maleic-acid and Triple-Negative-Breast-Neoplasms

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that differs in progression, recurrence, and prognosis from other forms of breast cancer. The heterogeneity of TNBC has remained a challenge as no targeted therapy is currently available. Previously, we and others have demonstrated that raloxifene, a selective oestrogen receptor modulator, was also acting independently of the oestrogen receptor-α. However, raloxifene is characterised by a low bioavailability

Topics: Animals; Cell Line, Tumor; ErbB Receptors; Estrogen Receptor beta; Estrogens; Female; Human Umbilical Vein Endothelial Cells; Humans; Maleates; Mice, SCID; Micelles; Nanoparticles; Raloxifene Hydrochloride; Random Allocation; Triple Negative Breast Neoplasms; Xenograft Model Antitumor Assays

Patients with triple negative breast cancer have a poor prognosis due in part to the lack of targeted therapies. In the search for novel drugs, our laboratory has developed a second-generation curcumin derivative, 3,5-bis(3,4,5-trimethoxybenzylidene)-1-methylpiperidine-4-one (RL71), that exhibits potent in vitro cytotoxicity. To improve the clinical potential of this drug, we have encapsulated it in styrene maleic acid (SMA) micelles. SMA-RL71 showed improved biodistribution, and drug accumulation in the tumor increased 16-fold compared to control. SMA-RL71 (10 mg/kg, intravenously, two times a week for 2 weeks) also significantly suppressed tumor growth compared to control in a xenograft model of triple negative breast cancer. Free RL71 was unable to alter tumor growth. Tumors from SMA-RL71-treated mice showed a decrease in angiogenesis and an increase in apoptosis. The drug treatment also modulated various cell signaling proteins including the epidermal growth factor receptor, with the mechanisms for tumor suppression consistent with previous work with RL71 in vitro. The nanoformulation was also nontoxic as shown by normal levels of plasma markers for liver and kidney injury following weekly administration of SMA-RL71 (10 mg/kg) for 90 days. Thus, we report clinical potential following encapsulation of a novel curcumin derivative, RL71, in SMA micelles.

Topics: Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation; Curcumin; Diarylheptanoids; Disease Models, Animal; Female; Humans; Maleates; Mice, Inbred BALB C; Mice, SCID; Micelles; Neoplasm Proteins; Styrene; Tissue Distribution; Triple Negative Breast Neoplasms; Xenograft Model Antitumor Assays