Quantitative imaging technologies for the characterization of the size-dependent tumor vascular permeability (i.e., in the macro- to nano- size range) are of great clinical interest. Such technologies will be extremely useful for oncologists to assess the tumor vascular permeability to drugs at different sizes and, based on the drug accessibility, to stratify patients for the appropriate treatment. Moreover it can be used to monitor the tumor responses to any interventions that can potentially modulate the tumor vascular permeability and improve the drug delivery. In the current application, we propose to directly use the highly-safe, clinically-available dextrans as new MRI probes for assessing tumor vascular permeability without the need for any radioactive, paramagnetic, or super-paramagnetic label. In this approach, dextran is detected directly via its exchangeable hydroxyl (OH) protons using a recently emerged MRI contrast mechanism, Chemical Exchange Saturation Transfer (CEST), namely dextran-enhanced CEST (dexCEST). Because dextrans are available in a wide range of particle sizes-- from 5 to 54 nm for molecular weights (MW) from 10 kD to 2 MD, respectively, it is therefore feasible to use them as macro- and nano-sized MR imaging agents in a broad range of applications. As such, we hypothesize that dexCEST MRI can be used to assess the size-dependent tumor vascular permeability, and to monitor the response in the tumor vascular permeability of pancreatic cancer to stroma-targeting therapies. In particular, we will first fully optimize and validate dexCEST MRI detection to assess size-dependent tumor vascular permeability of experimental pancreatic ductal adenocarcinoma (PDAC) tumors. Then, we will use this technique to monitor the tumor response to stroma-targeting therapies in experimental PDAC tumors, which will lead to the evaluation of the use of dexCEST MRI as an imaging biomarker to quantify the efficacy of stroma-depleting drugs. The successful completion of this project will have an immediate impact on the pre-clinical development and clinical implementation of stroma-targeting therapies to treat hypo-permeable PDAC in a personalized medicine manner. Because many new drugs are in macro-size range (i.e., monocolonal antibodies) and nano-size range (nanomedicine), our approach is expected to play an important role in the clinical implementation of newly developed chemotherapy and immunotherapy, as well as their combination with stroma-targeting therapies. In addition, we expect that these developments can be easily tailored to other types of solid tumors.
The project is relevant to public health because it is expected to result in innovative and translatable medical imaging technology. This will establish an imaging-based protocol for characterizing the tumor vascular permeability in solid tumors such as Pancreatic ductal adenocarcinoma (PDAC), one of the most lethal types of cancer, and assessing the response of the tumor vasculature to therapies. This proposed technology relies on the use of clinically available dextrans and a label-free MRI method that directly detects dextrans via the MRI signal inherently carried by hydroxyl protons using a technique called chemical exchange saturation transfer (CEST). Thus, there is no need for extra chemical-, paramagnetic-, or radioactive- imaging labeling. The successful accomplishment of the proposed research will lead to a highly translatable MR image-guidance method for the development and clinical implementation of nanomedicine in a personalized medicine manner, which is highly relevant to the mission of NIH.
