Controlled Drug Release and Chemotherapy Response in a Novel Acoustofluidic 3D Tumor Platform

• Published in: Small (Weinheim an der Bergstrasse, Germany) Germany), 2016-05, Vol.12 (19), p.2616-2626
• Main Authors: Zervantonakis, Ioannis K., Arvanitis, Costas D.
• Format: Article
• Language: English
• Subjects: Acoustics - instrumentation; acoustofluidics; Antineoplastic Agents - administration & dosage; Batch Cell Culture Techniques - instrumentation; Cell Line, Tumor; Chemotherapy; controlled release; Damage; Delayed-Action Preparations - administration & dosage; drug delivery; Drug delivery systems; Drug Monitoring - instrumentation; Drugs; Equipment Design; Equipment Failure Analysis; Flow Injection Analysis - instrumentation; focused ultrasound; Humans; Lab-On-A-Chip Devices; Micro-Electrical-Mechanical Systems - instrumentation; Nanotechnology; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - pathology; Platforms; Printing, Three-Dimensional - instrumentation; Sonication - instrumentation; Three dimensional; Transport; tumor microenvironments; Tumors; Uptakes
• ISSN: 1613-6810; 1613-6829
• DOI: 10.1002/smll.201503342

Overcoming transport barriers to delivery of therapeutic agents in tumors remains a major challenge. Focused ultrasound (FUS), in combination with modern nanomedicine drug formulations, offers the ability to maximize drug transport to tumor tissue while minimizing toxicity to normal tissue. This potential remains unfulfilled due to the limitations of current approaches in accurately assessing and quantifying how FUS modulates drug transport in solid tumors. A novel acoustofluidic platform is developed by integrating a physiologically relevant 3D microfluidic device and a FUS system with a closed‐loop controller to study drug transport and assess the response of cancer cells to chemotherapy in real time using live cell microscopy. FUS‐induced heating triggers local release of the chemotherapeutic agent doxorubicin from a liposomal carrier and results in higher cellular drug uptake in the FUS focal region. This differential drug uptake induces locally confined DNA damage and glioblastoma cell death in the 3D environment. The capabilities of acoustofluidics for accurate control of drug release and monitoring of localized cell response are demonstrated in a 3D in vitro tumor mode. This has important implications for developing novel strategies to deliver therapeutic agents directly to the tumor tissue while sparing healthy tissue. A novel 3D acoustofluidic tumor platform to study the effects of focused ultrasound‐triggered drug release and uptake in glioma cell lines in real time and monitor tumor cell death and DNA damage is presented. This platform can be used to discover new noninvasive protocols that target tumor cells regionally without damaging normal cells.