HDAC inhibitor가 탑재된 PLGA 나노입자를 이용한 표적 암 치료

Abstract

Chromosomes are highly condensed with histone proteins after replication. Histone acetylation by Histone acetylases (HATs) allows the RNA pol Ⅲ to access acetylation to start transcription. This gene transcription can be inhibited by histone deacetylases (HDACs) by removing the acetyl group. These enzymes play important role in gene expression, proliferation differentiation and apoptosis through remodeling of chromatin. In addition, HDACs and HATs regulate activity of non-histone protein including transcription factors such as p53 and several cytoplasmic proteins. HDACs have known that are aberrantly overexpressed in various tumors. HDACs can be inhibited by HDAC inhibitors inducing the activity of HATs. It has been shown that HDAC inhibitors can reactivate aberrantly silenced tumor suppressor genes and block the tumor cell growth through inhibition of the HDACs. However the targeted delivery of HDAC inhibitors to cancer cells is essential to minimize the adverse activation of bystander cells. In this study, we used the FDA-approved, biodegradable polymer, PLGA for drug delivery system that can be sustainably released. SAHA(vorinostat) is one of the HDAC inhibitors that inhibit the classⅠ, classⅡa and classⅡb, classⅣ HDACs. For overcoming of adverse effects of SAHA such as thrombus formation and neutropenia and developing the antitumor effects, we designed HDAC inhibitors encapsulated PLGA nanoparticles. As targeted molecule, RVG peptide binds the acetylcholine receptor in B16F10 cells. We confirmed the ability of delivery to cancer cells using FACS. And RVG conjugated PLGA nanoparticles also have a cancer specific targeting ability in invivo model. Further the 200 nm sized modified cancer targeting PLGA/HDAC inhibitors nanoparticles inhibited tumor growth in mice subcutaneously implanted with melanoma cancer cell in upon I.V. injection.