Abstract
Labeling of metastatic tumors can aid in their staging and resection of cancer. Near infrared (NIR) dyes have been used in the clinic for tumor labeling. However, there can be a nonspecific uptake of dye by the liver, lungs, and lymph nodes, which hinders detection of metastasis. In order to overcome these problems, we have used two NIR dyes (DyLight 650 and 750) conjugated to a chimeric anti-carcinoembryonic antigen antibody to evaluate how polyethylene glycol linkage (PEGylation) can improve specific tumor labeling in a nude mouse model of human pancreatic cancer. The conjugated PEGylated and non-PEGylated DyLight 650 and 750 dyes were injected intravenously into non-tumor-bearing nude mice. Serum samples were collected at various time points in order to determine serum concentrations and elimination kinetics. Conjugated PEGylated dyes had significantly higher serum dye concentrations than non-PEGylated dyes (p=0.005 for the 650 dyes and p<0.001 for the 750 dyes). Human pancreatic tumors subcutaneously implanted into nude mice were labeled with antibody-dye conjugates and serially imaged. Labeling with conjugated PEGylated dyes resulted in significantly brighter tumors compared to the non-PEGylated dyes (p<0.001 for the 650 dyes; p=0.01 for 750 dyes). PEGylation of the NIR dyes also decreased their accumulation in lymph nodes, liver, and lung. These results demonstrate enhanced selective tumor labeling by PEGylation of dyes conjugated to a tumor-specific antibody, suggesting their future clinical use in fluorescence-guided surgery.
Highlights
We have previously used chimeric anti-carcinoembryonic antigen (CEA) antibodies conjugated with visible or near-infrared fluorescent dyes for imaging pancreatic cancer in orthotopic nude mouse models.[1]
Since polyethylene glycol (PEG) conjugation can alter the pharmacokinetics and biodistribution of molecules,[2,3,4,5,6,7] we hypothesized that the polyethylene glycol linkage (PEGylation) of near infrared (NIR) dyes conjugated with anti-CEA antibodies could enable enhanced tumor labeling in a nude
Maawy et al.: Specific tumor labeling enhanced by polyethylene glycol linkage of near infrared dyes
Summary
We have previously used chimeric anti-carcinoembryonic antigen (CEA) antibodies conjugated with visible or near-infrared fluorescent dyes for imaging pancreatic cancer in orthotopic nude mouse models.[1] The longer wavelength dyes in the 650 and 750 nm wavelength range had increased depth of penetration and ability to detect the smallest tumor deposits and provided the highest tumor to background ratios, resistance to hemoglobin quenching, and specificity compared with shorter wavelength dyes in the 488 and 550 nm range. There was nonspecific uptake in the liver and lymph nodes of the near infrared (NIR) dyes, which could limit their use in specific tumor imaging. Since polyethylene glycol (PEG) conjugation can alter the pharmacokinetics and biodistribution of molecules,[2,3,4,5,6,7] we hypothesized that the polyethylene glycol linkage (PEGylation) of NIR dyes conjugated with anti-CEA antibodies could enable enhanced tumor labeling in a nude
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