One of the foremost challenges in translating nanoparticle technologies to the clinic is the need to produce well-controlled materials on a large-scale. Many publications describe the small, laboratory-scale synthesis and testing of nanoparticles. While far fewer in number, there are also several “success stories” of nanoparticles that have been scaled-up and translated to the clinic (e.g., Abraxane, Doxil). Yet, between the early-stage “lab-scale” and clinical-stage “large-scale” production of nanoparticles lies a critical and rarely discussed realm, that of “pilot-scale” production. Here, we describe the process of scaling up production of the “expansile nanoparticle”, or “eNP”, technology to the pilot-scale. eNPs are pH-responsive nanoparticles that swell and expand in response to a mildly-acidic pH. The particles themselves are notable for their novel Materials-Based Tumor Targeting strategy that is unique and dissimilar from traditional active or passive targeting. Previous studies demonstrate the ability of eNPs to: provide pH-triggered drug release; localize to tumors with &gt;92% specificity; yield 10-100-fold higher tumoral drug concentrations than free drug; and, more than double animal survival compared to “free” drug controls. Initial production scale-up was attempted using an LV1 Microfluidizer (Microfluidics Corp.). This instrument employs high pressures and micro channels to generate high shear environments that enable uniform control over particle size using a scalable process. However, the originally employed two-step emulsion/<i>in situ </i>polymerization method, which was previously successful on the lab (2-10 mL) scale, was found to be incompatible with the Microfluidizer process. To overcome this, we altered the order of the synthesis steps, first polymerizing the eNP polymer and then using this “pre-polymerized” eNP material in the Microfluidizer process. In this manner, we successfully synthesized “pre-polymerized eNPs”, or “pp(eNPs)”. pp(eNP) diameter and polydispersity (PDI) are tuned by titering the number of Microfluidizer processing passes and the surfactant ratio. Sterilization protocols were investigated including the use of gamma irradiation and filtration, the latter being selected for its ease of use. Lastly, we developed methods for the incorporation of cryoprotectants to enable long-term storage as a lyophilized powder as production at the pilot-scale is only useful inasmuch as the product can be stored stably for long-term use.<br/>

Pilot-scale production of expansile nanoparticles

256th National Meeting (2018)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.