Bioinspired Polymerization of Quercetin to Produce a Curcumin-Loaded Nanomedicine with Potent Cytotoxicity and Cancer-Targeting Potential in Vivo

Abstract

Nanomedicine has had a profound impact on the treatment of many diseases especially cancer. However, synthesis of multifunctional nanoscale drug carriers often requires multistep coupling and purification reactions, which can pose major scale-up challenges. Here we leveraged bioinspired oxidation-triggered polymerization of catechols to synthesize nanoparticles (NPs) from the plant polyphenol quercetin (QCT) loaded with a hydrophobic anti-cancer drug, curcumin, and functionalized with poly(ethylene glycol) (PEG) for steric stabilization in one reaction step.NPs were formed by base-catalyzed oxidative self-polymerization of QCT in the presence of curcumin and thiol-terminated PEG upon mixing in a universal solvent (dimethyl sulfoxide), followed by self-assembly with the gradual addition of water. Dynamic light scattering and X-ray photoelectron spectroscopy were used to confirm NP PEGylation. Drug loading was verified by UV-Vis spectroscopy. Curcumin-loaded NPs were efficiently internalized by CT26 murine colon cancer cells as determined by flow cytometry and confocal microscopy. NPs also demonstrated sustained release and potent cytotoxicity in vitro. Moreover, in vivo imaging of CT26 tumorbearing Balb/c mice following tail vein injection of DiR-labeled QCT NPs showed steady tumor accumulation of the NPs up to 24 h. This was further supported by significant tumor uptake of curcumin-loaded QCT NPs as measured by flow cytometry analysis of tumor homogenates. Our findings present a greener synthetic route for the fabrication of drug-loaded surface functionalized NPs from poorly water-soluble plant polyphenols such as QCT as promising anti-cancer delivery systems.

Development of a Thymoquinone Polymeric Anticancer Nanomedicine through Optimization of Polymer Molecular Weight and Nanoparticle Architecture

“…TQ release was investigated in phosphate buffer (pH 7.4) and acetate buffer (pH 5.0) to simulate physiologic and lysosomal/tumor microenvironment pH, respectively. All release media contained 0.5% w/v Tween 80 to ensure sink conditions [ 25 , 26 , 27 , 28 ]. For the release test, triplicate samples of freshly prepared NPs (1 mL) were each transferred to a dialysis bag with 12–14 kD MWCO (Spectrum laboratories Inc., Rancho Dominguez, CA, USA) and immersed in 30 mL release media in tightly closed glass vials.…”

Polyphenol-Mediated Assembly for Particle Engineering

“…Recently, the polymerized polyphenol-based particles from quercetin were used to load hydrophobic drugs (e.g., curcumin) in a one-pot method. 59 Furthermore, polyphenols react with both small molecules and macromolecules. One welldocumented example is that aldehydes cross-link polyphenols in the presence of acetic acid or hydrochloric acid, 60,61 wherein the protonation of acetaldehyde results in a carbocation that attacks the aromatic rings of the polyphenol, followed by nucleophilic attack by another polyphenol.…”

Recent Advances in Antioxidant Polymers: From Sustainable and Natural Monomers to Synthesis and Applications

“…The polymerization of quercetin is part of a broader effort in recent years to enhance the performance of natural and synthetic antioxidant polymers via covalent insertion of antioxidant species (such as vitamins, curcumin, and quercetin) into polymeric chains [77]. The polymerization products have demonstrated appropriate properties in food packaging (as preserving agents) [78], biomedical and pharmaceutical applications, especially in the production of antioxidant-laden nanoparticles for cancer treatment [77,79,80], or contact lenses and hemodialysis membranes. In both applications, the potency of the antioxidants is contingent on successful polymerization.…”

“…Moreover, the antioxidant inhibits the release and expression of apoptosis-related proteins triggered by LPS/d-GalN, suppresses oxidation marker-mediated production of LPS/d-GalN. Following the inhibition of the mechanisms listed above, quercetin catalyzes the antioxidant signal transduction pathways (particularly Nrf2/GCL/GSH) and other processes that increase the concentration of glutathione in the cells [79].…”