PEG-Heparin hydrogels allow for the assessment of breast cancer tumouroid response to anti-cancer treatment for personalised medicine

Abstract

Objectives The validation of accurate three-dimensional (3D) models holds significant importance for anti-cancer drug development and screening processes, aiming to minimise the time and resources lost during their development using conventional procedures. Here, we investigated whether bioengineered PEG-Hep hydrogels, a bioengineered breast tumour model, can be used to characterise the responses of immortalised breast cancer cell lines or primary patient-derived breast cancer tumouroids to anti-cancer treatments in 3D. Methods Drug-hydrogel interactions were first assessed using ultraviolet spectroscopy and liquid chromatography-mass spectrometry to determine drug retention and penetration within PEG-Hep hydrogels. Subsequently, we used several different anti-cancer drugs representing first-, second- and third-line treatments across three molecular subtypes (ER/PR+, HER2+ and TNBC) using five breast cancer cell lines. Drug responses were compared between conventional two-dimensional (2D) cultures and 3D PEG-Hep cultures through dose-response and IC50 analyses. Finally, primary breast cancer cells were cultured in PEG-Hep hydrogels and exposed to clinically relevant therapies, including doxorubicin, paclitaxel, and eribulin. Results PEG-Hep hydrogels exhibited distinct drug retention profiles dependent on drug-polymer interactions. Cell lines formed spheroids within PEG-Hep hydrogels, and treatments significantly inhibited spheroid formation and growth while increasing HIF1-α accumulation, indicative of drug-induced cellular stress. Patient-derived tumouroids responded to one or more anti-cancer agents, with doxorubicin demonstrating efficacy across all samples. Conclusions This study has demonstrated PEG-Hep hydrogels to be a versatile and robust 3D platform for elucidating drug-cell interactions within the context of breast cancer. Moreover, this study contributes towards the implementation of semi-synthetic hydrogels for the advancement of personalised medicine.