Abstract
Conventional cancer treatment protocols are either toxic or of minimal therapeutic value, necessitating investigation of new modalities for efficacious treatment and management of cancers. Among the various novel compounds, histone deacetylase inhibitors (HDACIs) target cancer cells over-expressing deacetylases (HDACs). The inhibition of HDACs changes gene expression without altering the DNA sequence. In the present study, an albumin-based microparticulate drug delivery system containing vorinostat was formulated and evaluated for breast cancer therapy. Drug-loaded microparticles were prepared by a microencapsulation method through spray drying. Prepared microparticles containing the active drug were characterized for their physiochemical properties, including size, surface morphology, Zeta potential and surface properties. Dissolution studies were carried out to examine the release profile of the drug from the delivery system. For in vitro characterization and efficacy studies, breast carcinoma HTB-126 wells were used. Histone deacetylase (HDAC) activity was determined from cancer cells, and the efficacy of the free vorinostat and microparticle formulations was compared. Global histone changes in cells were analyzed using two-dimensional polyacrylamide gel electrophoresis (2D-PAGE). Western blot was also utilized to detect acetylation marks in cells. Uptake studies were carried out in cancer cells to examine the internalization capability of microparticle drug formulations. Data indicated that microparticles were approximately 2-μm in size with Zeta potential measurements of about -30 mV. Release studies in cells showed that the drug released from the microparticulate delivery system at an extended rate over a period of over 24 hours. In vitro data in cancer cell line indicated that there was at least 10% more inhibition of cell viability when vorinostat was used with the microparticles. Similar results were observed from clonogenic studies. Additionally, in vitro data suggested that cell death induced by the drug-loaded microparticles was caused by apoptosis. Drug-loaded microparticle formulations were able to be internalized into cancer cells. Microparticles were shown to be a promising targeting strategy for cancer epigenetic therapy by providing an extended-release of the drug in the body.
Citation Format: Duc P. Do, Keane O. Soluade. Delivery of an epigenetic agent using a microparticle drug delivery system. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3637. doi:10.1158/1538-7445.AM2015-3637
