Abstract
Triple-negative breast cancer (TNBC) is a heterogeneous subtype of tumors that tests negative for estrogen receptors, progesterone receptors, and excess HER2 protein. The mainstay of treatment remains chemotherapy, but the therapeutic outcome remains inadequate. This paper investigates the potential of a duocarmycin derivative, tafuramycin A (TFA), as a new and more effective chemotherapy agent in TNBC treatment. To this extent, we optimized the chemical synthesis of TFA, and we encapsulated TFA in a micellar system to reduce side effects and increase tumor accumulation. In vitro and in vivo studies suggest that both TFA and SMA–TFA possess high anticancer effects in TNBC models. Finally, the encapsulation of TFA offered a preferential avenue to tumor accumulation by increasing its concentration at the tumor tissues by around four times in comparison with the free drug. Overall, the results provide a new potential strategy useful for TNBC treatment.
Highlights
The International Agency for Research on Cancer recently reported for the year 2020 an incidence of almost 20 million new cancer cases and around 10 million cancer deaths [1]
Progress in the treatment of breast cancer has been reported in recent decades, especially with the identification of molecular markers for targeted therapies
Triple-negative breast cancer (TNBC) is defined by the deficiency of the aforementioned therapeutic markers and represents a variegated subfamily of tumors showing an aggressive clinical profile manifested by rapid proliferation, high recurrence and chemoresistance risk, fast progression, distant metastasis, and poor prognosis [3]
Summary
The International Agency for Research on Cancer recently reported for the year 2020 an incidence of almost 20 million new cancer cases and around 10 million cancer deaths [1]. These natural derivatives have long fascinated researchers due to their notably anticancer activity, exclusive mechanism of action, and efficacy in multidrug-resistant tumor models These molecules exert their cytotoxic effect through binding at the minor groove of AT-rich sequences in the DNA and by covalently alkylating adenine-N3 [10]. Strategies to improve the safety of duocarmycin derivatives are focusing on the development of prodrugs activated at the site of action, antibody–drug conjugates, small-molecule drug conjugates, peptide–drug conjugates, and chemical modification/simplification of the duocarmicin’s structure [16]. Another convenient avenue commonly explored to reduce side effects is the nanoformulation of active compounds. The use of these cell lines will allow the comparison of TFA formulation in different biological settings and, enable the comparison of our results to others research in the field
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