Recent Progress in Nanotechnology Improving the Therapeutic Potential of Polyphenols for Cancer

Abstract

Polyphenols derived from fruits, vegetables, and plants are bioactive compounds potentially beneficial to human health. Notably, compounds such as quercetin, curcumin, epigallocatechin-3-gallate (EGCG), and resveratrol have been highlighted as antiproliferative agents for cancer. Due to their low solubility and limited bioavailability, some alternative nanotechnologies have been applied to encapsulate these compounds, aiming to improve their efficacy against cancer. In this comprehensive review, we evaluate the main nanotechnology approaches to improve the therapeutic potential of polyphenols against cancer using in vitro studies and in vivo preclinical models, highlighting recent advancements in the field. It was found that polymeric nanomaterials, lipid-based nanomaterials, inorganic nanomaterials, and carbon-based nanomaterials are the most used classes of nanocarriers for encapsulating polyphenols. These delivery systems exhibit enhanced antitumor activity and pro-apoptotic effects, particularly against breast, lung, prostate, cervical, and colorectal cancer cells, surpassing the performance of free bioactive compounds. Preclinical trials in xenograft animal models have revealed decreased tumor growth after treatment with polyphenol-loaded delivery systems. Moreover, the interaction of polyphenol co-delivery systems and polyphenol-drug delivery systems is a promising approach to increase anticancer activity and decrease chemotherapy side effects. These innovative approaches hold significant implications for the advancement of clinical cancer research.

Keywords: bioactive compounds; carcinogenesis; encapsulation; nanocarriers; nanomaterials; resveratrol; tumor.

Figure 1

Main polyphenols with therapeutic potential against cancer and nanomaterials typically used as nanocarriers.

Figure 2

An overview of journal articles concentrating on the applications of polyphenol-loaded delivery systems in cancer therapies from 2013 to 2023 (25 April 2023) in relevance to (a) the number of publications and (b) types of cancer. The search was conducted in the Scopus, Web of Science, and PubMed databases using the keywords “nano-delivery system” OR “drug delivery systems” OR nanocarrier* OR nanoformulation* AND polyphenol* AND cancer* OR tumor*.

Figure 3

The main classes of polyphenols (stilbenes, lignans, phenolic acids, and flavonoids) and respective sub-classes are represented by the basic chemical structure of the compounds and their food sources. Their main anticancer effects include the induction of apoptosis, antiangiogenic and antimetastatic effects, and acting on cancer cell differentiation and cell cycle regulation.

Figure 4

Schematic representation of some polyphenol-loaded delivery systems based on inorganic nanomaterials: (a) epigallocatechin-3-gallate (EGCG)-loaded gold nanoparticles (EGCG-GNP) exhibit superior antitumor activity compared to the free polyphenol compound. EGCG-GNP show a sustained drug release over time, inducing more apoptosis in cancer cells than free EGCG. Mechanistically, EGCG-GNP inhibited the nuclear translocation and transcriptional activity of nuclear factor-kappa B (NF-κB) more potently than EGCG, and (b) smart pH-responsive magnetic graphene quantum dot (GQD) nanocarriers improve the efficiency of curcumin as a non-toxic and hydrophobic anticancer drug. Folic acid (FA) was conjugated with GQD-Fe₃O₄ nanoparticles as a selective nanocarrier targeting agent. An acid medium (pH 5.5) favored a sustained drug delivery, being ideal for cancer-targeted nanocarriers.

Figure 5

Schematic representation of some polyphenol-loaded delivery systems based on carbon nanomaterials: (a) chitosan/halloysite/carbon nanotube (CNT) nanocarrier for the pH-sensitive delivery of curcumin to cancerous media. The controlled and sustained release of the drug in an acid medium promotes the induction of apoptosis in cancer cells, with an improved cytotoxicity for the curcumin-loaded nanocarrier compared to free curcumin, and (b) graphene oxide (GO) nanocarriers coated with pH-sensitive gelatin-poly(vinylpyrrolidone) (PVP) to enhance quercetin delivery. After forming the GO-gelatin-PVP nanocomposite and drug loading, a nanoemulsion was obtained as a sustained and targeted release system. The acidic pH of 5.5 promoted a greater drug release, which may favor the imbalance of the tumor microenvironment, causing cell death by apoptosis.

Figure 6

Schematic representation of the anticancer effect of a folate-decorated epigallocatechin-3-gallate (EGCG)-loaded nanoformulation in breast cancer xenograft mice models: the EGCG-loaded formulation is injected intravenously into mice with a xenografted breast tumor (1); the folate receptor on the surface of nanoparticles favors endocytosis due to its ability to bind to other receptors on tumor cells (2, 3); the targeted release of EGCG enhances the cytotoxic effect on the tumor cell (4), resulting in apoptosis and cell death (5), which reduces tumor size and weight (6).

Figure 7

(a) Scheme of the treatment of a cervical tumor induced by HeLa cells in xenograft mice using folic-acid-conjugated curcumin-PLGA nanoparticles (PPF-curcumin), and (b) possible mechanism of action of PPF-curcumin nanoparticles in the chemosensitization of cervical cancer cells.