Synthesis and Analysis of ⁶⁴Cu-Labeled GE11-Modified Polymeric Micellar Nanoparticles for EGFR-Targeted Molecular Imaging in a Colorectal Cancer Model

Abstract

Polymeric micellar nanoparticles represent versatile and biocompatible platforms for targeted drug delivery. However, tracking their biodistribution, stability, and clearance profile in vivo is challenging. The goal of this study was to prepare surface-modified micelles with peptide GE11 for targeting the epidermal growth factor receptor (EGFR). In vitro fluorescence studies demonstrated significantly higher internalization of GE11 micelles into EGFR-expressing HCT116 colon cancer cells versus EGFR-negative SW620 cells. Azo coupling chemistry of tyrosine residues in the peptide backbone with aryl diazonium salts was used to label the micelles with radionuclide 64Cu for positron emission tomography (PET) imaging. In vivo analysis of 64Cu-labeled micelles showed prolonged blood circulation and predominant hepatobiliary clearance. The biodistribution profile of EGFR-targeting GE11 micelles was compared with nontargeting HW12 micelles in HCT116 tumor-bearing mice. PET revealed increasing tumor-to-muscle ratios for both micelles over 48 h. Accumulation of GE11-containing micelles in HCT116 tumors was higher compared to HW12-decorated micelles. Our data suggest that the efficacy of image-guided therapies with micellar nanoparticles could be enhanced by active targeting, as demonstrated with cancer biomarker EGFR.

Surface functionalization of nanomaterials by aryl diazonium salts for biomedical sciences

“…Aryl diazonium salt chemistry were used to conjugate and label peptide-decorated polymeric micellar NPs by 64 Cu radionuclide for positron emission tomography (PET) imaging. [154] The polymeric micelles were first modified with peptide GE11, which displays a high binding affinity to epidermal growth factor receptor (K d =22 nM), a well-known biomarker of proliferating and aggressive cancers. Their labeling with 64 Cu was performed through the in situ generation of 64 Cu-complexes containing a diazonium salt group (Figure 13a), enabling chemoselective azo coupling to tyrosine residues of GE11 peptides present at the surface of polymeric micellar NPs, via electrophilic aromatic substitution.…”

“…Table 1 summarizes the various diazonium salt functionalized nanomaterials described in this review, and their potential applications. Polymeric micellar NPs (PMNPs), 64 Cu -NOTA-Bn-NH 2 64 Cu-NOTA-GE11-PMNPs EGFR-targeted molecular positron emission tomography imaging [154] 9. CONCLUSIONS This review presents a number of examples of nanoparticle functionalization by diazonium salts for biomedical sciences.…”

Controlled-Release Nanosystems with a Dual Function of Targeted Therapy and Radiotherapy in Colorectal Cancer

“…Targeted nanosystems can be used to interact with over-expressed active biological molecules on the surface of tumor cells, allowing the effective release of antitumor agents [ 13 ]. In addition, the incorporation of radionuclides into nanoparticles results in the formation of versatile nanosystem platforms with numerous applications for cancer detection and treatment [ 14 ]. Combinatorial therapy is a promising strategy for the synergistic treatment of several kinds of cancer.…”

Biodistribution and Activity of EGFR Targeted Polymeric Micelles Delivering a New Inhibitor of DNA Repair to Orthotopic Colorectal Cancer Xenografts with Metastasis

“…The effect of this modification on homing of polymeric micelles in orthotopic and metastatic CRC lesions that mimic the actual location of CRC tumors was not known, however. 18 Here, for the first time, the effect of GE11 modification on homing of polymeric micelles in an orthotopic CRC model with metastasis to different organs was evaluated. Finally, the effect of GE11 modification of micellar carriers of A83B4C63 on the growth of orthotopic and mCRC tumors with PTEN deficiency was assessed.…”