Abstract 3207: Chemical fabrication and characterization of a novel nanoparticle of the histone deacetylase (HDACi) romidepsin

Abstract

Abstract Introduction: Histone Deacetylase inhibitors (HDACi) are important drugs for the treatment of patients with PTCL (peripheral T-cell lymphoma). Romidepsin (R), a potent Class I HDACi, is given intravenously, weekly for three to four consecutive weeks. R has a half-life of three hours and is extensively protein bound. The indication for R in PTCL was recently withdrawn due to a failed Phase 4 study. Given the need for new drugs in PTCL, and the importance of epigenetically targeted drugs for the disease, we developed a first-in-class nanoparticle of R (NR) deploying a proprietary nanochemistry platform. Methods: We modified the bulk nanoprecipitation method with FDA approved and Generally Recognized as Safe (GRAS) materials, specifically including PEGylated amphiphilic diblock copolymers, to develop NR combinatorially. By combining a drug and polymer solution with an anti-solvent, we produced core-shell structured NR particles with “stealth” properties. To achieve high R loading, stability, purity, scalability, and reproducibility, we devised a multi-pronged optimization system by modulating parameter sets in tandem. We determined the optimal parameters for the "lockdown" formulation. We purified NR by using centrifugal filters and determined stability by storing at 4°C. We used Cryo-electron microscopy (cryo-EM), Dynamic Light Scattering (DLS), and Liquid Chromatography-Mass Spectrometry (LC-MS) to determine the morphology, size, PDI, and drug concentration of NR. We developed fluorescent-NR with DiO dye to test bioavailability. We tested NR in T-cell lymphoma cell lines for histone acetylation and apoptosis induction. Furthermore, we investigated the in vivo pharmacokinetics and toxicity of NR in PTCL xenograft mouse model and quantified the drug by LC-MS. Results: The physiochemical analysis of NR demonstrated that the particles were spherical, with a hydrodynamic diameter of 46 ±5 nm and PDI of 0.15 - 0.2. NR had a negative zeta potential and an exceptional drug encapsulation efficiency of over 50% (>500 µg/mL). NR exhibited high stability with respect to size, PDI and drug concentration for over two years. Flow cytometry and western blot analyses indicate NR induces apoptosis and histone acetylation in a time and dose-dependent manner, equivalent to or better than that observed for R. NR’s AUC increased 25-fold when administered intravenously. NR had superior tolerability, and DiO-NR confirmed superior biodistribution in tumor in a PTCL xenograft mouse model. Conclusion: We developed a cutting-edge approach with minimum excipients, which enabled NR scale up with batch-to-batch reproducibility and high quality co-packaging of fluorescent dye and drug. NR improved R’s pharmacokinetic profile and efficacy in pre-clinical xenograft mice models. Our versatile technology enables Chemistry Materials and Controls products, an essential step in clinical product development. Citation Format: Samir Zuberi, Deepthi P. Damera, Ipsita Pal, Susan Walker, Ramesh Katla, Colin Haws, Akhil Gajjala, Andrea Joyner, Kallesh D. Jayappa, David J. Feith, Todd E. Fox, Thomas P. Loughran, Owen A. O'Connor, Anuradha Illendula. Chemical fabrication and characterization of a novel nanoparticle of the histone deacetylase (HDACi) romidepsin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3207.