Recent Strategies for Cancer Therapy: Polymer Nanoparticles Carrying Medicinally Important Phytochemicals and Their Cellular Targets

Abstract

Cancer is a leading cause of death in the world today. In addition to the side effects of the chemotherapeutic drugs used to treat cancer, the development of resistance to the drugs renders the existing drugs ineffective. Therefore, there is an urgent need to develop novel anticancer agents. Medicinally important phytochemicals such as curcumin, naringenin, quercetin, epigallocatechin gallate, thymoquinone, kaempferol, resveratrol, genistein, and apigenin have some drawbacks, including low solubility in water, stability and bioavailability issues, despite having significant anticancer effects. Encapsulation of these natural compounds into polymer nanoparticles (NPs) is a novel technology that could overcome these constraints. In comparison to the free compounds, phytochemicals loaded into nanoparticles have greater activity and bioavailability against many cancer types. In this review, we describe the preparation and characterization of natural phytochemical-loaded polymer NP formulations with significant antioxidant and anti-inflammatory effects, their in vitro and in vivo anticancer activities, as well as their possible cellular targets.

Keywords: antioxidants; cancer; flavonoids; phytochemicals; polymeric nanoparticles.

Figure 1

Phytochemical compounds loaded in polymeric NPs and their anticancer activities.

Figure 2

Naringenin-loaded, pH- and thermo-sensitive smart polymeric nanoparticles showed cytotoxic activity against human breast cancer cells (reproduced with permission from Yıldırım et al., 2022 [36]).

Figure 3

Epigallocatechin gallate (EGCG) encapsulated in targeted nanoparticles induces depolarization in spheroid cultures. Both 22Rv1 (a) and PC3 (b) cells were grown on poly-HEMA-coated plates and treated with either empty targeted nanoparticles or EGCG in targeted nanoparticles (6 μM) for 6 days. At the end of the time-point, JC-1 dye was added to the treated spheroids and incubated for 30 min at 37 °C. The fluorescence intensity was measured using a Guava Flow Cytometer at the standardized wavelength provided by the manufacturer. Values are shown as mean ± SEM (n = 6). ** p < 0.01; NS: no significance (reproduced with permission from Alserihi et al., 2022 [45]).

Figure 4

MTT cell viability assay of the effect of different formulations of thymoquinone (TQ) and their co-delivery with free doxorubicin (DOX) on the colon cancer cell line C26. Cell viability following treatment with (A) free DOX, (B) free TQ, and (C) NPs at various concentrations of DOX and TQ (n = 3). Cell viability of DOX (IC20), which was co-delivered with (D) free TQ, (E) PLGA/TQ, and (F) PLGA-PC/TQ in C26 cells, measured by the MTT assay (n = 3). * indicates a significant difference between two types of NPs. The asterisks indicate the following p-values: ** p ≤ 0.01, *** p ≤ 0.001 and ****p < 0.0001 (reproduced with permission from Moghaddam et al., 2021 [48]).

Figure 5

Illustration of the preparation of thymoquinone (TQ) nanoparticles. (A) TQ self-assembles with an amphiphilic molecule of Pluronic F68 and PLGA-PEG, forming a hydrophobic core, while intact TQ is located within the core. (B) TEM observation of TQ-PLGA-PF68 nanoparticles (reproduced from Noor et al., 2021 [49]).

Figure 6

Tumor colonies representing the in vivo anti-pulmonary metastasis (B16F10) efficacy of different formulations of apigenin (APG). Four- to six-week-old C57BL/6 mice (20–25 g body weight) were divided randomly into six groups (n = 6), and melanoma lung metastasis was induced by injecting B16F10 cells (1 × 10⁶ in 100 μL of PBS) intravenously (via the tail vein). Metastatic nodule formation was reduced in mice treated with free APG (5 mg/kg body weight) and APG-NPs (dose equivalent to conjugated NPs). The lungs of mice treated with the DMSA-conjugated formulation had much lower tumor mass and number compared to the other treatment groups and the saline-treated controls (reproduced with permission from Sen et al. [63]).