pH-Responsive Artemisinin Derivatives and Lipid Nanoparticle Formulations Inhibit Growth of Breast Cancer Cells In Vitro and Induce Down-Regulation of HER Family Members

Abstract

Artemisinin (ART) dimers show potent anti-proliferative activities against breast cancer cells. To facilitate their clinical development, novel pH-responsive artemisinin dimers were synthesized for liposomal nanoparticle formulations. A new ART dimer was designed to become increasingly water-soluble as pH declines. The new artemisinin dimer piperazine derivatives (ADPs) remained tightly associated with liposomal nanoparticles (NPs) at neutral pH but were efficiently released at acidic pH's that are known to exist within solid tumors and organelles such as endosomes and lysosomes. ADPs incorporated into nanoparticles down regulated the anti-apoptotic protein, survivin, and cyclin D1 when incubated at low concentrations with breast cancer cell lines. We demonstrate for the first time, for any ART derivative, that ADP NPs can down regulate the oncogenic protein HER2, and its counterpart, HER3 in a HER2+ cell line. We also show that the wild type epidermal growth factor receptor (EGFR or HER1) declines in a triple negative breast cancer (TNBC) cell line in response to ADP NPs. The declines in these proteins are achieved at concentrations of NP109 at or below 1 µM. Furthermore, the new artemisinin derivatives showed improved cell-proliferation inhibition effects compared to known dimer derivatives.

pH-Responsive Artemisinin Dimer in Lipid Nanoparticles Are Effective Against Human Breast Cancer in a Xenograft Model

“…48 The immortal nontumorigenic human breast epithelial cell line, MCF10A, was less susceptible to both the free compound and its liposome formulations. In both NP109 30 and NP209 assays, more than 50% of MCF10A cells were still viable after 48 h of incubation at 10 μM ADP109 concentration. We have yet to test concentrations higher than 10 μM on MCF10A cells.…”

“…30 To evaluate pH-responsive drug release, NP209 was exposed to pH 7.4, 6.0, and 4.0 to measure the ART dimer release over time. NP209 released ADP109 more efficiently at pH 4 than physiological neutral.…”

A survey on anticancer effects of artemisinin, iron, miconazole, and butyric acid on 5637 (bladder cancer) and 4T1 (Breast cancer) cell lines

“…Anticancer properties of pure artemisinin and its derivatives and different combination therapies with it are shown in many in vivo and in vitro experiments, [1][2][3] but there are no studies on its combination with butyric acid and miconazole. Anticancer effects of butyric acid and miconazole are suggested in a few publications.…”

“…This compound is a sesquiterpene phytolactone with an endoperoxide bridge (R-O-O-R'), which induces lipid proxidation by forming carbon-based free radicals after reacting with the iron atom. [2] Artemisinin acts selectively on malarial parasites or cancerous cells, because they have large quantities of iron deposit due to their metabolic activity. Many studies have shown that artemisinin has different cytotoxic effects on various cancer cell lines.…”

Metabolic analyses elucidate non-trivial gene targets for amplifying dihydroartemisinic acid production in yeast

“…Artemisinin, the primary component of ACT, is a naturally produced sesquiterpene lactone endoperoxide. Artemisinin and its derivatives have also been found to exhibit anti-cancer properties (Ferreira et al, 2010) such as inducing apoptosis in lung cancer cells (Gao et al, 2013) and preventing cell proliferation in breast cancer cells (Ba et al, 2012; Zhang et al, 2013). In nature, artemisinin is synthesized by the plant Artemisia annua through conversion of the intermediate sesquiterpene farnesyl pyrophosphate (FPP; Bertea et al, 2005; Liu et al, 2011).…”