title: Near Infrared Fluorescent Nanoparticles Derived from Hyaluronic Acid Improve Tumor Contrast for Image-Guided Surgery.
abstract: Tumor tissue that remains undetected at the primary surgical site can cause tumor recurrence, repeat surgery, and treatment strategy alterations that impose a significant patient and healthcare burden. Intraoperative near infrared fluorescence (NIRF) imaging is one potential method to identify remaining tumor by visualization of NIR fluorophores that are preferentially localized to the tumor. This requires development of fluorophores that consistently identify tumor tissue in different patients and tumor types. In this study we examined a panel of NIRF contrast agents consisting of polymeric nanoparticle (NP) formulations derived from hyaluronic acid (HA), with either physically entrapped indocyanine green (ICG) or covalently conjugated Cy7.5. Using orthotopic human breast cancer MDA-MB-231 xenografts in nude mice we identified two lead formulations. One, NanoICGPBA, with physicochemically entrapped ICG, showed 2.3-fold greater tumor contrast than ICG alone at 24 h (p < 0.01), and another, NanoCy7.5100-H, with covalently conjugated Cy7.5, showed 74-fold greater tumor contrast than Cy7.5 alone at 24 h (p < 0.0001). These two lead formulations were then tested in immune competent BALB/c mice bearing orthotopic 4T1 breast cancer tumors. NanoICGPBAshowed 2.2-fold greater contrast than ICG alone (p < 0.0001), and NanoCy7.5100-Hshowed 14.8-fold greater contrast than Cy7.5 alone (p < 0.0001). Furthermore, both NanoICGPBAand NanoCy7.5100-Hprovided strong tumor enhancement using image-guided surgery in mice bearing 4T1 tumors. These studies demonstrate the efficacy of a panel of HA-derived NPs in delineating tumorsin vivo, and identifies promising formulations that can be used for futurein vivotumor removal efficacy studies.
authors.affiliation: Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, United States.
authors.forename: Tanner K
authors.initials: TK
authors.lastname: Hill
authors.affiliation: Department of Plastic and Reconstructive Surgery, Wake Forest University Health Sciences, Winston-Salem, NC 27157, United States.
authors.forename: Sneha S
authors.initials: SS
authors.lastname: Kelkar
authors.affiliation: Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, United States.
authors.forename: Nicholas E
authors.initials: NE
authors.lastname: Wojtynek
authors.affiliation: Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, United States.
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Souchek
authors.affiliation: Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, United States.
authors.forename: William M
authors.initials: WM
authors.lastname: Payne
authors.affiliation: Wake Forest Institute for Regenerative Medicine, Wake Forest University Health Sciences, Winston-Salem, NC 27157, United States.
authors.forename: Kristina
authors.initials: K
authors.lastname: Stumpf
authors.affiliation: Wake Forest Institute for Regenerative Medicine, Wake Forest University Health Sciences, Winston-Salem, NC 27157, United States;; Department of Cancer Biology, Wake Forest University Health Sciences, Winston-Salem, NC 27157, United States.
authors.forename: Frank C
authors.initials: FC
authors.lastname: Marini
authors.affiliation: Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, United States;; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, United States.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Mohs
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000000981:diagnostic imaging* / Q000601:surgery; D003287:Contrast Media / Q000008:administration & dosage*; D004195:Disease Models, Animal; D064593:Heterografts; D006801:Humans; D006820:Hyaluronic Acid / Q000008:administration & dosage*; D007259:Infrared Rays; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D053758:Nanoparticles / Q000008:administration & dosage*; D061848:Optical Imaging / Q000379:methods*; D025321:Surgery, Computer-Assisted / Q000379:methods*
chemical_list: D003287:Contrast Media; D006820:Hyaluronic Acid
keywords: near infrared fluorescence