Targeted Drug Delivery with Cyclodextrin-based Nanocarriers and Focused Ultrasound Triggering

摘要

Background: The Nanoporation project set out to explore specific solutions to overcome the current challenges of targeted drug delivery (TDD) to tumours using magnetic resonance imaging guided focused ultrasound (MRgFUS) to cavitate microbubbles (MBs) for increasing cell permeability and to open ‘drug nano-capsules’ to release proven active anticancer drugs directly to the tumour site with reduction of systemic drug dosage needed for the desired therapeutic effect.Objective: The work reported here aimed to develop novel nano-carriers for existing anticancer drugs, by establishment of human cancer cell models to evaluate the carriers’ encapsulation efficiency in vitro and in vivo, by using animal models and a clinical MRgFUS system to investigate the carrier-drug vehicles’ in vivo distribution and localised drug release / cellular drug uptake.Methods: A novel ?-cyclodextrin (?-CD) based carrier for encapsulation of doxorubicin (DOX) was synthesised and fully characterised. The encapsulation efficiency was assessed under various temperatures and pH levels by both chemical analysis and in vitro human cancer cell modeling with KB and HCT116 cells. A high-throughput in vitro FUS device was designed and applied, in combination with carrier-DOX inclusion. SonoVue® MBs was used to investigate TDD in cell monolayers. Ex vivo and in vivo trials were carried out with a clinically approved ExAblate MRgFUS system (InSightec, Israel) to establish a safe and efficient clinical TDD protocol on small rodents. Results: The desired ?-CD based carrier greatly reduced DOX’s toxicity and the carrier-DOX inclusion was highly stable under physiological temperature conditions as well as under a wide range of acidic conditions (pH 1.0 ~ 7.0); the encapsulated DOX is slowly released under hyperthermic conditions (up to 50 °C). In the presence of MBs, application of FUS with low mechanical indexes, under which no thermal effect was observed, enhanced the drug uptake into tumour cells for both encapsulated and free DOX. Optimal setups of MR parameters and FUS parameters were identified ex vivo and in vivo, allowing application of MRgFUS treatments to 4 live mice bearing tumours (human colorectal carcinoma, up to 1059.71 mm3) under anaesthesia with full recovery.Conclusions: The study demonstrated the possibility of translation of the constructed ?-CD derivative to potential clinical use as a delivery vehicle for DOX using combined thermal and mechanical release mechanisms by clinically applicable MRgFUS– triggered TDD with the potential for cancer therapy.