The objective of this work is to develop a robust, scalable platform for synthesizing nano-scale polymeric drug carriers via Flash NanoPrecipitation (FNP). Many cancer therapeutics used currently are hydrophobic; hence, in vivo
and clinical studies often encounter limited biodistribution, as well as a rapid clearance. One approach to overcome these challenges is encapsulating the hydrophobic drug molecules inside polymeric micro/nanoparticles. For example, micelles are polymeric nanoparticles capable of encapsulating hydrophobic molecules in the hydrophobic core. Generally, micelles are formed via self-assembly of amphiphilic block copolymers (BCPs), and hydrophobic molecules can be encapsulated in the micelle core during self-assembly. Conventional techniques for producing micellar drug carriers include water addition (WA), thin film hydration, and interfacial instability (IS). However, these methods are primarily limited to the bench scale; and, therefore, are not commercially viable. FNP was developed by Prudâhomme to synthesize polymeric nanoparticles encapsulating hydrophobic species at scale. In this approach, the nucleation and growth of hydrophobic compounds in water-miscible organic solvent are induced by rapidly mixing the organic solvent with an aqueous solvent. FNP has shown significant advantages for drug delivery applications, such as high product throughput and encapsulation efficiency. However, a typical FNP process requires large flow rates, ranging between 3 to 120 ml min-1
, for achieving sufficient mixing intensity.
Inspired by previous FNP studies, we developed an FNP process that utilizes electrospray atomization to enable rapid mixing, as opposed to impinging jet flow. Liquid-Liquid Electrospray (LLE) is a technique in which, unlike conventional electrospray, a nonconductive solvent is atomized inside a more conductive solvent. Using LLE, water-miscible organic solvent (i.e. tetrahydrofuran) containing BCPs and hydrophobic therapeutics was sprayed into water, inducing atomization and rapid mixing. This resulted in an FNP process yielding highly monodisperse polymeric drug. Unlike traditional impinging jet approachces, the rapid mixing achieved in LLE-FNP is independent of flow rate because fluid atomization is primarily based on the applied voltage. Using this approach, we produced monodisperse polymeric nanocarriers (monodispersity ~ 0.07) encapsulating a variety of cancer therapeutics, including dexamethasone, vorinostat, and lutein; the encapsulation efficiency and drug release characteristics were examined (encapsulation efficiency ~ 30 - 70%).