Vorinostat-Polymer Conjugate Nanoparticles for Acid-Responsive Delivery and Passive Tumor Targeting
Biomacromolecules 2014 October 21 [Epub ahead of print] [Link]
Denis I, El Bahhaj F, Collette F, Delatouche R, Gueugnon G, Pouliquen D, Pichavant L, Heroguez V, Gregoire M, Bertrand P, Blanquart C.
Abstract
In vivo histone deacetylase inhibition by Vorinostat at clinically acceptable dosing is limited by its poor pharmacokinetics properties. A new type of non-toxic pH-responsive delivery system has been synthesized by Ring-Opening Metathesis Polymerization, allowing in vivo selective distribution and histone reacetylation in mesothelioma tumor by Vorinostat. The delivery system is synthesized by generic click chemistry, possesses native stealth properties for passive tumor targeting, and does not need additional chemistry for cellular internalization. While SAHA alone at 50 mg/kg in mice showed no effect, our new delivery system with 2mg/kg SAHA gave histone re-acetylation in tumors without side effects demonstrating that our strategy improves the activity of this HDACi in vivo.