Ultrasonic Delivery of Theranostic Anti-Cancer Agents (360G-Wellcome-201406_Z_16_Z)

Key words: platinum, controlled release, cancer, ultrasound, drug delivery This research develops a powerful new methodology for treating cancer with a highly specific, potent action and markedly lower side-effects, compared with existing therapies. It combines the potency of platinum anti-cancer complexes – encapsulated to prevent unwanted side-reactions – with the selectivity of drug release at a tumour afforded by focused ultrasound. We will synthesise new PtIV prodrugs designed for encapsulation and delivery using ultrasound; a novel approach for platinum drug delivery. Groups will be attached to the PtIV centre to aid tracking both in cellulo and in vivo. Once inside cancer cells, the PtIV complexes will be rapidly converted to PtII by intracellular reducing agents. The resultant PtII fragment is anticipated to form DNA lesions, ultimately inducing cell death. The PtIV prodrugs will be liposomally encapsulated, and the liposomes attached to large gas-filled microbubbles, creating a drug delivery vehicle. Ultrasound – focused at the site of a tumour – will destroy the vehicle, releasing the prodrug and enhancing the penetration of the prodrug into the tumour. We will investigate PtIV prodrug characterisation, release from the delivery vehicle, cellular uptake, reduction to PtII species, cellular distribution and cytotoxicity.