International Journal of Nanomedicine (Oct 2020)
AT101-Loaded Cubosomes as an Alternative for Improved Glioblastoma Therapy
Abstract
Dorota K Flak,1 Vivian Adamski,2 Grzegorz Nowaczyk,1 Kosma Szutkowski,1 Michael Synowitz,2 Stefan Jurga,1 Janka Held-Feindt2 1NanoBioMedical Centre, Adam Mickiewicz University Poznań, Poznań, Poland; 2Department of Neurosurgery, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, GermanyCorrespondence: Dorota K Flak NanoBioMedical CentreAdam Mickiewicz University Poznań, Wszechnicy Piastowskiej 3, Poznań PL 61614, PolandTel +48 8296713Email [email protected]: AT101, the R-(-)-enantiomer of the cottonseed-derived polyphenol gossypol, is a promising drug in glioblastoma multiforme (GBM) therapy due to its ability to trigger autophagic cell death but also to facilitate apoptosis in tumor cells. It does have some limitations such as poor solubility in water-based media and consequent low bioavailability, which affect its response rate during treatment. To overcome this drawback and to improve the anti-cancer potential of AT101, the use of cubosome-based formulation for AT101 drug delivery has been proposed. This is the first report on the use of cubosomes as AT101 drug carriers in GBM cells.Materials and Methods: Cubosomes loaded with AT101 were prepared from glyceryl monooleate (GMO) and the surfactant Pluronic F-127 using the top–down approach. The drug was introduced into the lipid prior to dispersion. Prepared formulations were then subjected to complex physicochemical and biological characterization.Results: Formulations of AT101-loaded cubosomes were highly stable colloids with a high drug entrapment efficiency (97.7%) and a continuous, sustained drug release approaching 35% over 72 h. Using selective and sensitive NMR diffusometry, the drug was shown to be efficiently bound to the lipid-based cubosomes. In vitro imaging studies showed the high efficiency of cubosomal nanoparticles uptake into GBM cells, as well as their marked ability to penetrate into tumor spheroids. Treatment of GBM cells with the AT101-loaded cubosomes, but not with the free drug, induced cytoskeletal rearrangement and shortening of actin fibers. The prepared nanoparticles revealed stronger in vitro cytotoxic effects against GBM cells (A172 and LN229 cell lines), than against normal brain cells (SVGA and HMC3 cell lines).Conclusion: The results indicate that GMO-AT101 cubosome formulations are a promising basic tool for alternative approaches to GBM treatment.Keywords: cubosome, lipid nanoparticles, glyceryl monooleate, drug delivery, GBM therapy, NMR diffusometry
