Targeted Polymer-Based Probes for Fluorescence Guided Visualization and Potential Surgery of EGFR-Positive Head-and-Neck Tumors

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.

EGFR and αvβ6 as Promising Targets for Molecular Imaging of Cutaneous and Mucosal Squamous Cell Carcinoma of the Head and Neck Region

“…The proper identification of tumor-specific targets for molecular imaging is key to the success of FGS [16,17]. For HNSCC, epidermal growth factor receptor (EGFR) has been identified as a suitable candidate and various exploratory preclinical and clinical trials have indicated the potential of this concept in aiding surgeons during head and neck tumor removal [18,19]. However, an appropriate study comparing the expression of molecular targets suitable for rapid translation towards the clinic in HNSCC and CSSC for the goal of FGS has not yet been undertaken.…”

HPMA Copolymer-Based Nanomedicines in Controlled Drug Delivery

“…Generally, the targeting efficacy was found significantly higher for the monoclonal antibodies in contrast to smaller molecular weight targeting ligands. Even in the case of multiple presentations of oligopeptides originated from the active site of antibodies, it is not able to reach the same affinity to their target ligands [ 119 ]. Recently, the targeting efficacy of antibody-targeted pHPMA nanomedicines was reviewed in detail [ 120 ].…”

“…Indeed, the efficacy of the active targeting was also thoroughly studied in a time-dependent manner to prove the potential benefit of the active targeting. Either epidermal growth factor (EGF)-based [ 125 ] or tumor endothelium-based targeting [ 119 ] have been employed to study the time dependence of the active targeting. In both cases, it was observed that the active targeting is worth being effective in short times up to the 1 or 4 h, respectively.…”

“…Similarly, the EGF-targeting to FaDu head and neck carcinoma in mice showed a short time effective prevalence of the active targeting showing the rapid accumulation in tumors within 15 min. Nevertheless, after 4 h, the nontargeted star-like nanosystems reached the same accumulation of similarly sized antibody-targeted conjugates [ 119 ].…”

Unique Benefits of Tumor-Specific Nanobodies for Fluorescence Guided Surgery

“…Other synthetic molecules such as N -(2-hydroxypropyl) methacrylamide (HPMA), a hydrophilic polymer can increase circulation time [ 96 ]. This has been shown to be efficacious in peptide-based probes against EGFR, which face similar challenges as nanobodies in clearance [ 97 , 98 , 99 ]. The goal is titration of serum half-life to extend the window of time for probe and tumor binding for improved tumor labeling.…”