A Repurposed Drug for Brain Cancer: Enhanced Atovaquone Amorphous Solid Dispersion by Combining a Spontaneously Emulsifying Component with a Polymer Carrier

Abstract

Glioblastoma multiforme (GBM) is the most common and lethal central nervous system tumor. Recently, atovaquone has shown inhibition of signal transducer and activator transcription 3, a promising target for GBM therapy. However, it is currently unable to achieve therapeutic drug concentrations in the brain with the currently reported and marketed formulations. The present study sought to explore the efficacy of atovaquone against GBM as well as develop a formulation of atovaquone that would improve oral bioavailability, resulting in higher amounts of drug delivered to the brain. Atovaquone was formulated as an amorphous solid dispersion using an optimized formulation containing a polymer and a spontaneously emulsifying component (SEC) with greatly improved wetting, disintegration, dispersibility, and dissolution properties. Atovaquone demonstrated cytotoxicity against GBM cell lines as well as provided a confirmed target for atovaquone brain concentrations in in vitro cell viability studies. This new formulation approach was then assessed in a proof-of-concept in vivo exposure study. Based on these results, the enhanced amorphous solid dispersion is promising for providing therapeutically effective brain levels of atovaquone for the treatment of GBM.

Targeting tumor hypoxia and mitochondrial metabolism with anti-parasitic drugs to improve radiation response in high-grade gliomas

“…Upregulated STAT3 contributes to tumorigenesis by increasing cancer proliferation, metastasis, drug resistance, and prevents apoptosis [129]. Atovaquone is found to inhibit STAT3 in thyroid cancer, acute myeloid leukemia (AML), and glioblastoma, therefore decreasing cell viability and inducing apoptosis in these cancers [87,90,91].…”

Dissolution Enhancement in Cocoa Extract, Combining Hydrophilic Polymers through Hot-Melt Extrusion

“…The thermal shear caused by HME is not only capable of greatly increasing the degree of interaction between the drug and polymer but also gives rise to a dense and uniform matrix producing granules with excellent flow characteristics, as previously described [ 9 , 11 ].…”

“…Hot-melt extrusion (HME) has gained interest in the pharmaceutical field as a processing technology capable of producing solid dispersions with a high degree of drug-polymer interactions. The simultaneous mechanical and thermal shear of samples achieved by HME can noticeably modify drug properties such as solubility [ 9 ], poor taste, and flowability [ 10 ], while producing sustained drug delivery systems [ 11 ]. Moreover, the association of HME with computer-aided design and computer-aided manufacturing is expanding its medical potential in the production of prostheses and even in 3D printed drug products [ 12 , 13 ].…”

Efficacy of atovaquone on EpCAM⁺CD44⁺ HCT‑116 human colon cancer stem cells under hypoxia

“…ATO is structurally similar to coenzyme Q10 and competitively inhibits its binding to the cytochrome bc1 complex, resulting in mitochondrial membrane potential (MMP) collapse and parasite death (17). ATO has attracted attention as a novel anticancer agent for targeting various types of cancer cell (18)(19)(20)(21)(22). Ashton et al (23) revealed that ATO reduces the oxygen consumption rate by inhibiting mitochondrial respiration complex III activity, reduces hypoxia in both spheroids and xenografted tumors and causes tumor growth delay in combination with radiation.…”