Nanoconjugation; a case study towards improving nanoparticle-based therapeutics
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Abstract
Nanoparticles (NPs), nanometer scale materials possessing intriguing novel properties different from that of bulk materials of same nature, are proving to have a prodigious potential not only for improving current therapeutics but also for modulating fundamental processes of living organisms in the nanometer scale. Covalent attachment of a biological functionality to NPs, i.e. nanoconjugation, has, in fact, provided new opportunities for controlling and enhancing the function of molecular functionalities tethered to NPs.
Epidermal Growth Factor (EGF), a growth factor known to signal for cell growth after binding to EGF receptor (EGFR), has been indicated to enhance EGFR-mediated apoptosis in nanoconjugated form in EGFR-overexpressing cancer cells. Many aspects of the induction of apoptosis through nanoconjugated EGF remain, however, insufficiently understood. To address this knowledge gap, the work described in this thesis investigates the role of physicochemical NP properties, such as size, shape, core material composition, and EGF surface loading in enhancing EGF-mediated apoptosis in breast cancer cells. In particular, this thesis aims to elucidate the mechanism(s) through which nanoconjugation changes the outcome of intracellular EGF-initiated cell signaling from cell growth and proliferation to apoptosis in EGFR-overexpressing breast cancer cells.
Data are presented that demonstrate that spherical NP-EGF with a diameter of 80 nm in core size show the highest efficacy in enhancing EGF-mediated apoptosis. These NPs were found to switch the outcome of EGFR signaling from growth and proliferation to apoptosis by modulating EGFR-mediated generation and activity of intracellular signaling molecules, such as reactive oxygen species (ROS) and Mitogen-activated protein kinases (MAPKs) family enzymes, in particular, c-Jun N-terminal kinases (JNKs). Intriguingly, it was found that nanoconjugated EGF was particularly effective in inducing apoptosis in difficult-to-treat EGFR-overexpressing basal-like breast cancer cells known for poor prognosis. Furthermore, some experimental observations indicate that nitric oxide inhibitors and NP-EGF show potential to synergistically enhance EGF-mediated apoptosis. This finding suggests a potential cell protective role for the EGFR-induced nitric oxide generation and introduces a potential therapeutic approach to improve cancer therapeutics.