Title: Hyaluronic acid carrier-cell interactions: a tri-culture model of the tumour microenvironment to study siRNA delivery under flow conditions

Authors: Julio M. Rios De La Rosa; Nicola Tirelli; Annalisa Tirella

Addresses: NorthWest Centre of Advanced Drug Delivery (NoWCADD), School of Health Sciences, University of Manchester, Oxford Road, Manchester, M13 9PT, UK; BiOncoTech Therapeutics, Science 2 Business Foundation, Calle Santiago Grisolia 2, Tres Cantos Technology Park, 28760, Madrid, Spain ' NorthWest Centre of Advanced Drug Delivery (NoWCADD), School of Health Sciences, University of Manchester, Oxford Road, Manchester, M13 9PT, UK; Laboratory for Polymers and Biomaterials, Fondazione Instituto Italiano di Tecnologia, 16163, Genova, Italy ' NorthWest Centre of Advanced Drug Delivery (NoWCADD), School of Health Sciences, University of Manchester, UK; Division of Pharmacy and Optometry, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester, M13 9PL, UK

Abstract: CD44 is often over expressed in solid tumours, rendering this protein a 'hot' target in drug delivery. As CD44 is the main surface receptor of hyaluronic acid (HA), one of the most common therapeutic approaches consists of hijacking the cell's mechanism of HA endocytosis to deliver active principles. This approach, however, presents two caveats: the poor understanding of HA-cell interactions and the ubiquitous expression of CD44 in other cell types, e.g., stromal cells. To predict the interaction of HA-decorated nanocarriers with CD44-expressing cells in the multi-cellular and complex tumour microenvironment, we have established a tri-culture, non-contact in vitro model (PANC-1 tumoural cells, HDF stromal cells, THP-1 macrophages) and quantified the delivery and kinetics of nanoparticle internalisation (via flow cytometry), investigating the system in both static and dynamic culturing conditions. We report that HA-decorated nanocarriers are able to preferentially deliver siRNA to pancreatic cancer cells, interestingly even under flow/dynamic conditions.

Keywords: hyaluronic acid; CD44; tumour microenvironment; pancreatic cancer; macrophages; tumour-associated fibroblasts; nanoparticle; targeted drug delivery; siRNA.

DOI: 10.1504/IJNBM.2019.101755

International Journal of Nano and Biomaterials, 2019 Vol.8 No.2, pp.106 - 117

Received: 30 Dec 2017
Accepted: 20 Jul 2018
Published online: 26 Aug 2019 *

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