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 intravenous treatment of solid cancers. Barriers such as a selective endothelium, 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 into 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 of controlled length to delineate the interstitial and transcellular permeabilities of an array of MCTS models. Additionally, by appropriately functionalizing the surface of the nanotube, the permeability of the nanoprobes into the MCTSs will be selectively enhanced, as well as introducing the ability to deliver a chemotherapeutic payload. 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 enhance the permeability and introduce the capacity for drug delivery in the multicellular tumor spheroid nanoprobes. 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). Utilizing characterized endothelial penetration increasing molecules, tumor-penetrating peptide sequences, and anti-neoplastic drugs, the co-functionalized nanoprobes will have immense co-functionalized applicability. Altogether, the proposed research portends the broad relevance of fluorescent nanotubes for biomedical usage.

Human Health Relevance: The proposed research introduces a new tool and drug delivery vehicle for researchers to better understand and treat 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.