β-Cyclodextrin-Poly (β-Amino Ester) Nanoparticles Are a Generalizable Strategy for High Loading and Sustained Release of HDAC Inhibitors

Here, we describe a simple, efficient formulation of a novel library of β-cyclodextrin-poly (β-amino ester) networks (CDN) to achieve this goal. We observed that network architecture was a critical determinant of CDN encapsulation of candidate molecules, with a more hydrophobic core enabling effective self-assembly and a PEGylated surface enabling high loading (up to ~30% w/w), effective self assembly of the nanoparticle, and slow release of drug into aqueous media (24 days) for the model HDACi panobinostat. Optimized CDN nanoparticles were taken up by GL261 cells in culture, and released panobinostat was confirmed to be bioactive. Pharmacokinetic analyses demonstrated that panobinostat was delivered to the brainstem, cerebellum, and upper spinal cord following intrathecal administration via cisterna magna injection in healthy mice. We next constructed a library of CDNs to encapsulate various small, hydrophobic, ionizable molecules (panobinostat, quisinostat, dacinostat, givinostat, and bortezomib, camptothecin, nile red, and cytarabine), which yielded important insights into the structural requirements for effective drug loading and CDN self-assembly. Taken in sum, these studies present a novel nanocarrier platform for encapsulation of HDACi via both ionic and hydrophobic interactions, which is an important step toward better treatment of disease via HDACi therapy.