Abstract:Tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) is nowadays envisaged as a natural cytokine useful in nanomedicine to eradicate the cancer cells and not the healthy surrounding ones. However, it suffers from cell resistance and strong dispersion in body to prove its efficiency. The understanding at the molecular level of the TRAIL interaction with death receptors (DRs) on cancer cells is thus of fundamental importance to improve its action. We demonstrate here via molecular simulations that TRA… Show more
“…Further, molecular docking and molecular dynamics simulations have shown that the adsorption of TRAIL on graphene nanoflakes as a potential cargo is feasible and could lead to the recruitment of the receptors DR4 and DR5 with enhanced efficacy toward the targeted cancer cell. Thus, solid nanoparticles based on graphene flakes are perspective for multiple spatial drug deliveries, including TRAIL protein, due to their form and size [ 31 ].…”
Section: Inorganic Nanoparticles Modified With Trail Pathway-targetin...mentioning
The TRAIL (TNF-related apoptosis-inducing ligand) apoptotic pathway is extensively exploited in the development of targeted antitumor therapy due to TRAIL specificity towards its cognate receptors, namely death receptors DR4 and DR5. Although therapies targeting the TRAIL pathway have encountered many obstacles in attempts at clinical implementation for cancer treatment, the unique features of the TRAIL signaling pathway continue to attract the attention of researchers. Special attention is paid to the design of novel nanoscaled delivery systems, primarily aimed at increasing the valency of the ligand for improved death receptor clustering that enhances apoptotic signaling. Optionally, complex nanoformulations can allow the encapsulation of several therapeutic molecules for a combined synergistic effect, for example, chemotherapeutic agents or photosensitizers. Scaffolds for the developed nanodelivery systems are fabricated by a wide range of conventional clinically approved materials and innovative ones, including metals, carbon, lipids, polymers, nanogels, protein nanocages, virus-based nanoparticles, dendrimers, DNA origami nanostructures, and their complex combinations. Most nanotherapeutics targeting the TRAIL pathway are aimed at tumor therapy and theranostics. However, given the wide spectrum of action of TRAIL due to its natural role in immune system homeostasis, other therapeutic areas are also involved, such as liver fibrosis, rheumatoid arthritis, Alzheimer’s disease, and inflammatory diseases caused by bacterial infections. This review summarizes the recent innovative developments in the design of nanodelivery systems modified with TRAIL pathway-targeting ligands.
“…Further, molecular docking and molecular dynamics simulations have shown that the adsorption of TRAIL on graphene nanoflakes as a potential cargo is feasible and could lead to the recruitment of the receptors DR4 and DR5 with enhanced efficacy toward the targeted cancer cell. Thus, solid nanoparticles based on graphene flakes are perspective for multiple spatial drug deliveries, including TRAIL protein, due to their form and size [ 31 ].…”
Section: Inorganic Nanoparticles Modified With Trail Pathway-targetin...mentioning
The TRAIL (TNF-related apoptosis-inducing ligand) apoptotic pathway is extensively exploited in the development of targeted antitumor therapy due to TRAIL specificity towards its cognate receptors, namely death receptors DR4 and DR5. Although therapies targeting the TRAIL pathway have encountered many obstacles in attempts at clinical implementation for cancer treatment, the unique features of the TRAIL signaling pathway continue to attract the attention of researchers. Special attention is paid to the design of novel nanoscaled delivery systems, primarily aimed at increasing the valency of the ligand for improved death receptor clustering that enhances apoptotic signaling. Optionally, complex nanoformulations can allow the encapsulation of several therapeutic molecules for a combined synergistic effect, for example, chemotherapeutic agents or photosensitizers. Scaffolds for the developed nanodelivery systems are fabricated by a wide range of conventional clinically approved materials and innovative ones, including metals, carbon, lipids, polymers, nanogels, protein nanocages, virus-based nanoparticles, dendrimers, DNA origami nanostructures, and their complex combinations. Most nanotherapeutics targeting the TRAIL pathway are aimed at tumor therapy and theranostics. However, given the wide spectrum of action of TRAIL due to its natural role in immune system homeostasis, other therapeutic areas are also involved, such as liver fibrosis, rheumatoid arthritis, Alzheimer’s disease, and inflammatory diseases caused by bacterial infections. This review summarizes the recent innovative developments in the design of nanodelivery systems modified with TRAIL pathway-targeting ligands.
“…Another form of carbon-based nanoparticles is made from graphene, an allotrope of carbon. A graphenebased co-delivery nanosystem composed of graphene oxide, a PEG linker, and a furin-cleaved peptide encapsulated with TRAIL and doxorubicin (Dox) resulted in the efficient release of TRAIL and Dox to their sites of action by digesting the peptide linker by furin with the increased expression of death receptors in lung and colon adenocarcinoma cells [105] .…”
Section: Carbon-based Nanoparticlesmentioning
confidence: 99%
“…These studies showed that when adsorbed on graphene, TRAIL self-assembling and TRAIL affinities enhanced efficacy towards the targeted cancer cell. TRAIL bound to DR4 and DR5 more effectively when transported by graphene nanoflakes [ 106 ] . The synthesis of a novel nanohybrid system, sTRAIL (TRAIL fused with crystalline bacterial cell surface layer (S layer) protein), combined with graphene quantum dots or GQDs elevated the functional stability of TRAIL by improving pro-caspase-8 activation and mitochondria-dependent cell death in doxorubicin-pretreated human colon cancer cells (HT-29) when compared to S-TRAIL alone.…”
Section: Nanoparticle-based Drug and Gene Delivery Systemsmentioning
Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand, also called apo-2 ligand (TRAIL/Apo-2L), is a cytokine that triggers apoptosis by binding to TRAIL-R1 (DR4) and TRAIL-R2 (DR5) death receptors. Apoptosis occurs through either the extrinsic or intrinsic pathway. The administration of recombinant human TRAIL (rhTRAIL) or TRAIL-receptor (TRAIL-R) agonists promotes apoptosis preferentially in cancerous cells over normal cells in vitro; this phenomenon has also been observed in clinical studies. The limited efficacy of rhTRAIL in clinical trials could be attributed to drug resistance, short half-life, targeted delivery issues, and off-target toxicities. Nanoparticles are excellent drug and gene delivery systems characterized by improved permeability and retention, increased stability and biocompatibility, and precision targeting. In this review, we discuss resistance mechanisms to TRAIL and methods to overcome TRAIL resistance by using nanoparticle-based formulations developed for the delivery of TRAIL peptides, TRAIL-R agonists, and TRAIL genes to cancer cells. We also discuss combinatorial approaches of chemotherapeutic drugs with TRAIL. These studies demonstrate TRAIL’s potential as an anticancer agent.
The death ligand tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a member of the TNF cytokine superfamily, has long been recognized for its potential as a cancer therapeutic due to its low toxicity against normal cells. However, its translation into a therapeutic molecule has not been successful to date, due to its short in vivo half-life associated with insufficient tumor accumulation and resistance of tumor cells to TRAIL-induced killing. Nanotechnology has the capacity to offer solutions to these limitations. This review provides a perspective and a critical assessment of the most promising approaches to realize TRAIL’s potential as an anticancer therapeutic, including the development of fusion constructs, encapsulation, nanoparticle functionalization and tumor-targeting, and discusses the current challenges and future perspectives.
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