Surgical resection is a cornerstone of therapy for patients with solid cancers, including breast cancer and head and neck squamous cell carcinoma (HNSCC). Obtaining tumor-free surgical margins is an important determinant of disease-free survival and minimal removal of normal tissue is equally important in the functional preservation of normal tissues. The long-term goal of this project is to establish tumor-activatable near infrared (NIR) nanoprobes to delineate the tumor/normal tissue boundaries to help surgeons achieve a safe and accurate resection of breast, head and neck cancers. We will capitalize on our recent invention of ultra-pH sensitive (UPS) nanoprobes to target aerobic glycolysis, a ubiquitous hallmark of cancer, which allow for non-linear amplification of tumor microenvironment signals with signal suppression in blood for the cancer-specific imaging of tumors. We adopted the UPS design to indocyanine green (I-UPS), an FDA-approved NIR dye with improved pH response (pHON/OFF = 0.15 pH, compared with 2 pH for small molecular pH sensors). Using a SPY Elite(r) clinical camera, we have shown the effectiveness of I-UPS nanoprobes in the visualization of various solid cancers with diverse genotypes and anatomical sites. Preliminary data show significantly improved long-term survival in mice bearing head and neck or breast tumors after I-UPS- guided surgery over conventional white light control. In the proposed project, we will specifically investigate the mechanism of UPS activation in the tumor microenvironment, particularly in the context of tumor margin delineation as a function of cancer type, stage and size, as well as the transition pH of the nanoprobes. We will test the central hypothesis that I-UPS-guided delineation of tumor margins will allow accurate tumor resection and functional preservation of normal tissues for improved safety and long-term survival. To test our hypothesis, we will carry out the following specific aims: (1) Establish a tunable series of UPS nanoprobes with Always ON/ON-OFF dual reporters; (2) Quantify and optimize UPS nanoprobe activation relative to microscopic tumor margins in breast and HNSCC; (3) Evaluate the safety and pharmacokinetics of I-UPS nanoprobes. If successfully demonstrated, I-UPS technology will offer a broadly applicable strategy for the real-time visualization of tumor margins in a variety of cancer types to achieve cancer-specific surgeries with functional preservation of normal tissues.
