By Gail Dutton

The need to improve the pharmacological properties of biomolecular therapeutics led to the development of nanocarriers. Those nanocarriers, however, can face challenges when loading disparate types of cargo with different physicochemical properties.

Flash nanoprecipitation (FNP), a nanocarrier formulation technique being advanced by researchers at Vanderbilt University, addresses that challenge by producing diverse, polymeric nanocarriers using existing infrastructure.

“The novelty of our paper is that we demonstrated that FNP can make nanoparticles comprised of an endosomolytic polymer without including a hydrophobic drug to drive nucleation and particle formation, which is how the process has traditionally been used,” John T. Wilson, PhD, associate professor of chemical & biomolecular engineering, Vanderbilt University, tells GEN.

This work is based on the confined impingement jet mixing (CIJ) method pioneered by  Robert K. Prud’homme, PhD, at Princeton University. Because FNP forces mixing within milliseconds, it physically mixes and supersaturates the dissolved block copolymer and biomolecule solute. That leads to phase separation and results in “monodisperse polymeric nanocarriers…capable of encapsulating both hydrophilic and hydrophobic biomolecular cargoes,” Wilson and colleagues wrote.

“Our study shows that multiple impingements can result in nanoparticles of different sizes, polydispersity, and morphology,” Wilson says. The nanocarrier morphologies it produced include micelles, unilamellar vesicles, polymersomes, and multicompartment vesicles.

Promoting endosomal escape

“The most exciting finding is that we can use CIJ mixing to produce nanoparticles of diverse and defined architectures with tunable capacity to promote endosomal escape of cargo,” Wilson says. “Endosomal escape is the critical barrier to translation of intracellularly-acting biologics, including nucleic acid therapeutics like small interfering and messenger RNA (siRNA and mRNA).” This study, therefore, may help biopharmaceutical manufacturers “optimize nonviral drug delivery systems for intracellular delivery of therapeutic cargo.”

The diblock polymer Wilson and his colleagues used needs FDA approval before it can be used in humans, but CIJ mixing already is in use by Pfizer to manufacture its COVID-19 vaccines.

Before biopharmaceutical manufacturers adopt this method, they should weigh the expected gains from process optimization against the decreases in process efficiency that accompany multiple impingements. Wilson advises keeping the impingement number as low as possible—ideally, achieving target properties with a single impingement.

Looking forward, “We currently are evaluating the platform for loading and delivering peptide and RNA immunotherapeutics,” Wilson says. His team also is considering FNP as an alternative to formulate lipid nanoparticles to deliver mRNA vaccines and other therapeutics safely and effectively.

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