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Targeted optical fluorescence imaging of human ovarian adenocarcinoma using a galactosyl serum albumin-conjugated fluorophore.

ABSTRACT: Achieving maximal cytoreduction during surgery is a critical prognostic factor for women with advanced-stage ovarian cancer. Targeting optical imaging agents directly to ovarian cancer cells by attaching them to galactosyl (galactosamine-conjugated) serum albumin, whose sugar residues bind surface lectins that are expressed in certain ovarian adenocarcinomas, may improve metastatic tumor identification and resection. Thus, we sought to demonstrate that galactosyl serum albumin-conjugated fluorophores would be a robust mechanism through which to target ovarian cancer by evaluating its tumor-targeting capability in nine human ovarian adenocarcinoma cell lines. The optical fluorophore rhodamine green was conjugated to galactosyl serum albumin, a non-immunogenic targeting molecule. Galactosyl serum albumin-rhodamine green's ability to target nine human ovarian adenocarcinoma cell lines was evaluated by flow cytometry, fluorescence microscopy and in vivo optical fluorescence imaging using female athymic nu/nu mice. All nine cell lines tested bound galactosyl serum albumin-rhodamine green more effectively than non-glycosylated controls (P < 0.0001). Fluorescence microscopy demonstrated that galactosyl serum albumin-rhodamine green was internalized into each cell line in a galactosamine-dependent manner. In vivo optical fluorescence images of intraperitoneal tumor-bearing mice acquired 3 h after intraperitoneal injection of galactosyl serum albumin-rhodamine green successfully differentiated between tumor and normal tissue. This technique also allowed the visualization of submillimeter-sized ovarian tumor implants. These results indicate that galactosyl serum albumin-rhodamine green can selectively target a variety of human ovarian adenocarcinomas for optical fluorescence imaging and thus may improve intraoperative tumor detection and resection.

SUBMITTER: Gunn AJ

PROVIDER: S-EPMC2585545 | biostudies-literature | 2007 Nov

REPOSITORIES: biostudies-literature

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Targeted optical fluorescence imaging of human ovarian adenocarcinoma using a galactosyl serum albumin-conjugated fluorophore.

Gunn Andrew J AJ Hama Yukihiro Y Koyama Yoshinori Y Kohn Elise C EC Choyke Peter L PL Kobayashi Hisataka H

Cancer science 20070902 11

Achieving maximal cytoreduction during surgery is a critical prognostic factor for women with advanced-stage ovarian cancer. Targeting optical imaging agents directly to ovarian cancer cells by attaching them to galactosyl (galactosamine-conjugated) serum albumin, whose sugar residues bind surface lectins that are expressed in certain ovarian adenocarcinomas, may improve metastatic tumor identification and resection. Thus, we sought to demonstrate that galactosyl serum albumin-conjugated fluorop ...[more]

PMID: 17784874

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Project description:Patient survival depends on the completeness of resection of peritoneal ovarian cancer metastases (POCM), and therefore, it is important to develop methods to enhance detection. Previous probe designs based on activatable galactosyl human serum albumin (hGSA)-fluorophore pairs, which target lectin receptors expressed on POCM, have used only visible range dyes conjugated to hGSA. However, imaging probes emitting fluorescence in the NIR range are advantageous because NIR photons have deeper in vivo tissue penetration and result in lower background autofluorescence than those emitting in the visible range. A NIR-activatable hGSA fluorophore was synthesized using a bacteriochlorin-based dye, NMP1. NMP1 has two unique absorption peaks, one in the green range and the other in the NIR range, but emits at a NIR peak of 780 nm. NMP1, thus, has two different Stokes shifts that have the potential to allow imaging of POCM both at the peritoneal surface and just below it. hGSA was conjugated with 2 NMP1 molecules to create a self-quenching complex (hGSA-NMP1). The activation ratio of hGSA-NMP1 was measured by the fluorescence intensity before and after exposure to 10% SDS. The activation ratio of hGSA-NMP1 was ~100-fold in vitro. Flow cytometry, fluorescence microscopy, and in vivo spectral fluorescence imaging were carried out to compare hGSA-NMP1 with hGSA-IR800 and hGSA-ICG (two always-on control agents with similar emission to NMP1) in terms of comparative fluorescence signal and the ability to detect POCM in mice models. The sensitivity and specificity of hGSA-NMP1 for POCM implant detection were determined by colocalizing NMP1 emission spectra with red fluorescent protein (RFP) expressed constitutively in SHIN3 tumor implants at different depths below the peritoneal surface. In vitro, SHIN3 cells were easily detectable after 3 h of incubation with hGSA-NMP1. In vivo submillimeter POCM foci were clearly detectable with spectral fluorescence imaging using hGSA-NMP1. Among 555 peritoneal lesions, hGSA-NMP, using NIR and green excitation light, respectively, detect 75% of all lesions and 91% of lesions ~0.8 mm or greater in diameter. Few false positives were encountered. Nodules located at a depth below the small bowel surface were only depicted with hGSA-NMP1. We conclude that hGSA-NMP1 is useful in imaging peritoneal ovarian cancer metastases, located both superficially and deep in the abdominal cavity.

Dataset Information

Targeted optical fluorescence imaging of human ovarian adenocarcinoma using a galactosyl serum albumin-conjugated fluorophore.

Publications

Targeted optical fluorescence imaging of human ovarian adenocarcinoma using a galactosyl serum albumin-conjugated fluorophore.

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