P07.15.A ELECTROACTIVE DRUG DELIVERY DEVICE FOR TARGETED INTRATUMORAL THERAPY

Abstract BACKGROUND Despite recent advances in cancer therapeutics, the prognosis for glioblastoma multiforme (GBM) remains exceptionally poor, stemming from the limited ability of systemically administered chemotherapeutics to cross the blood brain barrier (BBB). Mechanically circumventing the BBB represents a promising avenue. However, biomaterials previously used for local delivery suffer from low control over drug release, further limiting their translation. To address this, an implantable bioelectronic drug delivery device was developed to enable targeted, ‘on demand’ voltage-controlled solid-phase drug release. This consists of 3D-printed insertion guides and shunts, designed to be compatible with routinely used stereotactic frames for neurosurgery MATERIAL AND METHODS The efficacy of doxorubicin and cisplatin release from the device were assessed in both active (+2V, 1 h), and passive (0V, 1 h) conditions in Human U87 glioblastoma cells. AlamarBlue was used to confirm the cytotoxic effect of these drugs post-release at 24, 48, and 72 h timepoints. Devices were also implanted in vivo in an orthotopic mouse model (SB28) during the terminal surgery. Doxorubicin was released actively and passively for 0.5 h, with the brains cryosectioned to assess spread of doxorubicin. RESULTS In the U87 human glioblastoma cell line, dramatic anti-tumour responses were elicited under active release of doxorubicin compared to passive and unloaded device controls. Similar results were obtained for cisplatin release; however, the passive release of cisplatin also elicited a significant anti-tumour effect. Cytotoxicity data obtained in GBM 3D tumour spheroid models has demonstrated significantly improved anti-tumour effects of actively released cisplatin compared to passively released cisplatin and unloaded controls. Further, release into mouse brain tumours confirmed greater doxorubicin diffusion under active release, a finding also confirmed in a similar study but in agarose gel brain tissue phantoms. CONCLUSION This device shows promise for targeted, ‘dry’ delivery of a chemotherapeutic drug within a short time window (0.5 - 1 h). This represents an economically viable treatment option by reducing patient burden and is complementary to the current neurosurgical workflow, thus promoting technology translation. For example, an efficacious payload of chemotherapy can be delivered during biopsy procedures. Work is ongoing to determine efficacy in more complex patient-derived 3D tumour models with additional readouts including single cell resolution metabolomics and immunohistochemistry. Further, plans are underway to commence a pilot in vivo study to investigate the safety and efficacy of this device in an SB28 orthotopic mouse brain tumour model.