Recent Biomaterial-Assisted Approaches for Immunotherapeutic Inhibition of Cancer Recurrence.

Biomaterials possess distinctive properties, notably their ability to encapsulate active biological products while providing biocompatible support. The immune system plays a vital role in preventing cancer recurrence, and there is considerable demand for an effective strategy to prevent cancer recurrence, necessitating effective strategies to address this concern. This review elucidates crucial cellular signaling pathways in cancer recurrence. Furthermore, it underscores the potential of biomaterial-based tools in averting or inhibiting cancer recurrence by modulating the immune system. Diverse biomaterials, including hydrogels, particles, films, microneedles, etc., exhibit promising capabilities in mitigating cancer recurrence. These materials are compelling candidates for cancer immunotherapy, offering in situ immunostimulatory activity through transdermal, implantable, and injectable devices. They function by reshaping the tumor microenvironment and impeding tumor growth by reducing immunosuppression. Biomaterials facilitate alterations in biodistribution, release kinetics, and colocalization of immunostimulatory agents, enhancing the safety and efficacy of therapy. Additionally, how the method addresses the limitations of other therapeutic approaches is discussed.

Metformin-loaded nanoerythrosomes: An erythrocyte-based drug delivery system as a therapeutic tool for glioma.

Glioma is an intra-cranial malignancy with the origin of neural stem cells or precursor cells, the most prevalent brain tumor worldwide. Glioblastoma, the fourth-grade glioma, is a common brain tumor whose incidence rate is 5-7 people per 100,000 populations annually. Despite their high mortality rate, all efforts for treatment have yet to achieve any desirable clinical outcome. The Wnt signaling pathway is a conserved pathway among species that seems to be a candidate for cancer therapy by its inhibition. Metformin is a known inhibitor of the Wnt signaling pathway. Its effects on glioma treatment have been observed in cellular, animal, and clinical experiments. Nanoerythrosomes are drug carriers obtained from the cellular membrane of red blood cells in nano size which can offer several characteristics to deliver metformin to brain tumors. They are good at loading and carrying hydrophilic drugs, they can protect metformin from its metabolizing enzymes, which are present in the blood-brain barrier, and they can extend the period of metformin presence in circulation. In this study, nanoerythrosomes were prepared by using the hypotonic buffer. They had particle sizes in the range of 97.1 ± 34.2 nm, and their loading efficiency and loading capacity were 72.6% and 1.66%, respectively. Nanoerythrosomes could reserve metformin in their structure for a long time, and only 50% of metformin was released after 30 h. Moreover, they released metformin at a low and approximately constant rate. Besides, nanoerythrosomes could tolerate various kinds of stress and maintain most of the drug in their structure. Altogether, nanoerythrosome can be a suitable drug delivery system to deliver therapeutic amounts of metformin to various tissues.

Enhancing Methotrexate Delivery in the Brain by Mesoporous Silica Nanoparticles Functionalized with Cell-Penetrating Peptide using in Vivo and ex Vivo Monitoring.

The blood-brain barrier (BBB) acts as a physical/biochemical barrier that protects brain parenchyma from potential hazards exerted by different xenobiotics found in the systemic circulation. This barrier is created by "a lipophilic gate" as well as a series of highly organized influx/efflux mechanisms. The BBB bottleneck adversely affects the efficacy of chemotherapeutic agents in treating different CNS malignancies such as glioblastoma, an aggressive type of cancer affecting the brain. In the present study, mesoporous silica nanoparticles (MSNs) were conjugated with the transactivator of transcription (TAT) peptide, a cell-penetrating peptide, to produce MSN-NH-TAT with the aim of improving methotrexate (MTX) penetration into the brain. The TAT-modified nanosystem was characterized by Fourier transform infrared spectrometry (FTIR), field emission scanning electron microscopy (FE-SEM), transmission electron microscopy (TEM), atomic force microscopy (AFM), dynamic light scattering (DLS), and N2 adsorption-desorption analysis. In vitro hemolysis and cell viability studies confirmed the biocompatibility of the MSN-based nanocarriers. In addition, in vivo studies showed that the MTX-loaded MSN-NH-TAT improved brain-to-plasma concentration ratio, brain uptake clearance, and the drug's blood terminal half-life, compared with the use of free MTX. Taken together, the results of the present study indicate that MSN functionalization with TAT is crucial for delivery of MTX into the brain. The present nanosystem represents a promising alternative drug carrier to deliver MTX into the brain via overcoming the BBB.

Vesicles of yeast cell wall-sitagliptin to alleviate neuroinflammation in Alzheimer's disease.

A cell-based drug delivery system based on yeast-cell wall loaded with sitagliptin, a drug with an anti-inflammatory effect, was developed to control neuroinflammation associated with Alzheimer's disease. The optimized nanoparticles had a spherical shape with a negative surface charge, and were shown to be less toxic than the carrier and sitagliptin. Moreover, the nanoparticles caused anti-inflammatory effects against tumor necrosis factor-alpha in mice model of neuroinflammation. The pharmacokinetics study showed the brain concentration of drug in the nanoparticles group was much higher than in the control group. To evaluate the effect of P-glycoprotein on brain entry of sitagliptin, the experiment was repeated with verapamil, as a P-glycoprotein inhibitor. Brain concentration of the nanoparticles group remained approximately unchanged, proving the "Trojan Horse" effect of the developed nanocarriers. The results are promising for using yeast-cell wall as a carrier for targeted delivery to immune cells for the management of inflammation.

Apolipoprotein J in Alzheimer's Disease: Shedding Light on Its Role with Cell Signaling Pathway Perspective and Possible Therapeutic Approaches.

Apolipoprotein J (ApoJ), or clusterin, is one of the main apolipoproteins in the brain. It is synthesized and released from astrocytes in a healthy brain, and its expression increases in neurodegenerative disorders. Genetic evidence has suggested an association between ApoJ polymorphism and the risk of Alzheimer's disease (AD)-it is now considered the third main genetic risk factor for late-onset AD. However, the role of ApoJ overexpression in the state of disorder, toxicity, or protection is not yet clear. Since ApoJ plays different roles in AD, we review the function of ApoJ using different cell signaling pathways in AD and outline its paradoxical roles in AD. ApoJ helps in amyloid-beta (Aß) clearance. Vice versa, ApoJ gene knock-out causes fibrillary Aß reduction and prevents Aß-induced neuron cell death. Understanding ApoJ, through various cellular signaling pathways, creates a new perspective on AD's cellular principles. The overall message is that ApoJ can be a valuable tool in controlling AD.

Inflammation: A bridge between diabetes and COVID-19, and possible management with sitagliptin.

Patients with SARS-CoV-2 infections experience lymphopenia and inflammatory cytokine storms in the severe stage of the disease, leading to multi-organ damage. The exact pattern of immune system changes and their condition during the disease process is unclear. The available knowledge has indicated that the NF-kappa-B pathway, which is induced by several mediators, has a significant role in cytokine storm through the various mechanisms. Therefore, identifying the state of the immune cells and the dominant mechanisms for the production of cytokines incorporated in the cytokine storm can be a critical step in the therapeutic approach. On the other hand, some studies identified a higher risk for diabetic patients. Diabetes mellitus exhibits a close association with inflammation and increases the chance of developing COVID-19. Patients with diabetes mellitus have shown to have more virus entry, impaired immunity response, less viral elimination, and dysregulated inflammatory cytokines. The parallel analysis of COVID-19 and diabetes mellitus pathogenesis has proposed that the control of the inflammation through the interfering with the critical points of major signaling pathways may provide the new therapeutic approaches. In recent years, the role of Dipeptidyl Peptidase 4 (DPP4) in chronic inflammation has been proved. Numerous immune cells express the DPP4 protein. DPP4 regulates antibody production, cytokine secretion, and immunoglobulin class switching. DPP4 inhibitors like sitagliptin reduce inflammation intensity in different states. Following the accumulating data, we hypothesize that sitagliptin might reduce COVID-19 severity. Sitagliptin, an available DPP4 inhibitor drug, showed multidimensional anti-inflammatory effects among diabetic patients. It reduces the inflammation mostly by affecting on NF-kappa-B signaling pathway. Under the fact that inflammatory mediators are active in individuals with COVID-19, blocking the predominant pathway could be helpful.

Statins as the Controlling Agents for Non-Hodgkin's Lymphomas via Increasing the Casein Kinase 2 Interacting Protein-1: A Hypothesis.

BACKGROUND: Non-Hodgkin's lymphomas (NHL), derived from B- or T-cell, consist of a heterogeneous group of malignant lymphoproliferative disorders. Knockdown of Casein kinase 2 interacting protein-1 (CKIP-1) in NHL promoted cell proliferation and inhibited apoptosis via enhancing phosphorylated Protein Kinase B (PKB or AKT) expression. Statins are the class of drugs that inhibit the ratelimiting step of the mevalonate pathway, which is essential for the biosynthesis of various compounds, including cholesterol. Also, statins have anticancer properties being mediated by different mechanisms. METHODS: A search on databases like Scopus and PubMed with keywords such as statin and non- Hodgkin's lymphomas was performed and Kyoto Encyclopedia of Genes and Genomes (KEGG) website was used to evaluate and reconfirm the involved cellular signaling pathway. RESULTS: CKIP-1 is involved in the regulation of cell proliferation and apoptosis while plays an important role in many cancers. We can hypothesize that statins may increase the expression levels of CKIP-1 which could contribute to the reductions in phospho-AKT level. Hence, they may ameliorate the NHL patients via suppressing AKT phosphorylation and increasing CKIP- expression. CONCLUSION: Present review confirms the positive effect of statins on NHL by increasing CKIP-1 and reducing cell proliferation, subsequently.