13
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

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

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          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.

          Related collections

          Most cited references59

          • Record: found
          • Abstract: not found
          • Article: not found

          Glioblastoma multiforme: The terminator

          E Holland (2000)
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Inhibition of constitutively active Stat3 suppresses proliferation and induces apoptosis in glioblastoma multiforme cells.

            Glioblastoma multiforme (GBM), the most common and malignant central nervous system tumor in humans, is highly proliferative and resistant to apoptosis. Stat3, a latent transcription factor being activated by aberrant cytokine or growth factor signaling, acts as a suppressor of apoptosis in a number of cancer cells. Here we report that GBM tumors and cell lines contain high levels of constitutively activated Stat3 when compared with normal human astrocytes, white matter, and normal tissue adjacent to tumor. The persistent activation of Stat3 is in part, attributable to an autocrine action of interleukin-6 in the GBM cell line U251. Janus kinase inhibitor AG490 inhibits Stat3 activation with a concomitant reduction in steady-state levels of Bcl-X(L), Bcl-2 and Mcl-1 proteins and induces apoptosis in U251 cells as revealed by Poly (ADP-ribose) polymerase cleavage and Annexin-V staining. Expression of a dominant negative mutant Stat3 protein or treatment with AG490 markedly reduces the proliferation of U251 cells by inhibiting the constitutive activation of Stat3. These results provide evidence that constitutive activation of Stat3 contributes to the pathogenesis of glioblastoma by promoting both proliferation and survival of GBM cells. Therefore, targeting Stat3 signaling may provide a potential therapeutic intervention for GBM.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: found
              Is Open Access

              The anti-malarial atovaquone increases radiosensitivity by alleviating tumour hypoxia

              Tumour hypoxia renders cancer cells resistant to cancer therapy, resulting in markedly worse clinical outcomes. To find clinical candidate compounds that reduce hypoxia in tumours, we conduct a high-throughput screen for oxygen consumption rate (OCR) reduction and identify a number of drugs with this property. For this study we focus on the anti-malarial, atovaquone. Atovaquone rapidly decreases the OCR by more than 80% in a wide range of cancer cell lines at pharmacological concentrations. In addition, atovaquone eradicates hypoxia in FaDu, HCT116 and H1299 spheroids. Similarly, it reduces hypoxia in FaDu and HCT116 xenografts in nude mice, and causes a significant tumour growth delay when combined with radiation. Atovaquone is a ubiquinone analogue, and decreases the OCR by inhibiting mitochondrial complex III. We are now undertaking clinical studies to assess whether atovaquone reduces tumour hypoxia in patients, thereby increasing the efficacy of radiotherapy.
                Bookmark

                Author and article information

                Journal
                Pharmaceutics
                Pharmaceutics
                pharmaceutics
                Pharmaceutics
                MDPI
                1999-4923
                19 May 2018
                June 2018
                : 10
                : 2
                : 60
                Affiliations
                [1 ]Division of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy, University of Texas at Austin, Austin, TX 78712, USA; yjzhang@ 123456utexas.edu (Y.Z.); davis.daniel@ 123456utexas.edu (D.A.D.); hugh.smyth@ 123456austin.utexas.edu (H.D.C.S.); bill.williams@ 123456austin.utexas.edu (R.O.W.I.)
                [2 ]Division of Pharmacotherapy, College of Pharmacy, University of Texas at Austin, Austin, TX 78712, USA; KUHN@ 123456uthscsa.edu
                [3 ]Institute for Drug Development, Cancer Therapy and Research Center (CTRC), University of Texas Health San Antonio, 7979 Wurzbach Dr., San Antonio, TX 78229, USA; Weitman@ 123456uthscsa.edu
                Author notes
                [* ]Correspondence: hiroyuki.takabe@ 123456utexas.edu (H.T.); Zwarnken@ 123456utexas.edu (Z.N.W.); Tel.: +1-512-471-7182 (H.T.); +1-512-471-3027 (Z.N.W.)
                Author information
                https://orcid.org/0000-0002-9331-7570
                https://orcid.org/0000-0002-1028-134X
                Article
                pharmaceutics-10-00060
                10.3390/pharmaceutics10020060
                6027483
                29783757
                b0bbe12a-9d04-4d57-b6d2-fdaeb3db4ccd
                © 2018 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 24 April 2018
                : 16 May 2018
                Categories
                Article

                atovaquone,hot-melt extrusion,amorphous solid dispersion,supersaturation,glioblastoma multiforme,repurposing drugs

                Comments

                Comment on this article