Development of a macromolecular dual-modality MR-optical imaging for sentinel lymph node mapping.
OBJECTIVE
To evaluate the effectiveness of a dual magnetic resonance-near infrared fluorescence optical imaging agent, poly(l-glutamic acid)-DTPA-Gd-NIR813, for both preoperative and intraoperative visualization and characterization of sentinel lymph nodes (SLN) in mice.


METHODS
Poly(L-glutamic acid) was conjugated with DTPA-Gd and NIR813 dye to obtain PG-DTPA-Gd-NIR813. To confirm drainage into the SLNs, this agent was injected subcutaneously into the front paw of nude mice followed by isosulfan blue (n = 6). Furthermore, PG-DTPA-Gd-NIR813 was injected subcutaneously at doses of 0.002 mmol Gd/kg (4.8 nmol eq. NIR813) and 0.02 mmol Gd/kg (48 nmol eq. NIR813) (n = 3/dose). To differentiate metastatic from nonmetastatic lymph nodes, nude mice bearing human oral squamous cell carcinoma (DM14) were injected intralingually with 0.02 mmol Gd/kg PG-DTPA-Gd-NIR813 (n = 3). Pre- and postcontrast images were taken using 4.7 T Bruker MRI scanner and Xenogen optical imaging system. The status of lymph nodes resected under the guidance of optical imaging was confirmed by histologic examinations.


RESULTS
PG-DTPA-Gd-NIR813 colocalized with isosulfan blue, indicating drainage to the SLN. After subcutaneous injection, axiliary and branchial lymph nodes were clearly visualized with both T1-weighted MR and optical imaging within 3 minutes of contrast injection, even at the lowest dose tested (0.002 mmol Gd/kg). After intralingual injection in tumor-bearing mice, MR imaging identified 4 of the 6 superficial cervical lymph nodes, whereas near-infrared fluorescence (NIRF) optical imaging identified all 6 cervical nodes. The pattern of contrast enhancement of SLN visualized in MR images showed a characteristic ring-shaped appearance with a central filling defect, possibly resulting from nodal infiltration of metastatic lesions. Histopathologic examination of the SLNs resected under NIRF imaging guidance revealed micrometastases in all 6 SLNs identified by NIRF imaging.


CONCLUSIONS
The dual modality imaging method demonstrated in this study represents an effective technique for localization and characterization of SLN.
Melancon
Marites P
MP
Departments of Experimental Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Wang
Yuetang
Y
Wen
Xiaoxia
X
Bankson
James A
JA
Stephens
L Clifton
LC
Jasser
Samar
S
Gelovani
Juri G
JG
Myers
Jeffrey N
JN
Li
Chun
C
D000818:Animals; D001549:Benzamides / Q000737:chemistry; D045744:Cell Line, Tumor; D003287:Contrast Media / Q000737:chemistry*; D005260:Female; D005456:Fluorescent Dyes / Q000737:chemistry*; D006801:Humans; D007211:Indoles / Q000737:chemistry; D008198:Lymph Nodes / Q000473:pathology*; D008207:Lymphatic Metastasis / Q000175:diagnosis*; D008279:Magnetic Resonance Imaging / Q000295:instrumentation / Q000379:methods*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011099:Polyglutamic Acid / Q000737:chemistry; D012995:Solubility; D019265:Spectroscopy, Near-Infrared; D002583:Uterine Cervical Neoplasms / Q000175:diagnosis* / Q000556:secondary; D014867:Water / Q000737:chemistry
D001549:Benzamides; D003287:Contrast Media; D005456:Fluorescent Dyes; D007211:Indoles; C524070:NIR 813; C524071:poly(glutamic acid)-DTPA-gadolinium-NIR813; D014867:Water; D011099:Polyglutamic Acid