(265a) The Future of Nanoparticle Drug Delivery: Challenges in Scale-Up and Delivery

Nanoparticle drug delivery has been hailed as a revolutionary in medicine with the potential ability to protect delicate cargoes, solvate hydrophobic cargoes, targe delivery to specific sites and generally improve biodistribution and pharmacokinetics. Nanopharmaceuticals currently comprise 15% of the total pharmaceutical market and most of the new growth [1]. However, nanoparticle drug delivery has also encountered several obstacles, such as inefficiencies resulting from reticuloendothelial system uptake and incomplete understanding of delivery via the enhanced permeation and retention mechanism [2]. Apart from this, there are significant challenges in translating the vast wealth of nanoparticle carriers in the literature to commercial scale manufacturing [3]. I will begin by discussing the current state of the art and these crucial challenges facing our field. Then, I will discuss our translational work in hydrophobic drug encapsulation toward commercial scales using two different nanoparticle synthesis platforms. The first, electrohydrodynamic mixing nanoprecipitation (EMNP), is a liquid-in-liquid reverse form of electrospray in which an organic phase is injected into an electrified aqueous phase. Electrohydrodynamic mixing of the aqueous phase generates small nanoparticles encapsulating drugs. The second process, flash nanoprecipitation (FNP), was first introduced by Prud’homme [4], and involves rapid mixing of organic and aqueous fluid streams in a confined space to generate nanoparticles. We recently introduced a jet mixing reactor design that enables unequal flow rates, reducing the amount of high value cargoes needed. Both of these approaches can be operated with miscible or immiscible solvents, which changes the nanoparticle formation mechanisms and at different organic to aqueous ratios, which changes nanoparticle size. I will discuss the influence of operating parameters on nanoparticle size, polydispersity, and encapsulation efficiency. Finally, I will provide a glimpse of potential active carriers that extend beyond passive diffusion, with the potential to surmount delivery barriers in our field.

1. Ragelle, H., F. Danhier, V. Préat, R. Langer, and D.G. Anderson, Nanoparticle-based drug delivery systems: a commercial and regulatory outlook as the field matures. Expert Opinion on Drug Delivery, 2017. 14(7): p. 851-864.
2. Barua, S. and S. Mitragotri, Challenges associated with penetration of nanoparticles across cell and tissue barriers: A review of current status and future prospects. Nano Today, 2014. 9(2): p. 223-243.
3. Behrens, S.H., V. Breedveld, M. Mujica, and M.A. Filler, Process Principles for Large-Scale Nanomanufacturing. Annual Review of Chemical and Biomolecular Engineering, 2017. 8(1): p. 201-226.
4. Johnson, B.K., Flash NanoPrecipitation of organic actives via confined micromixing and block copolymer stabilization Dissertation, Princeton University, 2003,