Fine-Tuning the Physicochemical Properties of Poly(lactic Acid) Nanoparticles for the Controlled Release of the BET Inhibitor JQ1: Influence of PVA Concentration.

The compounds targeting the bromo and extra terminal domain proteins (BET), such as the JQ1, present potent anti-cancer activity in preclinical models, however, the application of JQ1 at the clinical level is limited by its short half-life, rapid clearance, and non-selective inhibition of BET family proteins, leading to off-target effects and resistance. To address these challenges, the optimization of JQ1 delivery has been accomplished through polylactide (PLA) nanoparticles. PLA derivatives with varying molecular weights were synthesized via ring-opening polymerization using a zinc-based initiator and characterized using thermogravimetric analysis, differential scanning calorimetry, and infrared spectroscopy. PLA nanoparticles (NPs) were subsequently formulated, and the effects of key parameters-including PLA molecular weight, organic phase concentration, and surfactant concentration-on particle size, polydispersity index (PDI), and encapsulation efficiency were systematically investigated. PLA molecular weight and organic phase concentration mainly influenced the NPs size whilst the thermodynamic state of the NPs was unaffected by these two parameters. The surfactant concentration is correlated to the encapsulation efficacy of JQ1 as well as the release profile, suggesting the potential tool that the variation of these parameters represent for customizing the release of JQ1 according to specific needs.