Enhanced Anticancer Activity of Nanoformulation of Dasatinib against Triple-Negative Breast Cancer.

Fatemah Bahman,Mohamed Haider,Valeria Pittalà,Khaled Greish

doi:10.3390/jpm11060559

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.

Highlights

Breast cancers are the top widespread type of tumor among females in the U.S, and in 2021, it is predicted that 280,000 new breast cancers will be diagnosed [1,2]
Micelles average size measuring showed that SMA. Dasatinib was co-melic acid (SMA)–dasatinib micelles were 198 nm and had a polydispersity index (PDI) of 0.17, which was determined by dynamic light scattering (DLS)
Our current work aims at encapsulating dasatinib into SMA micelles to generate an SMA–dasatinib micellar system that can improve its solubility in water, protect the drug against enzymatic degradation, potentiate its chemotherapeutic effect, and minimize the rate of drug resistance

Summary

Introduction

Breast cancers are the top widespread type of tumor among females in the U.S, and in 2021, it is predicted that 280,000 new breast cancers will be diagnosed [1,2]. The disease is globally affecting about 1 in 8 women in the U.S during their lifetime. Breast cancer mortality could be attributed to metastasis by 80–90% [3]. Triple negative breast cancer (TNBC) is a long-lasting orphan disease and among the most clinically challenging breast cancer subtype. TNBC is the most aggressive and heterogeneous breast tumor that lacks all of three therapeutically relevant biomarkers including estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) [4]. The conventional treatment for TNBC involves surgical excision and radiotherapy with a combination of adjuvant chemotherapies [5,6].

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Discussion

Conclusion