Multi-Modal Imaging in a Mouse Model of Orthotopic Lung Cancer.

Priya Patel,Hideki Ujiie,Daiyoon Lee,Hsin-Pei Hu,Jinzi Zheng,Kentaro Hirohashi,Hironobu Wada,Tatsuya Kato,Kazuhiro Yasufuku,Jin Young Ahn,Robert M Hoffman

doi:10.1371/journal.pone.0161991

Abstract

BackgroundInvestigation of CF800, a novel PEGylated nano-liposomal imaging agent containing indocyanine green (ICG) and iohexol, for real-time near infrared (NIR) fluorescence and computed tomography (CT) image-guided surgery in an orthotopic lung cancer model in nude mice.MethodsCF800 was intravenously administered into 13 mice bearing the H460 orthotopic human lung cancer. At 48 h post-injection (peak imaging agent accumulation time point), ex vivo NIR and CT imaging was performed. A clinical NIR imaging system (SPY®, Novadaq) was used to measure fluorescence intensity of tumor and lung. Tumor-to-background-ratios (TBR) were calculated in inflated and deflated states. The mean Hounsfield unit (HU) of lung tumor was quantified using the CT data set and a semi-automated threshold-based method. Histological evaluation using H&E, the macrophage marker F4/80 and the endothelial cell marker CD31, was performed, and compared to the liposomal fluorescence signal obtained from adjacent tissue sectionsResultsThe fluorescence TBR measured when the lung is in the inflated state (2.0 ± 0.58) was significantly greater than in the deflated state (1.42 ± 0.380 (n = 7, p<0.003). Mean fluorescent signal in tumor was highly variable across samples, (49.0 ± 18.8 AU). CT image analysis revealed greater contrast enhancement in lung tumors (a mean increase of 110 ± 57 HU) when CF800 is administered compared to the no contrast enhanced tumors (p = 0.0002).ConclusionPreliminary data suggests that the high fluorescence TBR and CT tumor contrast enhancement provided by CF800 may have clinical utility in localization of lung cancer during CT and NIR image-guided surgery.

Highlights

Lung cancer is the leading cause of cancer death in the Western world, and there has been an alarming increased in incidence and deaths from lung cancer in the United States for 2014, estimated at more than 224,000 and 159,000, respectively [1]
computed tomography (CT) image analysis revealed greater contrast enhancement in lung tumors when CF800 is administered compared to the no contrast enhanced tumors (p = 0.0002)
Preliminary data suggests that the high fluorescence TBR and CT tumor contrast enhancement provided by CF800 may have clinical utility in localization of lung cancer during CT and near infrared (NIR) image-guided surgery

Summary

Introduction

Lung cancer is the leading cause of cancer death in the Western world, and there has been an alarming increased in incidence and deaths from lung cancer in the United States for 2014, estimated at more than 224,000 and 159,000, respectively [1]. Lobectomy, for localized disease is the standard of care for patients with Stage I-II NSCLC yet the five-year survival rate remains 60% to 80% for stage I and only 30% to 50% for stage II non small cell lung cancer (NSCLC) according to a large series of retrospective data [3]. These survival rates indicate that surgeons may not be able to totally detect all primary tumor, metastasis to lymph nodes (LN) [4], or ensure negative margins intra-operatively. An intravenous injection of macromolecular agents that can accumulate in tumor via the enhanced permeability and retention (EPR) effect, known as passive tumor targeting [8], would be an ideal preoperative localization technique method, and more importantly non-invasive

Objectives

Methods

Results

Conclusion