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Nanotechnology Platform for the Delivery of Docetaxel and Tyrosine Kinase Inhibitors for HER2-Positive Breast Cancer
Bharathi Mandala1, Yvonne Berko1, Gantamur Battogtok1
1Department of Pharmaceutical Sciences, College of Pharmacy, Howard University, USA.
Background:
HER2-positive breast cancer is an aggressive subtype characterized by the overexpression of the HER2 receptor, a transmembrane glycoprotein critical for tumor progression. Current therapies often face challenges like drug resistance and systemic toxicity, necessitating the development of advanced drug delivery systems.
Objective:
This study aimed to fabricate and determine the cytotoxicity of pH-sensitive PLA nanoparticles dual-loaded with docetaxel and each of the small molecule tyrosine kinase inhibitors (STKIs) (tucatinib, neratinib, lapatinib) in HER2-positive breast cancer cells.
Method:
Nanoparticles were synthesized by a dispersion polymerization method using an acidlabile crosslinking agent, PEG and lactide macromonomers. They were characterized for structure (TEM), surface morphology (SEM), particle size, polydispersity index, zeta potential, and drug loading capacity. Cytotoxicity was assessed in vitro on SKBR3 and MCF7 breast cancer cell lines, with IC50 values compared across formulations.
Results:
The nanoparticles were spherical with nanoscale sizes and negative zeta potential values. In vitro studies demonstrated enhanced antiproliferative effects of the drug-loaded nanoparticles, with synergistic activity observed between docetaxel and the STKIs. The drug concentrations were halved in combination formulations and resulted in better cytotoxicity compared to single-drug treatments, particularly against SKBR3 cells. The IC50 values were lower in SKBR3 cells than in MCF7 cells, highlighting the role of HER2 expression in the activity of TKIs.
Conclusion:
The pH-sensitive PLA nanoparticles effectively co-delivered docetaxel and STKIs and demonstrated enhanced efficacy and reduced drug dosages in HER2-positive breast cancer models. This study provides a foundation for further exploration of nanoparticle-based combination therapies with potential applications in treating other aggressive cancer types.
Insights
pH-sensitive nanoparticles co-delivered docetaxel and small molecule tyrosine kinase inhibitors (STKIs) for HER2-positive breast cancer. This combination therapy showed enhanced efficacy and reduced drug dosages, offering a promising approach for aggressive cancers.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- HER2-positive breast cancer is aggressive, driven by HER2 receptor overexpression.
- Current therapies face drug resistance and toxicity challenges.
- Advanced drug delivery systems are needed for improved treatment.
Purpose of the Study:
- To fabricate pH-sensitive polylactic acid (PLA) nanoparticles.
- To load nanoparticles with docetaxel and small molecule tyrosine kinase inhibitors (STKIs) like tucatinib, neratinib, and lapatinib.
- To evaluate the cytotoxicity of these dual-loaded nanoparticles in HER2-positive breast cancer cells.
Main Methods:
- Nanoparticles synthesized via dispersion polymerization with an acid-labile crosslinker.
- Characterization included TEM, SEM, particle size, polydispersity index, and zeta potential.
- In vitro cytotoxicity assessed on SKBR3 and MCF7 cell lines, comparing IC50 values.
Main Results:
- Spherical nanoparticles with nanoscale dimensions and negative zeta potential were produced.
- Drug-loaded nanoparticles exhibited enhanced antiproliferative effects and synergistic activity.
- Combination formulations showed improved cytotoxicity, especially against HER2-expressing SKBR3 cells, with halved drug concentrations.
Conclusions:
- pH-sensitive PLA nanoparticles effectively co-delivered docetaxel and STKIs.
- Enhanced efficacy and reduced drug dosages were observed in HER2-positive breast cancer models.
- This approach provides a foundation for nanoparticle-based combination therapies in aggressive cancers.
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