in tumor growth compared to PTS-solution. On the molecular level, CS/Lf/PTS-SLNs enhanced suppression of VEGF, down-regulated cyclin D1 and upregulated caspase-3 and BAX, compared to PTS-solution. Also, immunohistochemical assay confirmed the higher anti-tumorigenic effect of CS/Lf/PTS-SLNs (5.87-fold decrease in Bcl-2 expression) compared to PTS-solution. Our findings highlight CS/Lf/PTS-SLNs as a promising nanoplatform for phytotherapeutic targeted-breast cancer therapy.
Insights
Novel nanoparticles carrying pterostilbene (PTS) show enhanced breast cancer treatment. Dual-functionalized solid lipid nanoparticles (CS/Lf/PTS-SLNs) improved drug delivery, reduced tumor growth, and boosted anti-cancer effects in preclinical models.
Area of Science:
- Nanotechnology
- Pharmacology
- Oncology
Background:
- Breast cancer is a leading cause of mortality in women, necessitating novel therapeutic strategies.
- Pterostilbene (PTS) is a promising phytochemical for breast cancer, but its clinical use is limited by poor solubility, bioavailability, and stability.
- Developing advanced drug delivery systems is crucial to overcome these limitations and enhance PTS efficacy.
Purpose of the Study:
- To fabricate and characterize novel pterostilbene-loaded solid lipid nanoparticles (PTS-SLNs).
- To dual-functionalize PTS-SLNs with lactoferrin (Lf) and chondroitin sulfate (CS) for active targeting in breast cancer therapy.
- To evaluate the in vitro and in vivo anti-tumor efficacy and molecular mechanisms of the developed CS/Lf/PTS-SLNs.
Main Methods:
- PTS-loaded solid lipid nanoparticles (PTS-SLNs) were prepared using ultrasonication.
- Dual-functionalization with lactoferrin (Lf) and chondroitin sulfate (CS) was performed for active targeting.
- In vitro cytotoxicity, migration, and cellular uptake assays were conducted on MDA-MB-231 cells.
- In vivo anti-tumor efficacy was assessed in an orthotopic breast cancer mouse model.
- Molecular mechanisms involving VEGF, cyclin D1, caspase-3, BAX, and Bcl-2 were analyzed.
Main Results:
- CS/Lf/PTS-SLNs exhibited optimal nanoparticle size, low PDI, and controlled drug release.
- In vitro studies showed significantly enhanced cytotoxicity (2.63-fold IC50 reduction), anti-migratory effects, and cellular uptake of CS/Lf/PTS-SLNs compared to PTS solution.
- In vivo studies demonstrated superior anti-tumor efficacy, with a 2.4-fold decrease in tumor growth for CS/Lf/PTS-SLNs versus PTS solution.
- Molecular analysis revealed enhanced suppression of VEGF, down-regulation of cyclin D1, up-regulation of caspase-3 and BAX, and a 5.87-fold decrease in Bcl-2 expression with CS/Lf/PTS-SLNs.
Conclusions:
- Dual-functionalized CS/Lf/PTS-SLNs represent a promising nanoplatform for targeted breast cancer therapy.
- This approach effectively overcomes the limitations of pterostilbene, enhancing its therapeutic potential.
- The developed nanocarrier demonstrates significant potential for improving phytotherapeutic strategies against breast cancer.
