Synthesis and Preclinical Development of a Promising Novel Romidepsin Nanoparticle for the Treatment of Peripheral T‐Cell Lymphoma (PTCL)

Abstract

Introduction: The HDAC inhibitors are important drugs for the treatment of PTCL. While these drugs produce ORR of 25–30% with short PFS, responses can last over a year. There is still debate on the optimal ways to use HDAC inhibitors. Most HDAC inhibitors are oral with prolonged AUC of exposure. Romidepsin (R) is administered IV and exhibits a half-life of only 3 hours, though biological effects on chromatin may persist for 24–48 hours. A failed Phase 4 study led to the withdrawal of R for R/R PTCL. In an effort to try and create improved alternatives to R with better efficacy and safety, we deployed a proprietary nanochemistry platform to synthesize NanoRomidepsin (NR) particles, identifying a lead molecule that is comparable to or better than the predecessor R. Methods: Using a combinatorial strategy of solvent screening and polymer chemistry, we developed a first-in-class NR therapeutic with a unique and specific Drug/ Polymer/Surfactant ratio. We utilized dynamic Light Scattering (DLS), cryo-electron microscopy (EM) and liquid chromatography-mass spectrometry (LC-MS) to characterize the size, morphology, and drug encapsulation efficiency of the NR nanoparticles. Cell viability, flow cytometry and western blotting (WB) were performed to determine the effect of NR on cytotoxicity, apoptosis, and histone acetylation across a panel of PTCL cell lines. The maximum tolerated dose of NR was based on an in vivo single-dose and repeated dose toxicity study. Pharmacokinetic studies were performed in mice treated at ½ MTD with quantitation of plasma drug levels by LC-MS. Results: Cryo-EM and DLS confirmed that NR had a poly-dispersity index (PDI) between 0.16 to 0.27 and a z-average of 60–70 nm, indicating uniform size and homogenous particle distribution in the desired ranges. The cell viability assays demonstrated that R and NR produced comparable cytotoxicity (IC50 in range of 0.7–1.9 nM). Flow cytometry and WB analysis demonstrated that NR induced apoptosis and increased acetylation of H3/H4 in a time and concentration-dependent manner. In vivo single-dose and repeated dose toxicity assays revealed a clear correlation between dose and weight loss and/or clinical score in both R and NR treated groups. Pharmacokinetic analyses revealed a substantially greater AUC for NR, which was 3- and 25-fold higher compared to R for IP and IV routes of administration respectively. Interestingly, the markedly greater AUC for NR did not appear to be associated with increased in vivo toxicity. Conclusions: We have synthesized a lead nanotherapeutic of R that will be translated to the clinic. In keeping with other nanotherapeutic drugs, nanosizing drugs tend to increase their volume of distribution (Vd), AUC and markedly improve their tolerability. Large scale in vivo modeling of NR is underway. Data on the development and differentiation of our lead NR asset will be presented, as will the strategy for clinical development. The research was funded by: IVY grant, Translational Orphan Blood Cancer Research Initiative Fund Keyword: Molecular Targeted Therapies No conflicts of interests pertinent to the abstract.