(624i) Development of Retinoid ST1926 Nanoparticle Formulation Via Flash Nanoprecipitation

Natural retinoid compounds such as all-trans-retinoic acid constitute a promising class of anti-cancer compounds that have been used against various types of cancers. However, their clinical usage is hindered by undesirable side effects and acquired resistance. As a result, synthetic retinoids exhibiting increased specificity and reduced toxicity were developed. In particular, ST1926 is a hydrophobic synthetic retinoid that has shown promise in several solid and liquid tumors, and has reached Phase I clinical trials for ovarian cancer treatment. Further development of ST1926 is hindered by its reduced bioavailability and therapeutic efficacy due to glucuroconjugation in cancer patients, leading to its rapid excretion in urine.

In this research project, a nanoparticle-based formulation of ST1926 is developed to overcome limitations in formulation, efficacy, and bioavailability. Formulating ST1926 into controlled-size nanoparticle suspensions offers several advantages, including (1) overcoming the formulation challenge due to the drug’s low water solubility, (2) enhancing the drug’s efficacy through preferential tumor accumulation due to the Enhanced Permeability and Retention (EPR) effect observed with long-circulating nanoparticles, and (3) potentially reducing drug glucuronidation by providing nanoparticle surface protection during in vivo circulation using amphiphilic block copolymers.   

ST1926 nanoparticles (STNP) were prepared using a recently developed particle formation technology termed Flash Nanoprecipitation (FNP) which uses fast mixing in a confined volume to afford co-precipitation of the solute and a stabilizing amphiphilic diblock copolymer, yielding stable, controlled size nanoparticles.

STNP in the size range of 174-230 nm as determined by dynamic light scattering  were prepared using poly(styrene-b-ethylene oxide) stabilizing polymer at a drug/polymer weight ratio or 1/5, respectively. In vitro cell growth assays were conducted to compare the anti-cancer activity of ST1926 and its corresponding STNP formulation. Cells were seeded in 96-well plates, treated with ST1926 or STNP, and monitored over 72 hours. Preliminary results show that STNP exhibits potent anticancer activities similar to the native ST1926 in colorectal cancer cells, at pharmacologically achievable concentrations.

Further studies are planned to characterize, optimize, and further investigate the efficacy of STNP both in vitro and in vivo.