Double-Edged Lipid Nanoparticles Combining Liposome-Bound TRAIL and Encapsulated Doxorubicin Showing an Extraordinary Synergistic Pro-Apoptotic Potential.

Although TRAIL (TNF-related apoptosis-inducing ligand, also known as Apo2L) was described as capable of inducing apoptosis in transformed cells while sparing normal cells, limited results obtained in clinical trials has limited its use as an anti-tumor agent. Consequently, novel TRAIL formulations with enhanced bioactivity are necessary for overcoming resistance to conventional soluble TRAIL (sTRAIL) exhibited by many primary tumors. Our group has generated artificial liposomes with sTRAIL anchored on their surface (large unilamellar vesicle (LUV)-TRAIL), which have shown a greater cytotoxic activity both in vitro and in vivo when compared to sTRAIL against distinct hematologic and epithelial carcinoma cells.

Importance of TRAIL Molecular Anatomy in Receptor Oligomerization and Signaling. Implications for Cancer Therapy.

(TNF)-related apoptosis-inducing ligand (TRAIL) is able to activate the extrinsic apoptotic pathway upon binding to DR4/TRAIL-R1 and/or DR5/TRAIL-R2 receptors. Structural data indicate that TRAIL functions as a trimer that can engage three receptor molecules simultaneously, resulting in receptor trimerization and leading to conformational changes in TRAIL receptors. However, receptor conformational changes induced by the binding of TRAIL depend on the molecular form of this death ligand, and not always properly trigger the apoptotic cascade.

Role of Exosomes in the Regulation of T-cell Mediated Immune Responses and in Autoimmune Disease.

T-cell mediated immune responses should be regulated to avoid the development of autoimmune or chronic inflammatory diseases. Several mechanisms have been described to regulate this process, namely death of overactivated T cells by cytokine deprivation, suppression by T regulatory cells (Treg), induction of expression of immune checkpoint molecules such as CTLA-4 and PD-1, or activation-induced cell death (AICD). In addition, activated T cells release membrane microvesicles called exosomes during these regulatory processes.

Lipid Nanoparticles Decorated with TNF-Related Aptosis-Inducing Ligand (TRAIL) Are More Cytotoxic than Soluble Recombinant TRAIL in Sarcoma.

Sarcomas are rare and heterogeneous cancers classically associated with a poor outcome. Sarcomas are 1% of the cancer but recent estimations indicate that sarcomas account for 2% of the estimated cancer-related deaths. Traditional treatment with surgery, radiotherapy, and chemotherapy has improved the outcome for some types of sarcomas.

High-order TRAIL oligomer formation in TRAIL-coated lipid nanoparticles enhances DR5 cross-linking and increases antitumour effect against colon cancer.

During the last years, a great effort has been invested into developing new TRAIL formulations with increased bioactivity, trying to overcome the resistance to conventional soluble TRAIL (sTRAIL) exhibited by many primary tumours. In our group, we have generated artificial lipid nanoparticles decorated with sTRAIL (LUV-TRAIL), emulating the physiological TRAIL-containing exosomes by which T-cells release TRAIL upon activation. We already demonstrated that LUV-TRAIL has greater cytotoxicity against both chemoresistant haematologic tumour cells and epithelial carcinoma cells compared to a form of sTRAIL similar to that used in clinical trials.

Comparative proteomics of exosomes secreted by tumoral Jurkat T cells and normal human T cell blasts unravels a potential tumorigenic role for valosin-containing protein.

We have previously characterized that FasL and Apo2L/TRAIL are stored in their bioactive form inside human T cell blasts in intraluminal vesicles present in multivesicular bodies. These vesicles are rapidly released to the supernatant in the form of exosomes upon re-activation of T cells. In this study we have compared for the first time proteomics of exosomes produced by normal human T cell blasts with those produced by tumoral Jurkat cells, with the objective of identify proteins associated with tumoral exosomes that could have a previously unrecognized role in malignancy.

TRAIL-coated lipid-nanoparticles overcome resistance to soluble recombinant TRAIL in non-small cell lung cancer cells.

Purpose: Non-small cell lung cancer (NSCLC) is one the types of cancer with higher prevalence and mortality. Apo2-Ligand/TRAIL is a TNF family member able to induce apoptosis in tumor cells but not in normal cells. It has been tested in clinical trials against different types of human cancer including NSCLC.

Improved Anti-Tumor Activity of Novel Highly Bioactive Liposome-Bound TRAIL in Breast Cancer Cells.

Background: Apo2-ligand/TRAIL, a member of the TNF cytokine superfamily capable of inducing apoptosis on tumor cells while sparing normal cells, is a promising anti-tumor agent. However, about 50% of human cancer are TRAIL resistant. Consequently, future TRAIL-based therapies will require the use of novel highly bioactive forms of TRAIL and/or the addition of sensitizing agents to TRAIL-induced apoptosis.

Death ligands and granulysin: mechanisms of tumor cell death induction and therapeutic opportunities.

The immune system plays a key role in cancer immune surveillance to control tumor development. The final goal is recognizing and killing transformed cells and consequently the elimination of the tumor. The main effector cell types exerting cytotoxicity against tumors are natural killer (NK) cells and cytotoxic T lymphocytes (CTLs).

Liposome-bound TRAIL induces superior DR5 clustering and enhanced DISC recruitment in histiocytic lymphoma U937 cells.

Human Apo2-Ligand/TRAIL is a promising antitumor agent. Our group demonstrated that TRAIL was physiologically released to the extracellular medium inserted in lipid vesicles, known as exosomes. Recently we demonstrated that artificial lipid nanoparticles coated with bioactive TRAIL (LUV-TRAIL), which resemble the natural exosomes, greatly improved TRAIL activity compared with the soluble form of this death ligand and were able to induce apoptosis in hematological malignancies.