Abstract B19: Multimodal contrast agents for integrated preoperative and intraoperative imaging of cancer
Authors: Payne William M. , Svechkarev Denis A. , Boska Michael D. , Mohs Aaron M. 
Published: March 2017

Abstract
Background: Surgical resection remains the most promising potentially curative treatment strategy for many forms of cancer1. Residual malignant tissue after surgery, a consequence in part due to positive margins, contributes to the high mortality and disease recurrence that is further exacerbated by the aggressive nature of cancer2. In this study, multimodal contrast agents for integrated preoperative magnetic resonance imaging (MRI) and intraoperative fluorescence image-guided surgery (FIGS) are developed. Leveraging the strengths of preoperative MRI and intraoperative FIGS in tandem could provide superior guidance during surgery, potentially improving surgical resection outcome and reducing recurrence. However, integration of MRI and FIGS requires an imaging agent advanced beyond the current standard. To address this challenge, the imaging agent should consist of: (1) a fluorophore lacking photobleaching and toxicity while demonstrating a high quantum yield for FIGS and (2) an effective MRI contrast agent. In order to accommodate these requirements, a novel nanoparticle was synthesized based on hyaluronic acid (HA), a biopolymer that our group has demonstrated is a suitable carrier of fluorophores for FIGS3.
Experimental Procedures: Self-assembled multimodal imaging nanoparticles (SAMINs) were developed as a mixed micelle formulation using HA chains functionalized with either gadolinium, the optimal contrast agent for MRI, or Cy7.5, a fluorescent dye we have demonstrated as a fluorophore for FIGS. Synthesis was confirmed through Raman and fluorescence spectroscopy and NMR. SAMIN size and charge were characterized by dynamic light scattering and zeta potential, and SAMIN gadolinium content was determined via inductively-coupled plasma mass spectrometry. Relaxivity studies were performed on a Bruker Biospec MRI scanner to determine efficacy as an MRI contrast agent. To evaluate the relationship between MR and fluorescence signal from SAMINs, we employed a simulated surgical phantom that we routinely use to evaluate the depth at which NIR imaging agents can be detected by FIGS.
Results: Physicochemical characterization of SAMINs confirmed synthesis and stability. The T 1 and T 2 relaxivities of SAMINs were found to be R 1 = 5.5 mM-1s-1 and the R 2 = 10.7 mM-1s-1. After determining the relaxivity of the SAMINs, they were imaged using a LI-COR Trilogy fluorescence imaging unit to confirm fluorescence was retained. As the T1 and T2 signal increase and decrease, respectively, with increasing concentration of Gd3+, the fluorescence intensity increases with concentration of nanoparticles as expected. Tissue phantom studies showed the SAMINs to have high contrast for pre-operative MRI, and then demonstrated high contrast for fluorescence imaging and margin identification during FIGS.
Conclusions: Tumor margin identification during surgery remains a barrier in improving surgical resection of cancer. The SAMINs developed in this study demonstrate high MRI and fluorescence contrast in phantom models, providing the basis for use as an imaging agent for both preoperative MRI and intraoperative FIGS. These imaging agents show promise for guiding surgeons during surgery by providing enhanced contrast between the tumor and surrounding tissue, helping to improve resection by defining tumor margins more clearly.
1. Hartwig W, Werner J, Jäger D, Debus J, Büchler MW. Improvement of surgical results for pancreatic cancer. Lancet Oncol . 2013;14(11):e476-e485. doi:10.1016/S1470-2045(13)70172-4.
2. Ethun CG, Kooby DA. The importance of surgical margins in pancreatic cancer. J Surg Oncol . November 2015. doi:10.1002/jso.24092.
3. Hill TK, Abdulahad A, Kelkar SS, et al. Indocyanine Green-Loaded Nanoparticles for Image-Guided Tumor Surgery. Bioconjug Chem . 2015;26(2):294-303. doi:10.1021/bc5005679.
Citation Format: William M. Payne, Denis A. Svechkarev, Michael D. Boska, Aaron M. Mohs. Multimodal contrast agents for integrated preoperative and intraoperative imaging of cancer. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B19.