CBNS Paper featured as a prestigious ACS Editors Choice article
Publications | April 15, 2019

Congratulations to CBNS members Ms Ngoc Mai VuDr Pradeep RajasekharDr Daniel Poole, CBNS alumni Mr Song Yang KhorDr Nghia Truong PhuocDr John Quinn, Dr Michael Whittaker, Dr Nicholas Veldhuis, and CBNS Director Professor Tom Davis for having their paper Rapid Assessment of Nanoparticle Extravasation in a Microfluidic Tumor Model sponsored for immediate, free open access by ACS due to its potential for broad public interest, an honor given to only one article from the entire ACS portfolio each day of the year. The article was selected to be featured in ACS Editors’ Choice, in addition to being published in ACS Applied Nano Materials, based on recommendations by ACS journals’ editors.

Abstract

The development of nanoparticle-based targeted therapeutics for the treatment of cancer requires a well-defined understanding of the tumour microenvironment, which is challenging due to tumour complexity and heterogeneity. Recent advancements in three-dimensional (3D) cell models such as tumour-on-a-chip devices can overcome some of these challenges by providing co-culture in vitro systems (tumour surrounded by tubular endothelial cells) that mimic native cellular environments to accurately study the enhanced permeability and retention (EPR) potential of drug delivery systems under flow conditions. However, inducing “leaky” vasculature in endothelial cells surrounding solid tumours in microfluidic devices is not readily controllable and highly dependent on tumour cell identity. Utilising a microfluidic tumor model (MTM) consisting of a tumour region surrounded by a 3D microvascular network, we have simulated the EPR effect by activating a known regulator of endothelial junction formation and edema: the Transient Receptor Potential Vanilloid 4 (TRPV4) ion channel, to rapidly assess extravasation and tumour accumulation of nanoparticles of different sizes and surface chemistries. Treatment with a selective TRPV4 agonist stimulated reorganisation of the actin cytoskeleton and disruption of adherens junctions to provide a concentration-dependent or “tunable” leakiness, confirmed by increased tumour uptake of fluorescent dextran macromolecular tracers from the vascular channels. While this controlled 3D in vitro vascular-edema system may not exemplify all of the complexities of edema mechanisms in vivo, it provides a rapid, materials-focused screening method to assess the extravasation and tumour uptake potential of nanoparticles with distinct properties. We show that the passage of nanoparticles through leaky vasculature is not solely governed by particle size but also by surface chemistry, where surface tertiary amines limit tumour cell association due to unwanted endothelial interactions.