Degree
Doctor of Philosophy (PhD)
Department
Department of Chemistry
Document Type
Dissertation
Abstract
This dissertation discusses the design of EGFR-targeted small-molecule agents that unite molecular imaging with photodynamic therapy. Chapter 1 frames the clinical need for early detection and selective treatment and surveys BODIPY, aza-BODIPY, and chlorin scaffolds as tunable chromophores for near-infrared imaging and photosensitization. It also outlines EGFR as a validated target and compares two ligand classes used throughout this work: the tyrosine kinase inhibitor erlotinib and the cyclic peptide KLARLLT.
Chapter 2 describes the synthesis of a near-IR BODIPY bearing either one or two erlotinib units. Docking and SPR show specific interactions with the EGFR kinase domain, and both conjugates accumulate strongly in EGFR-overexpressing HEp-2 cells. Only the mono-TKI inhibits kinase activity, whereas the more hydrophobic di-TKI aggregates underperforms, highlighting how stoichiometry and physicochemical balance govern function.
Chapter 3 reports two series of 1,3,5,7-tetraphenyl-aza-BODIPYs with para-substituents. The study shows that a push–pull design, electron withdrawers at 1,7 positions and donors at 3,5-positions drive bathochromic shifts while preserving brightness, with top performers exhibiting high fluorescence within the therapeutic window. It also maps how donor placement can depress extinction coefficients or quantum yields, and how protonation toggles emissive states.
Chapter 4 develops isothiocyanate-based conjugation routes to attach TKIs and peptides to aza-BODIPYs, including hybrid TKI–peptide constructs. Although the chemistry is clean and scalable, initial conjugates lack measurable EGFR binding due to aggregation. This motivates solubility fixes such as glucose capping, now under evaluation.
Chapter 5 shows that methyl pheophorbide a is a practical scaffold for targeted PDT. New MPa–TKI and MPa–peptide conjugates retain chlorin-like absorption while displaying blue-shifted Q bands and quenched fluorescence consistent with enhanced intersystem crossing. The TKI conjugate is more lipophilic; the peptide conjugate is more polar, pointing to complementary uptake mechanisms. The work concludes by proposing dual-targeting MPa designs that combine peptide recognition with intracellular TKI engagement to improve selective delivery and photodynamic efficacy.
Date
11-1-2025
Recommended Citation
Dhingra, Simran, "Synthesis and Evaluation of BODIPY-, AzaBODIPY- and Chlorin-Based Conjugates for Imaging and Photodynamic Therapy of EGFR-Overexpressing Cancers" (2025). LSU Doctoral Dissertations. 6934.
https://repository.lsu.edu/gradschool_dissertations/6934
Committee Chair
Vicente, Graça