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Enhanced Anticancer Activity of Nanoformulation of Dasatinib against Triple-Negative Breast Cancer
Fatemah Bahman1, Valeria Pittalà2, Mohamed Haider3,4
1Department of Molecular Genetics, Kuwait Ministry of Health, Kuwait City 50000, Kuwait.
Abstract:
Triple negative breast cancer (TNBC) is the most aggressive breast cancer accounting for around 15% of identified breast cancer cases. TNBC lacks human epidermal growth factor receptor 2 (HER2) amplification, is hormone independent estrogen (ER) and progesterone receptors (PR) negative, and is not reactive to current targeted therapies. Existing treatment relies on chemotherapeutic treatment, but in spite of an initial response to chemotherapy, the inception of resistance and relapse is unfortunately common. Dasatinib is an approved second-generation inhibitor of multiple tyrosine kinases, and literature data strongly support its use in the management of TNBC. However, dasatinib binds to plasma proteins and undergoes extensive metabolism through oxidation and conjugation. To protect dasatinib from fast pharmacokinetic degradation and to prolong its activity, it was encapsulated on poly(styrene-co-maleic acid) (SMA) micelles. The obtained SMA-dasatinib nanoparticles (NPs) were evaluated for their physicochemical properties, in vitro antiproliferative activity in different TNBC cell lines, and in vivo anticancer activity in a syngeneic model of breast cancer. Obtained results showed that SMA-dasatinib is more potent against 4T1 TNBC tumor growth in vivo compared to free drug. This enhanced effect was ascribed to the encapsulation of the drug protecting it from a rapid metabolism. Our finding highlights the often-overlooked value of nanoformulations in protecting its cargo from degradation. Overall, results may provide an alternative therapeutic strategy for TNBC management.
Insights
Nanoformulations protect dasatinib from degradation, enhancing its potency against triple negative breast cancer (TNBC). This SMA-dasatinib nanoparticle approach offers a promising alternative therapy for TNBC management.
Area of Science:
- Oncology
- Nanotechnology
- Pharmacology
Background:
- Triple negative breast cancer (TNBC) is aggressive, lacking targeted therapy options.
- Current chemotherapy for TNBC often leads to resistance and relapse.
- Dasatinib shows potential for TNBC but suffers from rapid pharmacokinetic degradation.
Purpose of the Study:
- To develop a nanoformulation of dasatinib to overcome pharmacokinetic limitations.
- To evaluate the efficacy of SMA-dasatinib nanoparticles (NPs) against TNBC.
- To investigate the protective role of nanoencapsulation against drug degradation.
Main Methods:
- Dasatinib was encapsulated in poly(styrene-co-maleic acid) (SMA) micelles.
- Physicochemical properties of SMA-dasatinib NPs were assessed.
- In vitro antiproliferative and in vivo anticancer activities were evaluated in TNBC models.
Main Results:
- SMA-dasatinib NPs demonstrated enhanced potency against 4T1 TNBC tumor growth in vivo compared to free dasatinib.
- Encapsulation protected dasatinib from rapid metabolism, prolonging its activity.
- Nanoformulation effectively shielded the drug cargo from degradation.
Conclusions:
- Nanoencapsulation of dasatinib in SMA micelles provides a viable strategy to enhance its therapeutic efficacy for TNBC.
- This approach mitigates rapid drug metabolism and degradation.
- SMA-dasatinib NPs represent a potential alternative therapeutic strategy for managing TNBC.
