Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) are two extensively studied membrane-bound receptor tyrosine kinase proteins that are frequently overexpressed in many cancers. As a result, these receptor families constitute attractive targets for imaging and therapeutic applications in the detection and treatment of cancer. This review explores the dynamic structure and structure-function relationships of these two growth factor receptors and their significance as it relates to theranostics of cancer, followed by some of the common inhibition modalities frequently employed to target EGFR and VEGFR, such as tyrosine kinase inhibitors (TKIs), antibodies, nanobodies, and peptides. A summary of the recent advances in molecular imaging techniques, including positron emission tomography (PET), single-photon emission computerized tomography (SPECT), computed tomography (CT), magnetic resonance imaging (MRI), and optical imaging (OI), and in particular, near-IR fluorescence imaging using tetrapyrrolic-based fluorophores, concludes this review.

A series of five boron dipyrromethene (BODIPY) bioconjugates containing an epidermal growth factor receptor (EGFR)-targeted pegylated LARLLT peptide and/or a glucose or biotin ethylene diamine group were synthesized, and the binding capability of the new conjugates to the extracellular domain of EGFR was investigated using molecular modeling, surface plasmon resonance, fluorescence microscopy, competitive binding assays, and animal studies. The BODIPY conjugates with a LARLLT peptide were found to bind specifically to EGFR, whereas those lacking the peptide bound weakly and nonspecifically. All BODIPY conjugates showed low cytotoxicity (IC50 > 94 μM) in HT-29 cells, both in the dark and upon light activation (1.5 J/cm2). Studies of nude mice bearing subcutaneous human HT-29 xenografts revealed that only BODIPY conjugates bearing the LARLLT peptide showed tumor localization 24 h after intravenous administration. The results of our studies demonstrate that BODIPY bioconjugates bearing the EGFR-targeting peptide 3PEG-LARLLT show promise as near-IR fluorescent imaging agents for colon cancers overexpressing EGFR.

The effects of structural modification on the electronic structure and electron dynamics of cationic meso-(4-pyridyl)-BODIPYs were investigated. A library of 2,6-difunctionalized meso-(4-pyridyl)-BODIPYs bearing various electron-withdrawing substituents was designed, and DFT calculations were used to model the redox properties, while TDDFT was used to determine the effects of functionalization on the excited states. Structural modification was able to restructure the low-lying molecular orbitals to effectively inhibit d-PeT. A new meso-(4-pyridyl)-BODIPY bearing 2,6-dichloro groups was synthesized and shown to exhibit enhanced charge recombination fluorescence. The fluorescence enhancement was determined to be the result of functionalization modulating the kinetics of the excited state dynamics.

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Our results suggest that cationic methylated porphyrin derivatives are promising PDT photosensitizing agents. The epoxymethyl-containing derivatives showed increased efficacy relative to the neutral analogs, and are good candidates for further investigation. Lasers Surg. Med. 50:566-575, 2018. © 2018 Wiley Periodicals, Inc.