Targeted PLGA Nanoparticles Encapsulating Histone Deacetylase Inhibitor, Panobinostat Effectively Control T Cell Leukemia

Abstract

High levels of expression of histone deacetylases (HDACs) and hypo-acetylation of histone proteins are related with uncontrolled cell proliferation, differentiation, and pathogenesis of cancer. Thus, histone deacetylase inhibitors (HDACi) can potentially be used as anti-cancer drugs. HDACi are known to increase apoptosis of cancer cells by obstructing activity of HDACs, and increasing the accessibility of transcription factors for re-activating repressed tumor suppressor genes. An opportunity for improving HDACi activity is through the use of delivery systems that allow targeted access to cell and tissue types that are not normally a characteristic of the incorporated drug. In this study, we tested the efficacy of the HDACi, Panobinostat (LBH589) against human T cell leukemia through encapsulation in the biodegradable polymer, PLGA using a single chain variable fragment (scFv) antibody directed to the human CD7 molecule that is exclusively expressed on human T cells to achieve specific delivery of the drug. The T cell-specific scFvCD7-conjugated drug-encapsulated PLGA nanoparticles - CD7-PLGA/LBH589 sizing at ~200nm and loaded at 70% capacity, Further, systemic delivery of the formulation to tumors generated with the T cell leukemia line in immunodeficient mice controlled tumor growth through apoptosis induction through p21 gene expression, blockade of HDAC phosphorylation and acetylation of histone proteins.