Recent Findings on Thymoquinone and Its Applications as a Nanocarrier for the Treatment of Cancer and Rheumatoid Arthritis

Abstract

Cancer causes a considerable amount of mortality in the world, while arthritis is an immunological dysregulation with multifactorial pathogenesis including genetic and environmental defects. Both conditions have inflammation as a part of their pathogenesis. Resistance to anticancer and disease-modifying antirheumatic drugs (DMARDs) happens frequently through the generation of energy-dependent transporters, which lead to the expulsion of cellular drug contents. Thymoquinone (TQ) is a bioactive molecule with anticancer as well as anti-inflammatory activities via the downregulation of several chemokines and cytokines. Nevertheless, the pharmacological importance and therapeutic feasibility of thymoquinone are underutilized due to intrinsic pharmacokinetics, including short half-life, inadequate biological stability, poor aqueous solubility, and low bioavailability. Owing to these pharmacokinetic limitations of TQ, nanoformulations have gained remarkable attention in recent years. Therefore, this compilation intends to critically analyze recent advancements in rheumatoid arthritis and cancer delivery of TQ. This literature search revealed that nanocarriers exhibit potential results in achieving targetability, maximizing drug internalization, as well as enhancing the anti-inflammatory and anticancer efficacy of TQ. Additionally, TQ-NPs (thymoquinone nanoparticles) as a therapeutic payload modulated autophagy as well as enhanced the potential of other drugs when given in combination. Moreover, nanoformulations improved pharmacokinetics, drug deposition, using EPR (enhanced permeability and retention) and receptor-mediated delivery, and enhanced anti-inflammatory and anticancer properties. TQ's potential to reduce metal toxicity, its clinical trials and patents have also been discussed.

Keywords: arthritis; cancer; nanotechnology; synovial delivery; thymoquinone; toxicity reduction.

Figure 1

2D and 3D structure of thymoquinone, C₁₀H₁₂O_2.

Figure 2

Enzymatic catalytic pathway of TQ under physiological conditions.

Figure 3

Anti-arthritic mechanism of TQ. TQ significantly downregulated the elevated levels of TLR-7, TLR-4, MMP-13, MMP-3, and other inflammatory cytokines, including TNF-α, IL-1β, PGE2, and IL-6 and upregulated the expression of MMP-1 to reduce arthritis scoring and bone leaching in arthritis. TLR—Toll-like receptor; IL—interleukin; PGE2—prostaglandin E2; MDA—malondialdehyde; GSSG—glutathione; MMP—matrix metalloproteinase; RANKL—receptor-activated nuclear factor kappa-B ligand; COX—cyclooxygenase-2; MAPK—mitogen-activated protein kinase.

Figure 4

TQ prevents carcinogenic intermediate synthesis by inhibiting the G2/M phase of the cell cycle. It also inhibits ROS-mediated DNA damage to prevent tumorigenesis. TQ upregulates pro-apoptotic genes (p21 and p27) and downregulates the anti-apoptotic gene (Bcl-2), thereby arresting the G2/M phase of the cell cycle. (CDK—cyclin-dependent kinases; CYP—cytochrome P; TQ—Thymoquinone).

Figure 5

Systemic diagram depicting diverse approaches intended for passive targeting of TQ via nanoparticles.

Figure 6

Schematic diagram of TQ nanocarriers for receptor-based active targeting.