Polyphenol-Based Nanoparticles: A Promising Frontier for Enhanced Colorectal Cancer Treatment

Abstract

Colorectal cancer (CRC) poses a significant challenge in healthcare, necessitating the exploration of novel therapeutic strategies. Natural compounds such as polyphenols with inherent anticancer properties have gained attention as potential therapeutic agents. This review highlights the need for novel therapeutic approaches in CRC, followed by a discussion on the synthesis of polyphenols-based nanoparticles. Various synthesis techniques, including dynamic covalent bonding, non-covalent bonding, polymerization, chemical conjugation, reduction, and metal-polyphenol networks, are explored. The mechanisms of action of these nanoparticles, encompassing passive and active targeting mechanisms, are also discussed. The review further examines the intrinsic anticancer activity of polyphenols and their enhancement through nano-based delivery systems. This section explores the natural anticancer properties of polyphenols and investigates different nano-based delivery systems, such as micelles, nanogels, liposomes, nanoemulsions, gold nanoparticles, mesoporous silica nanoparticles, and metal-organic frameworks. The review concludes by emphasizing the potential of nanoparticle-based strategies utilizing polyphenols for CRC treatment and highlights the need for future research to optimize their efficacy and safety. Overall, this review provides valuable insights into the synthesis, mechanisms of action, intrinsic anticancer activity, and enhancement of polyphenols-based nanoparticles for CRC treatment.

Keywords: cancer cell death; chemical synthesis; colorectal cancer; drug delivery system; nanomedicine; nanoparticles; natural compounds; polyphenols; signaling pathways.

Figure 2

Graphically simplified representation of the different approaches for Polyphenol-based NPs synthesis. (A) Intracellular protein delivery enhanced by polyphenol-based boronic acid-decorated polymers: complexation of RNase A and polyphenols by Schiff’s base reactions followed by a second complexation to boronic acid polymers thanks to reaction between boronic acids and diol-based molecules [30]; (B) non-covalent bonding of hydrophobic drugs and tannic acid (TA); (C) fabrication of MMP-2-sensitive S-αPDL1/ICG nanoparticles: complexation of αPDL1 with photosensitizer ICG, stabilization with dEGCG, and compression by PEGylated EGCG dimer [46]; (D) polyphenol-coated mesoporous silica nanoparticles (MSNs) for cancer therapy: GSH-responsive polyphenol-coated MSNs loaded with doxorubicin (DOX) were developed for targeted cancer treatment: the preparation was based on EGCG-modified mesoporous silica nanoparticles (MSNs) for drug delivery purposes. The anticancer drug DOX was loaded into the MSNs through noncovalent adsorption, forming the MSN-DOX complex. The amine-terminated DNA aptamer made the complex physiologically stable and could be degraded under an acidic environment and by intracellular GSH, resulting in the release of drugs [30]; (E) fabricated Den−DOX−TA−Fe³⁺ (DDTF) nanocomplexes for delivering DOX to the nuclei via coating the DOX−Den complex with the TA−Fe³⁺ metal–polyphenol networks [47].

Figure 1

Therapeutic approaches for CRC, with conventional treatment (i.e., surgery, radiation, hormone therapy, targeted therapy, and chemotherapy) and some types of polyphenols used in CRC treatment (i.e., flavonoids, stilbenes, and phenolic acids).

Figure 3

Overview of the mechanisms of action of some nano-based drug delivery of natural polyphenolic compounds. (A) Polyphenol-based intracellular protein delivery by boronic acid-decorated polymers. The presence of polyphenols increased the affinity between boronic acid-containing polymers and proteins. In acidic environments, the pH-responsive catechol–boronate bonds formed between the boronic acid-conjugated polymers and polyphenols allowed for the release of the RNase that can cause cell death by destroying targeted RNA. (B) DOX−Den complex with the TA−Fe³⁺ MPN for chemodynamic therapy (CDT). DDTF efficiently transports DOX into cancer cells by evading drug efflux transporters on the plasma membrane. Inside the cells, DOX is delivered to the nuclei through the Fenton reaction-mediated CDT. The excessive production of reactive oxygen species (ROS) induced by the Fenton reaction and DOX ultimately leads to the elimination of drug-resistant cancer cells. (C) MMP-2-sensitive PEGylated EGCG dimer and EGCG dimer facilitated combination immune checkpoint blockade and photodynamic therapy using an αPD-L1/ICG nanocomplex. Once the nanoparticle is activated by MMP-2, it releases αPD-L1/ICG, and the antibody blocks the PLD1 checkpoint, whereas the illumination of the photosensitizer induces various effects including ROS generation and cell death.

Figure 4

Classification of nanocarriers that are commonly utilized to deliver polyphenols compounds in cancer therapy. (A) Polymeric NPs, (B) lipid-based NPs, (C) inorganic NPs.