Cu-doped TiO2 nanoparticles improve local antitumor immune activation and optimize dendritic cell vaccine strategies.

Nanoparticle-mediated cancer immunotherapy holds great promise, but more efforts are needed to obtain nanoformulations that result in a full scale activation of innate and adaptive immune components that specifically target the tumors. We generated a series of copper-doped TiO2 nanoparticles in order to tune the kinetics and full extent of Cu2+ ion release from the remnant TiO2 nanocrystals. Fine-tuning nanoparticle properties resulted in a formulation of 33% Cu-doped TiO2 which enabled short-lived hyperactivation of dendritic cells and hereby promoted immunotherapy. The nanoparticles result in highly efficient activation of dendritic cells ex vivo, which upon transplantation in tumor bearing mice, exceeded the therapeutic outcomes obtained with classically stimulated dendritic cells. Efficacious but simple nanomaterials that can promote dendritic cancer cell vaccination strategies open up new avenues for improved immunotherapy and human health.

The Role of Optical Imaging in Translational Nanomedicine.

Nanomedicines have been a major research focus in the past two decades and are increasingly emerging in a broad range of clinical applications. However, a proper understanding of their biodistribution is required to further progress the field of nanomedicine. For this, imaging methods to monitor the delivery and therapeutic efficacy of nanoparticles are urgently needed. At present, optical imaging is the most common method used to study the biodistribution of nanomaterials, where the unique properties of nanomaterials and advances in optical imaging can jointly result in novel methods for optimal monitoring of nanomaterials in preclinical animal models. This review article aims to give an introduction to nanomedicines and their translational impact to highlight the potential of optical imaging to study the biodistribution of nanoparticles and to monitor the delivery and therapeutic efficacy at the preclinical level. After introducing both domains, the review focuses on different techniques that can be used to overcome some intrinsic limitations of optical imaging and how this can specifically benefit nanoparticle studies. Finally, we point out some important key features of nanoparticles that currently hinder their full potential in the clinic and how the advances in optical imaging can help to provide us with the information needed to further boost the clinical translation and expand the field of nanomedicines.

Role of inorganic nanoparticle degradation in cancer therapy.

Nanomaterials are currently widely exploited for their potential in the development of novel cancer therapies, and so far, mainly nanoparticles (NPs) consisting of liposomes and polymers have made their way into the clinic. However, major bottlenecks for the clinical translation of other types of NPs (i.e. inorganic) are the lack of knowledge concerning their long-term distribution in vivo and their potential toxicity. To counter this, various research groups have worked on soluble NPs, such as zinc oxide (ZnO), copper oxide (CuO), and silver (Ag), which tend to dissolve spontaneously into their ionic form, releasing toxic metal ions and leading to reactive oxygen species (ROS) generation when exposed to cellular environments. By fine-tuning the dissolution kinetics of these NPs, it is possible to control the level of ROS production and thus cytotoxicity to selectively destroy tumor tissue. Specifically, cancer cells tend to exhibit a higher basal level of oxidative stress compared to normal cells due to their higher metabolic rates, and therefore, by engineering NPs that generate sufficient ROS that barely exceed toxic thresholds in cancer cells, normal cells will only experience reversible transient damage. This review focuses on the use of these soluble inorganic NPs for selective cancer therapy and on the various in vitro and in vivo studies that have aimed to control the dissolution kinetics of these NPs, either through particle doping or surface modifications.

The ER Stress Inducer l-Azetidine-2-Carboxylic Acid Elevates the Levels of Phospho-eIF2α and of LC3-II in a Ca2+-Dependent Manner.

Accumulation of misfolded proteins in the endoplasmic reticulum (ER) activates the unfolded protein response (UPR) to reduce protein load and restore homeostasis, including via induction of autophagy. We used the proline analogue l-azetidine-2-carboxylic acid (AZC) to induce ER stress, and assessed its effect on autophagy and Ca2+ homeostasis. Treatment with 5 mM AZC did not induce poly adenosine diphosphate ribose polymerase (PARP) cleavage while levels of binding immunoglobulin protein (BiP) and phosphorylated eukaryotic translation initiation factor 2α (eIF2α) increased and those of activating transcription factor 6 (ATF6) decreased, indicating activation of the protein kinase RNA-like ER kinase (PERK) and the ATF6 arms of the UPR but not of apoptosis. AZC treatment in combination with bafilomycin A1 (Baf A1) led to elevated levels of the lipidated form of the autophagy marker microtubule-associated protein light chain 3 (LC3), pointing to activation of autophagy. Using the specific PERK inhibitor AMG PERK 44, we could deduce that activation of the PERK branch is required for the AZC-induced lipidation of LC3. Moreover, both the levels of phospho-eIF2α and of lipidated LC3 were strongly reduced when cells were co-treated with the intracellular Ca2+ chelator 1,2-bis(O-aminophenoxy)ethane-N,N,N',N'-tetraaceticacid tetra(acetoxy-methyl) ester (BAPTA-AM) but not when co-treated with the Na⁺/K⁺ ATPase inhibitor ouabain, suggesting an essential role of Ca2+ in AZC-induced activation of the PERK arm of the UPR and LC3 lipidation. Finally, AZC did not trigger Ca2+ release from the ER though appeared to decrease the cytosolic Ca2+ rise induced by thapsigargin while also decreasing the time constant for Ca2+ clearance. The ER Ca2+ store content and mitochondrial Ca2+ uptake however remained unaffected.