Tumor-Targeting Fluorescence Probe for Real-Time Intraoperative Imaging
Abstract
Considering the current Breast Cancer Landscape and the Breast Cancer Research Program’s (BCRP’s) vision, relapse is one of the major problems to end breast cancer. The overall goal of the proposal is to develop a unique imaging agent with the ability to identify breast tumors and accurately distinguish tumors and surrounding normal tissues during surgical operation. With our proposed approach, it will potentially prevent breast cancer recurrence by precise surgical resection and improve the outcome of surgical treatment while saving overall cost by reducing rates of re-operation. With the recent advanced detection procedures, many breast tumors can be found at early stages. For patients with early stages of the disease, surgical removal of local cancer followed by chemotherapy or radiotherapy is the most common breast cancer treatment. The precise surgical resection directly influences patient prognosis. However, it is often very difficult or even impossible for surgeons to distinguish breast tumor from normal tissue during tumor resection. Currently, surgeons during surgical operation only have direct visual perception and palpation along with imaging results taken before surgery as their guide. In fact, cancer cells are sometimes found at the edge of the removed tissue after surgery (positive margin), then additional surgery is needed as breast cancer cells left behind increase risk of cancer recurrence and metastasis. Prior to any surgical procedure, tumor is usually assessed by the traditional imaging procedures such as mammography, ultrasound, MRI (magnetic resonance imaging), etc. Although these imaging technics are clearly useful to detect breast tumor and determine the extent of resection(s), they are not suitable to use as intraoperative imaging because handling of these imaging-instruments are typically too complicated or unsuitable to use during surgical operation or are incapable of detecting tumor margins with high contrast. Thus, development of new intraoperative imaging to clearly detect tumor margins is needed to completely remove tumor at the initial surgical operation. Recently, optical imaging is gaining traction in the image-guided surgery field especially when coupled with near-infrared (NIR) fluorescence agent. The advantages of using NIR fluorescent image-guided surgery are real-time detection with high-resolution image and flexible instrument without ionizing radiation. Furthermore, NIR imaging visualizes disease through skin before resection and does not change the appearance of the surgical field of view. Several NIR fluorescence agents have been preclinically developed, among them indocyanin green (ICG), which is a non-toxic NIR fluorescence agent and currently registered by the Food and Drug Administration for clinical applications. Although ICG is useful as cardiac output or hepatic function marker, it is a non-specific contrast agent limiting in discerning tumor from normal tissue. In order to use ICG as an intraoperative tumor marker, development of a tumor-targeting carrier is essential. Many attempts have been made in the development of carrier molecules; in particular, cell-penetrating peptides have shown to be a promising strategy for improving the delivery and intracellular uptake of diagnostic and therapeutic agents. We have identified that a 28 amino acids peptide fragment, p28, preferentially enters and is retained significantly longer in breast cancer cells. In addition to cancer-targeting property, p28 also has anticancer activity. Safety and toxicity of p28 as a single therapeutic agent, but not imaging carrier/agent, has been tested in two Phase I clinical trials in the US. Preclinical and clinical studies showed that p28 preferentially penetrates cancer cells without toxicity and immunogenicity in animals and humans. Based on the above facts, we hypothesize that developing p28 as a nontoxic tumor-targeting carrier for ICG will provide an ideal intrao
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710500
Entities
People
- Tohru Yamada
Organizations
- United States Army
- University of Illinois at Chicago