Biomimetic nanotechnology for cancer immunotherapy: State of the art and future perspective.

Cancer continues to be a significant worldwide cause of mortality. This underscores the urgent need for novel strategies to complement and overcome the limitations of conventional therapies, such as imprecise targeting and drug resistance. Cancer Immunotherapy utilizes the body's immune system to target malignant cells, reducing harm to healthy tissue. Nevertheless, the efficacy of immunotherapy exhibits variation across individuals and has the potential to induce autoimmune responses. Biomimetic nanoparticles (bNPs) have transformative potential in cancer immunotherapy, promising improved accurate targeting, immune system activation, and resistance mechanisms, while also reducing the occurrence of systemic autoimmune side effects. This integration offers opportunities for personalized medicine and better therapeutic outcomes. Despite considerable potential, bNPs face barriers like insufficient targeting, restricted biological stability, and interactions within the tumor microenvironment. The resolution of these concerns is crucial in order to expedite the integration of bNPs from the research setting into clinical therapeutic uses. In addition, optimizing manufacturing processes and reducing bNP-related costs are essential for practical implementation. The present research introduces comprehensive classifications of bNPs as well as recent achievements in their application in cancer immunotherapies, emphasizing the need to address barriers for swift clinical integration.

Energy modeling to compensate for the seasonal lack of electrical and thermal energy depending on the different climates of Iran.

Renewable energy sources are in focus for environment-friendly power generation when compared to non-renewable sources. Modeling an energy system of a statistical population can shed light on the possibilities and potential of using renewable resources. In this study, energy modeling of 4 provinces of Iran with different climates is done for 2020 and 2032. The lack of energy caused by seasonal climatic impacts is compensated for by using renewable energy systems. The modeling of three different scenarios is considered to indicate different policies in each energy system strategy. The energy system's past data is gathered and analyzed to predict future data, and then the 2032 energy system is modeled using EnergyPLAN. The results show that there will be a shortage of electrical energy in summers in hot & humid and hot & dry climates, while the energy shortage for cold and temperate & humid climates is the heating demand in winters. Three scenarios of business as usual (BAU), using maximum possible renewable energy (S1), and changing the structure of the energy supply system (S2) are considered with their specification. The results indicate that by using S1, 61.42 TWh of primary energy sources (PES), and by using S2, 136.7 TWh of PES consumption is reduced. Also, for the same scenarios, 29.98 Mt less CO2 is emitted for all climates. The climatic analysis illustrates that using solar in hot & humid and hot & dry, wind and geothermal in cold, and hydropower in hot & humid and temperate & humid climates produce the most amount of renewable potential which not only compensates the lack of seasonal energy but also replace 8% of the total energy needed, previously supplied by fossil fuels. Totally for the 4 provinces, 3250 MW of hydropower, 5625 MW of solar, 650 MW of wind, and 100 MW of geothermal energy are considered while other provinces with the same climate could benefit too based on their geographical specification.

Immunogenicity of Different Types of Adjuvants and Nano-Adjuvants in Veterinary Vaccines: A Comprehensive Review.

Vaccination is the best way to prevent and reduce the damage caused by infectious diseases in animals and humans. So, several vaccines are used for prophylactic purposes before the pathogen infects, while therapeutic vaccines strengthen the immune system after infection with the pathogen. Adjuvants are molecules, compounds, or macromolecules that enhance non-specific immunity and, in collaboration with antigen(s), can improve the body's immune responses and change the type of immune response. The potential and toxicity of adjuvants must be balanced to provide the safest stimulation with the fewest side effects. In order to overcome the limitations of adjuvants and the effective and controlled delivery of antigens, attention has been drawn to nano-carriers that can be a promising platform for better presenting and stimulating the immune system. Some studies show that nanoparticles have a more remarkable ability to act as adjuvants than microparticles. Because nano-adjuvants inactively target antigen-presenting cells (APCs) and change their chemical surface, nanoparticles also perform better in targeted antigen delivery because they cross biological barriers more easily. We collected and reviewed various types of nano-adjuvants with their specific roles in immunogenicity as a prominent strategy used in veterinary vaccines in this paper.

Primary Erlotinib Resistance in a Patient with Non-Small Cell Lung Cancer Carrying Simultaneous Compound EGFR L718A, Q849H, and L858R Mutations.

Nowadays, mutations in the epidermal growth factor receptor (EGFR) kinase domain are studied in targeted therapy of non-small cell lung cancer (NSCLC) with EGFR tyrosine kinase inhibitors including gefitinib and erlotinib. The present study reports a rare case of a patient harboring three simultaneous EGFR mutations (L718A, Q849H, and L858R). The development of erlotinib resistance was detected in the subsequent treatment. Using a computational approach, the current study investigated the conformational changes of wild-type and mutant EGFR's kinase domains in the interaction with erlotinib. Their binding modes with erlotinib were elucidated during molecular dynamics simulation, where higher fluctuations were detected in the mutated forms of the EGFR tyrosine kinase domain. Prediction of stability and functional effect of mutations revealed that amino acidic substitutions have decreased the protein stability as well as the binding affinity to erlotinib. These results may be useful for a recommendation of EGFR mutational analysis for patients with NSCLC carcinoma.

Cell-Penetrating Peptides: As a Promising Theranostics Strategy to Circumvent the Blood-Brain Barrier for CNS Diseases.

The passage of therapeutic molecules across the Blood-Brain Barrier (BBB) is a profound challenge for the management of the Central Nervous System (CNS)-related diseases. The ineffectual nature of traditional treatments for CNS disorders led to the abundant endeavor of researchers for the design the effective approaches in order to bypass BBB during recent decades. Cell-Penetrating Peptides (CPPs) were found to be one of the promising strategies to manage CNS disorders. CPPs are short peptide sequences with translocation capacity across the biomembrane. With special regard to their two key advantages like superior permeability as well as low cytotoxicity, these peptide sequences represent an appropriate solution to promote therapeutic/theranostic delivery into the CNS. This scenario highlights CPPs with specific emphasis on their applicability as a novel theranostic delivery system into the brain.

Magnetic bio-metal-organic framework nanocomposites decorated with folic acid conjugated chitosan as a promising biocompatible targeted theranostic system for cancer treatment.

In this work, a multifunctional magnetic Bio-Metal-Organic Framework (Fe3O4@Bio-MOF) coated with folic acid-chitosan conjugate (FC) was successfully prepared for tumor-targeted delivery of curcumin (CUR) and 5-fluorouracil (5-FU) simultaneously. Bio-MOF nanocomposite based on CUR as organic linker and zinc as metal ion was prepared by hydrothermal method in the presence of amine-functionalized Fe3O4 magnetic nanoparticles (Fe3O4@NH2 MNPs). 5-FU was loaded in the magnetic Bio-MOF and the obtained nanocarrier was then coated with FC network. The prepared nanocomposite (NC) was fully characterized by high resolution-transmission electron microscope (HR-TEM), field emission scanning electron microscopy (FE-SEM), Dynamic light scattering (DLS), X-ray diffraction analysis (XRD), thermogravimetric analysis (TGA), vibrating sample magnetometry (VSM), nuclear magnetic resonance (NMR), and UV-vis analyses. In vitro release study showed controlled release of CUR and 5-FU in acidic pH confirming high selectivity and performance of the carrier in cancerous microenvironments. The selective uptake of 5-FU-loaded Fe3O4@Bio-MOF-FC by folate receptor-positive MDA-MB-231 cells was investigated and verified. The ultimate nanocarrier exhibited no significant toxicity, while drug loaded nanocarrier showed selective and higher toxicity against the cancerous cells than normal cells. SDS PAGE was also utilized to determine the protein pattern attached on the surface of the nanocarriers. In vitro and in vivo MRI studies showed negative signal enhancement in tumor confirming the ability of the nanocarrier to be applied as diagnostic agent. Owing to the selective anticancer release and cellular uptake, acceptable blood compatibility as well as suitable T2 MRI contrast performance, the target nanocarrier could be considered as favorable theranostic in breast cancer.

Molecular interaction of fibrinogen with zeolite nanoparticles.

Fibrinogen is one of the key proteins that participate in the protein corona composition of many types of nanoparticles (NPs), and its conformational changes are crucial for activation of immune systems. Recently, we demonstrated that the fibrinogen highly contributed in the protein corona composition at the surface of zeolite nanoparticles. Therefore, understanding the interaction of fibrinogen with zeolite nanoparticles in more details could shed light of their safe applications in medicine. Thus, we probed the molecular interactions between fibrinogen and zeolite nanoparticles using both experimental and simulation approaches. The results indicated that fibrinogen has a strong and thermodynamically favorable interaction with zeolite nanoparticles in a non-cooperative manner. Additionally, fibrinogen experienced a substantial conformational change in the presence of zeolite nanoparticles through a concentration-dependent manner. Simulation results showed that both E- and D-domain of fibrinogen are bound to the EMT zeolite NPs via strong electrostatic interactions, and undergo structural changes leading to exposing normally buried sequences. D-domain has more contribution in this interaction and the C-terminus of γ chain (γ377-394), located in D-domain, showed the highest level of exposure compared to other sequences/residues.

Biomolecular Corona Dictates Aß Fibrillation Process.

Amyloid beta (Aß), which forms toxic oligomers and fibrils in brain tissues of patients with Alzheimer's disease, is broadly used as a model protein to probe the effect of nanoparticles (NPs) on oligomerization and fibrillation processes. However, the majority of the reports in the field have ignored the effect of the biomolecular corona on the fibrillogenesis of the Aß proteins. The biomolecular corona, which is a layer composed of various types of biomolecules that covers the surface of NPs upon their interaction with biological fluids, determines the biological fates of NPs. Therefore, during in vivo interaction of NPs with Aß protein, what the Aß actually "sees" is the human plasma and/or cerebrospinal fluid (CSF) biomolecular-coated NPs rather than the pristine surface of NPs. Here, to mimic the in vivo effects of therapeutic NPs as antifibrillation agents, we probed the effects of a biomolecular corona derived from human CSF and/or plasma on Aß fibrillation. The results demonstrated that the type of biomolecular corona can dictate the inhibitory or acceleratory effect of NPs on Aß1-42 and Aß25-35 fibrillation processes. More specifically, we found that the plasma biomolecular-corona-coated gold NPs, with sphere and rod shapes, has less inhibitory effect on Aß1-42 fibrillation kinetics compared with CSF biomolecular-corona-coated and pristine NPs. Opposite results were obtained for Aß25-35 peptide, where the pristine NPs accelerated the Aß25-35 fibrillation process, whereas corona-coated ones demonstrated an inhibitory effect. In addition, the CSF biomolecular corona had less inhibitory effect than those obtained from plasma.

Curcumin-lipoic acid conjugate as a promising anticancer agent on the surface of gold­iron oxide nanocomposites: A pH-sensitive targeted drug delivery system for brain cancer theranostics.

Brain tumor is a lethal, fast growing cancer and a difficult case for treatment. Receptor-mediated endocytosis has been recognized as one of the most effective methods for drug delivery to brain tissue by overcoming obstacles associated with conventional therapeutics. In this work, a targeted theranostic drug delivery system (DDS) was prepared based on gold­iron oxide nanocomposites (Fe3O4@Au NCs). Lipoic acid-curcumin (LA-CUR) was synthesized and introduced as a novel anticancer drug, and glutathione (GSH) was exploited as the targeting ligand. Both LA-CUR and GSH were easily attached to Fe3O4@Au NCs via Au-S interaction. As a negatively charged nanocarrier, the prepared DDS showed relatively less protein adsorption. Accordingly, hemocompatibility assays (complement, platelet, and leucocyte activation) revealed its hemocompatible virtue, especially in respect of free LA-CUR. GSH functionalization led to 2-fold increase of cellular uptake in GSH receptor-positive astrocyte cells which could primarily indicate the probable ability of the DDS to bypass BBB. Cytotoxicity and apoptosis assays together showed the noticeably enhanced cytotoxicity of LA-CUR against cancerous U87MG cells (IC50=2.69µg/ml) in comparison with curcumin (IC50=21.31µg/ml); moreover, the DDS demonstrated relatively higher cytotoxicity against cancerous U87MG cells than normal astrocyte cells which was in accordance with pH sensitive mechanism of LA-CUR release. Besides, the results of in vitro magnetic resonance imaging (MRI) (relaxation rate (r2)=80.73 (s-1·mM-1)) primarily revealed that the DDS can be applied as a negative MRI contrast agent. In sum, the prepared DDS appeared to be a promising candidate for brain cancer treatment and a favorable MRI contrast agent.

Sensing of Alzheimer's Disease and Multiple Sclerosis Using Nano-Bio Interfaces.

It is well understood that patients with different diseases may have a variety of specific proteins (e.g., type, amount, and configuration) in their plasmas. When nanoparticles (NPs) are exposed to these plasmas, the resulting coronas may incorporate some of the disease-specific proteins. Using gold (Au) NPs with different surface properties and corona composition, we have developed a technology for the discrimination and detection of two neurodegenerative diseases, Alzheimer's disease (AD) and multiple sclerosis (MS). Applying a variety of techniques, including UV-visible spectra, colorimetric response analyses and liquid chromatography-tandem mass spectrometry, we found the corona-NP complexes, obtained from different human serums, had distinct protein composition, including some specific proteins that are known as AD and MS biomarkers. The colorimetric responses, analyzed by chemometrics and statistical methods, demonstrate promising capabilities of the technology to unambiguously identify and discriminate AD and MS. The developed colorimetric technology might enable a simple, inexpensive and rapid detection/discrimination of neurodegenerative diseases.

Colon Cancer and Specific Ways to Deliver Drugs to the Large Intestine.

BACKGROUND: It has been postulated that colon cancer is the third cause of cancer death worldwide. Recently, colon-targeted drug delivery systems have been developed for improving systemic drug delivery and treatment of local colon associated diseases. Using such drug delivery systems increases the drug's effectiveness and results in reduced systemic side effects. Drug delivery systems formulated for the colon requires that the triggering of drug release mechanism is designed based on the colon's physiological conditions. However, improving the site specificity and drug release kinetics of colon-targeted drug delivery systems is desired and is currently under active research. OBJECTIVE: This review discusses colon cancer along with various colon-targeted drug delivery systems such as pro-drug formation, pH-sensitive polymers, hydrogels, time-dependent release systems, bio-adhesive and nanoparticle systems. The aim is to understand the effect of using colon-targeted drug delivery systems on therapeutic effectiveness of the drug by improving its degradation and bioavailability. Colon targeting holds a great promise as a therapeutic approach but it still requires more innovation. CONCLUSION: The distribution of the drugs in the colon suffers from problems related to the pH, retention time, micro-flora, and degrading enzymes of gastrointestinal tract. Moreover, these drug delivery systems are capable of overcoming some of the limitations in common targeting approaches. A precise assessment of such systems needs the use of various assaying protocols in order to characterize their traits and clarify their design rationales.

Zeolite Nanoparticles Inhibit Aß-Fibrinogen Interaction and Formation of a Consequent Abnormal Structural Clot.

EMT-type zeolite nanoparticles (EMT NPs) with particle size of 10-20 nm and external surface area of 200 m2/g have shown high selective affinity toward plasma protein (fibrinogen). Besides, the EMT NPs have demonstrated no adverse effect on blood coagulation hemostasis. Therefore, it was envisioned that the EMT NPs could inhibit possible ß-amyloid (Aß)-fibrinogen interactions that result in the formation of structurally abnormal clots, which are resistant to lysis, in cerebral vessels of patients with Alzheimer disease (AD). To evaluate this hypothesis, the clot formation and degradation of Aß-fibrinogen in the presence and absence of the EMT zeolite NPs were assessed. The results clearly showed that the delay in clot dissolution was significantly reduced in the presence of zeolite NPs. By formation of protein corona, the EMT NPs showed a negligible reduction in their inhibitory strength. Docking of small molecules (Aß-fibrinogen) introduced a novel potential inhibitory candidate. The zeolite NPs showed similar inhibitory effects on binding of fibrinogen to both Aß(25-35) and/or Aß(1-42). This indicates that the inhibitory strength of these NPs is independent of Aß sequence, and it is suggested that the zeolite NPs adsorb fibrinogen and specifically obstruct their Aß binding sites. Therefore, the zeolite NPs can be the safe and effective inhibitors in preventing Aß-fibrinogen interaction and consequent cognitive damage.