Local delivery of Doxorubicin and Olaparib loaded injectable hydrogels with adjuvant radiotherapy improves survival in a glioblastoma in vivo model

Abstract

Local drug delivery systems (LDDS) are a promising method to overcome challenges associated with chemotherapeutic treatment of brain tumours, namely poor blood-brain barrier penetration. Here we report a poly(ethyleneglycol)-poly(lactide)-poly(caprolactone)-poly(lactide)-poly(ethyleneglycol) based injectable hydrogel, PELCLE, loaded with Doxorubicin (Dox) and Olaparib (Ola) as an LDDS against glioblastoma (GBM), a primary malignant brain tumour with a poor prognosis. The thermoresponsive properties of the hydrogel, which behaved as a liquid at room temperature and formed a gel at elevated temperatures, were not impacted by the inclusion of chemotherapeutics whereby two-week sustained release was recorded for both Dox and Ola. Drug potency was assessed against a panel of GBM cell lines, both a syngeneic mouse line and primary patient-derived lines, and the combination of Dox/Ola demonstrated synergistic effects at a range of drug: drug ratios. The application of radiotherapy (XRT) in combination with Dox/Ola improved treatment efficacy both in vitro and in vivo, with a significant increase in median survival observed when Dox/Ola PELCLE hydrogels were applied against a surgical resection model of GBM (syngeneic mouse model SB28) with and without the addition of adjuvant XRT (28 and 23 days, respectively, p < 0.01). Furthermore, a long-term survivor was noted in the group treated with the drug loaded HG and XRT, which was associated with a very small residual tumour, indicating the efficacy of this treatment against a GBM in vivo model.