Investigator: Daniel Roxbury, University of Rhode Island

Scientific Theme: Cancer

Abstract:  The ability to deliver sufficiently high concentrations of chemotherapeutic drugs into patient tumors remains a significant hurdle for the non-invasive treatment of solid cancers. Barriers such as a thick extracellular matrix, densely packed cancer cells with tight junctions, and high interstitial fluid pressures prohibit the passive diffusion of conventional therapeutic agents. In the design of effective drug delivery strategies to surpass these barriers, including several novel nanotechnology-based approaches, it is crucial to fully understand the properties pertaining to the permeability of the tumors and furthermore how they can be modulated. Cancer cells growing in multicellular tumor spheroids (MCTS) have been proposed as a more efficient preclinical screening platform due to their intrinsic similarities to patient tumors. Existing tools to probe the permeability of MCTSs are limited in their functionality and are not accurately quantifiable. The objectives of this project are to develop a localizable near-infrared probe based on fluorescent carbon nanotubes to delineate the interstitial and transcellular permeabilities of an array of MCTS models. Additionally, a high-throughput screening platform will be introduced in order to identify pharmacological agents to enhance the MCTS permeabilities. By screening for compounds with the highest enhancement in MCTS permeability, the long- term potential of this project will be to increase the translational efficiency of existing chemotherapeutic drugs. To complete these objectives, the specific aims are 1) to develop live-cell localizable nanoprobes to quantify the interstitial and transcellular permeabilities, as functions of size and charge, in multicellular tumor spheroids and 2) to develop a quantitative high-throughput assay for identifying pharmacological agents to enhance tumor permeability. The nanotube probes will be rationally designed by modifying the surface functionalization, to control the charge, as well as average length, in order to quantify the interstitial vs. transcellular permeabilities (i.e. diffusion coefficients). In a developed high-throughput assay, hanging drop well plates will be used to identify compounds that enhance the localized MCTS permeabilities. Altogether, the proposed research portends the broad applicability of fluorescent nanotubes for biomedical usage.

Human Health Relevance:  The proposed research introduces a new tool for researchers to better understand preclinical tumor models. Such a tool aids in the development of novel strategies for enhancing the delivery of drugs. By increasing the efficiency of drug delivery, the overall number of molecular entities that translate into the clinic will likewise increase.