Ultrasound mediated Targeted Drug Delivery In Vitro: design, evaluation and application

Abstract

Background Targeted Drug Delivery (TDD) is a therapeutic modality which allows an increase in the medication dose at a treatment site, while simultaneously avoiding effects in the rest of the human body. This can be achieved via different types of delivery vehicles or carriers which encapsulate the free drug and release it only at the needed location. There are various methods of drug release, one of which is ultrasound, as in ultrasound-mediated TDD (USmTDD). The combination of focused ultrasound (FUS) and magnetic resonance imaging (MRI) provides a controllable system of drug release and impact assessment.
In the work reported here, a novel drug carrier was synthesized and assessed. Ultrasonic drug release from the carrier was evaluated in vitro using a clinical MRI-guided Focused Ultrasound Surgery (MRgFUS) system. As there was no properly controllable research environment for in-vitro studies available prior to the investigation of the carriers, such an environment was built and characterized.
Methods MCF7 and A375m human cancer cell lines were subjected to FUS using the ExAblate 2000 and 2100 systems (InSightec, Haifa, Israel). The experiments were conducted in a specially designed research environment, which was comprehensively evaluated to ensure both cell sterility and proper FUS propagation. Various sonication parameters were applied, in conjunction with a commercially available ultrasound contrast agent (USCA), to achieve maximal cellular uptake of Doxorubicin (Dox) with minimal decrease in cell viability. A novel cyclodextrin (CD) based drug carrier was synthesized, chemically evaluated, and investigated in vitro via two release mechanisms: heating and physical effects.
Results Two clinical MRgFUS systems were adapted for in-vitro work, showing controllable and repeatable results. Both of the assessed release mechanisms showed their competency: the application of FUS in the presence of USCA increased the cellular drug uptake of Dox by an average factor of 3 ±0.9, and up to a factor of 4 due to heating. The Dox release from the CD-based carrier was around 100% with both mechanisms.
Conclusions Adaptation of a clinical MRgFUS system for in-vitro research allows the use of a single system starting from in-vitro studies, through the pre-clinical stage to clinical trials. This gives physicians the ability to be a part of a wider USmTDD research group, from the beginning of the product definition, bringing real meaning to the term “from bench to bedside”. The baseline studies reported here have verified that intracellular drug uptake is increased through heating and sonoporation processes. The release mechanisms from the carriers were also observed, validating the concept of USmTDD from CD-based carriers.

Date of Award	2013
Original language	English
Awarding Institution	University of Dundee
Supervisor	Sandy Cochran (Supervisor)