Abstract
This report describes the design, synthesis and evaluation of tumor-targeted polymer probes to visualize epidermal growth factor receptor (EGFR)-positive malignant tumors for successful resection via fluorescence guided endoscopic surgery. Fluorescent polymer probes of various molecular weights enabling passive accumulation in tumors via enhanced permeability and retention were prepared and evaluated, showing an optimal molecular weight of 200,000 g/mol for passive tumor targeting. Moreover, poly(N-(2-hydroxypropyl)methacrylamide)-based copolymers labeled with fluorescent dyes were targeted with the EGFR-binding oligopeptide GE-11 (YHWYGYTPQNVI), human EGF or anti-EGFR monoclonal antibody cetuximab were all able to actively target the surface of EGFR-positive tumor cells. Nanoprobes targeted with GE-11 and cetuximab showed the best targeting profile but differed in their tumor accumulation kinetics. Cetuximab increased tumor accumulation after 15 min, whereas GE 11 needed at least 4 h. Interestingly, after 4 h, there were no significant differences in tumor targeting, indicating the potential of oligopeptide targeting for fluorescence-navigated surgery. In conclusion, fluorescent polymer probes targeted by oligopeptide GE-11 or whole antibody are excellent tools for surgical navigation during oncological surgery of head and neck squamous cell carcinoma, due to their relatively simple design, synthesis and cost, as well as optimal pharmacokinetics and accumulation in tumors.
Highlights
Surgery remains the primary treatment option for most solid malignant tumors [1]
2.40c a thiazolidine-2-thione content; b Dy-633content; c Cy-7 content; d number-average molecular weight calculated from the TT or maleinimide group content; e functionality of a polymer; f content of hydrazide groups; g content of Human EGF (hEGF) in conjugate; h content of monoclonal antibody in conjugate; i content of peptide determinate by aaa; j polymer precursor are listed in upper part using italic style, polymer conjugates are listed in bottom part
The GPC chromatograms showed that the polymers were not significantly cross-linked, and their molecular weight is equal to the attachment of approximately two hEGF molecules per one polymer chain
Summary
Surgery remains the primary treatment option for most solid malignant tumors [1]. Precise and complete resection of the whole tumor without unnecessary removal of the neighboring healthy tissue is a prerequisite for a successful outcome [2]. EGFR-specific cell binding of all the targeted polymer probes in vitro was evaluated using flow cytometry; fluorescent visualization of EGFR-positive tumors in vivo was performed using an in vivo imaging system in-Vivo Xtreme (Bruker). In parallel with the actively targeted polymer probes, we investigated high molecular weight fluorescent polymers without the targeting ligands described above These polymers passively accumulate within the tumor tissue due to the so-called enhanced permeability and retention (EPR) effect [16,17], which is based on a leaky neovasculature and impaired or missing lymphatic drainage in the tumor. The potential of the actively and passively targeted polymer probes for the fluorescence-guided surgery of malignant tumors was compared and discussed. Targeted polymeric fluorescent nanoprobes have the potential to increase the safety of oncological surgery in the upper aerodigestive tract and to improve the overall prognosis of patients
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