Riboflavin-targeted polymers improve tolerance of paclitaxel while maintaining therapeutic efficacy.

Active targeting can enhance precision and efficacy of drug delivery systems (DDS) against cancers. Riboflavin (RF) is a promising ligand for active targeting due to its biocompatibility and high riboflavin-receptor expression in cancers. In this study, RF-targeted 4-arm polyethylene glycol (PEG) stars conjugated with Paclitaxel (PTX), named PEG PTX RF, were evaluated as a targeted DDS. In vitro, PEG PTX RF exhibited higher toxicity against tumor cells compared to the non-targeted counterpart (PEG PTX), while free PTX displayed the highest acute toxicity. In vivo, all treatments were similarly effective, but PEG PTX RF-treated tumors showed fewer proliferating cells, pointing to sustained therapy effects. Moreover, PTX-treated animals' body and liver weights were significantly reduced, whereas both remained stable in PEG PTX and PEG PTX RF-treated animals. Overall, our targeted and non-targeted DDS reduced PTX's adverse effects, with RF targeting promoted drug uptake in cancer cells for sustained therapeutic effect.

Recent Advances In the development of enzymatic paper-based microfluidic biosensors.

Using microfluidic paper-based analytical devices has attracted considerable attention in recent years. This is mainly due to their low cost, availability, portability, simple design, high selectivity, and sensitivity. Owing to their specific substrates and catalytic functions, enzymes are the most commonly used bioactive agents in µPADs. Enzymatic µPADs are various in design, fabrication, and detection methods. This paper provides a comprehensive review of the development of enzymatic µPADs by considering the methods of detection and fabrication. Particularly, techniques for mass production of these enzymatic µPADs for use in different fields such as medicine, environment, agriculture, and food industries are critically discussed. This paper aims to provide a critical review of µPADs and discuss different fabrication methods as the central parts of the µPADs production categorized into printable and non-printable methods. In addition, state-of-the-art technologies such as fully printed enzymatic µPADs for rapid, low-cost, and mass production and improvement have been considered.

Biomolecular engineering of drugs loading in Riboflavin-targeted polymeric devices: simulation and experimental.

The synthesis of polymeric nanoparticles (NPs) with efficient drug loading content and targeting moieties is an attractive field and remains a challenge in drug delivery systems. Atomistic investigations can provide an in-depth understanding of delivery devices and reduce the number of expensive experiments. In this paper, we studied the self-assembly of poly (lactic-co-glycolic acid)-b-poly (ethylene glycol) with different molecular weights and surface compositions. The innovation of this molecular study is the loading of an antitumor drug (docetaxel) on a targeting ligand (riboflavin). According to this work, a novel, biocompatible and targeted system for cancer treatment has been developed. The obtained results revealed a correlation between polymer molecular weight and the stability of particles. In this line, samples including 20 and 10 w/w% moiety NPs formed from polymers with 3 and 4.5 kDa backbone sizes, respectively, are the stable models with the highest drug loading and entrapment efficiencies. Next, we evaluated NP morphology and found that NPs have a core/shell structure consisting of a hydrophobic core with a shell of poly (ethylene glycol) and riboflavin. Interestingly, morphology assessments confirmed that the targeting moiety located on the surface can improve drug delivery to receptors and cancerous cells. The developed models provided significant insight into the structure and morphology of NPs before the synthesis and further analysis of NPs in biological environments. However, in the best cases of this system, Dynamic Light Scattering (DLS) tests were also taken and the results were consistent with the results obtained from All Atom and Coarse Grained simulations.

Effect of ligand conjugation site on the micellization of Bio-Targeted PLGA-Based nanohybrids: A computational biology approach.

In this study, the effect of ligand binding position on the polymeric nanoparticles (NPs) is based on poly(lactic-co-glycolic acid) (PLGA) with two different polymer chain length at the atomistic level was presented. We explored the conjugation of riboflavin (RF) ligand from the end of the ribityl chain (N-10) to the polymer strands as well as from the amine group on the isoalloxazine head (N-3). The energy interactions for all samples revealed that the NPs containing ligands from N-10 positions have higher total attraction energies and lower stability in comparison with their peers conjugated from N-3. As NPs containing RF conjugated from N-3 exhibit the lower energy level with 20% and 10% of RF-containing composition for lower and higher. The introduction of RF from the N-10 position in any composition has increased the energy level of nanocarriers. The results of Gibb's free energy confirm the interatomic interaction energies trend where the lowest Gibbs free energy level for N-3 NPs occurs at 20 and 10% of RF-containing polymer content for PLGA10- and PLGA11- based NPs. Furthermore, with N-10 samples based on both polymers, non-targeted models form the stablest particles in each category. These findings are further confirmed with molecular docking analysis which revealed affinity energy of RF toward polymer chain from N-3 and N-10 are -981.57 kJ/mole and -298.23 kJ/mole, respectively. This in-silico study paves the new way for molecular engineering of the bio-responsive PLGA-PEG-RF micelles and can be used to nanoscale tunning of smart carriers used in cancer treatment.Communicated by Ramaswamy H. Sarma.

In-silico study on viability of MXenes in suppressing the coronavirus infection and distribution.

Herein, based on the paramount importance of combating emerging diseases, through employing a detailed in-silico study, the possibility of using MXenes in suppressing the coronavirus infection was elucidated. To this end, first, interactions of MXene nanosheets (Mn2C, Ti2C, and Mo2C) and spike protein (SP), the main infecting portion of the COVID-19, were investigated. It was found that the modeled MXenes were effective in attracting the SP, so that they can be exploited in filtering the coronavirus. In addition, the effect of the MXenes on the SP structure was assessed which demonstrated that the secondary structure of the SP could be changed. Therefore, the post-interactions of the SP/ACE2 (receptor of coronavirus in the body) could be interrupted, declaring the lower chance of coronavirus infecting. The in-silico studies revealed that the MXenes not only can be used to adsorb and hinder the distribution of the coronavirus but also affect the SP structure and the SP/ACE2 interactions to interrupt the COVID-19 threat. Therefore, MXenes can be exploited with simultaneous roles in physical inhibition and reactive weakening of the COVID-19. In this regard, the Mn2C nanosheet was well suited, which is suggested as a promising candidate to combat the coronavirus.

Atomistic insight into 2D COFs as antiviral agents against SARS-CoV-2.

The recent pandemic of COVID-19 has raised global health concerns. Preventing severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) activity in the body is a very promising method to overcome the COVID-19 pandemic. One of the prevention methods is constraining the binding process among the human cell receptor-ACE2 and coronavirus spike protein. In the research done, the effect of deformation of the spike protein structure, due to the covalent organic frameworks (COFs), in reducing the interactions of ACE2 and the spike protein by the computational method was investigated. In this regard, atomic analysis of the interactions of ACE2 and the spike protein is provided using a molecular dynamics simulation. First, we investigated the interactions of the three different COFs, including COF-78, DAAQ-TFP, and COF-OEt, with the spike protein by analyzing the bond energies, as well as structural changes of the spike protein. Then, intermolecular interactions of the deformed spike protein along with ACE2 were assessed to clarify the protein's fusion after the deformation. As indicated by the results, although all introduced COFs deformed the spike protein in an effective way, COF-78 showed the best performance in the prevention of spike protein-ACE2 interactions by changing the molecular structure of the protein. Indeed, the interaction analysis of the deformed spike protein by COF-78 with the ACE2 showed that their interactions had the lowest absolute value of energy, along with the least amount of hydrogen bonds, in which the compaction of the protein was lower compared to the other deformed proteins. Moreover, having a high contact area with an aqueous media as well as severe fluctuations during the simulation time confirmed the positive performance of COF-78. In the current study, we aimed to introduce novel materials and COVID-19 prevention methodology that can be used in face masks and for surface disinfection.

Engineering of 2D nanomaterials to trap and kill SARS-CoV-2: a new insight from multi-microsecond atomistic simulations.

In late 2019, coronavirus disease 2019 (COVID-19) was caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Spike protein is one of the surface proteins of SARS-CoV-2 that is essential for its infectious function. Therefore, it received lots of attention for the preparation of antiviral drugs, vaccines, and diagnostic tools. In the current study, we use computational methods of chemistry and biology to study the interaction between spike protein and its receptor in the body, angiotensin-I-converting enzyme-2 (ACE2). Additionally, the possible interaction of two-dimensional (2D) nanomaterials, including graphene, bismuthene, phosphorene, p-doped graphene, and functionalized p-doped graphene, with spike protein is investigated. The functionalized p-doped graphene nanomaterials were found to interfere with spike protein better than the other tested nanomaterials. In addition, the interaction of the proposed nanomaterials with the main protease (Mpro) of SARS-CoV-2 was studied. Functionalized p-doped graphene nanomaterials showed more capacity to prevent the activity of Mpro. These 2D nanomaterials efficiently reduce the transmissibility and infectivity of SARS-CoV-2 by both the deformation of the spike protein and inhibiting the Mpro. The results suggest the potential use of 2D nanomaterials in a variety of prophylactic approaches, such as masks or surface coatings, and would deserve further studies in the coming years.

Improving the self-assembly of bioresponsive nanocarriers by engineering doped nanocarbons: a computational atomistic insight.

Here, molecular dynamics (MD) simulations were employed to explore the self-assembly of polymers and docetaxel (DTX) as an anticancer drug in the presence of nitrogen, phosphorous, and boron-nitrogen incorporated graphene and fullerene. The electrostatic potential and the Gibbs free energy of the self-assembled materials were used to optimize the atomic doping percentage of the N- and P-doped formulations at 10% and 50%, respectively. Poly lactic-glycolic acid (PLGA)- polyethylene glycol (PEG)-based polymeric nanoparticles were assembled in the presence of nanocarbons in the common (corresponding to the bulk environment) and interface of organic/aqueous solutions (corresponding to the microfluidic environment). Assessment of the modeling results (e.g., size, hydrophobicity, and energy) indicated that among the nanocarbons, the N-doped graphene nanosheet in the interface method created more stable polymeric nanoparticles (PNPs). Energy analysis demonstrated that doping with nanocarbons increased the electrostatic interaction energy in the self-assembly process. On the other hand, the fullerene-based nanocarbons promoted van der Waals intramolecular interactions in the PNPs. Next, the selected N-doped graphene nanosheet was utilized to prepare nanoparticles and explore the physicochemical properties of the nanosheets in the permeation of the resultant nanoparticles through cell-based lipid bilayer membranes. In agreement with the previous results, the N-graphene assisted PNP in the interface method and was translocated into and through the cell membrane with more stable interactions. In summary, the present MD simulation results demonstrated the success of 2D graphene dopants in the nucleation and growth of PLGA-based nanoparticles for improving anticancer drug delivery to cells, establishing new promising materials and a way to assess their performance that should be further studied.

In-silico study on perovskites application in capturing and distorting coronavirus.

The COVID-19 pandemic, known as coronavirus pandemic, a global pandemic, emerged from the beginning of 2020 and became dominant in many countries. As COVID-19 is one of the deadliest pandemics in history and has a high rate of distribution, a fast and extensive reaction was needed. Considering its composition, revealing the infection mechanism is beneficial for effective decisions against the spread and attack of COVID-19. Investigating data from numerous studies confirms that the penetration of SARS-CoV-2 occurs along with bonding spike protein (S protein) and through ACE2; Therefore, these two parts were the focus of research on the suppression and control of the infection. Performing lab research on all promising candidates requires years of experimental study, which is time-consuming and not an acceptable solution. Molecular dynamic simulation can decipher the performance of nano-structures in preventing the spread of coronavirus in a shorter time. This study surveyed the effect of three nano-perovskite structures (SrTiO3, CaTiO3, and BaTiO3), a cutting-edge group of perovskite materials with outstanding properties on coronavirus. Various computational parameters evaluate the effectiveness of these structures. Results of the simulation indicated that SrTiO3 performs better in SARS-CoV-2 suppression.

Experimental and Computational Study on the Microfluidic Control of Micellar Nanocarrier Properties.

Microfluidic-based synthesis is a powerful technique to prepare well-defined homogenous nanoparticles (NPs). However, the mechanisms defining NP properties, especially size evolution in a microchannel, are not fully understood. Herein, microfluidic and bulk syntheses of riboflavin (RF)-targeted poly(lactic-co-glycolic acid)-poly(ethylene glycol) (PLGA-PEG-RF) micelles were evaluated experimentally and computationally. Using molecular dynamics (MD), a conventional "random" model for bulk self-assembly of PLGA-PEG-RF was simulated and a conceptual "interface" mechanism was proposed for the microfluidic self-assembly at an atomic scale. The simulation results were in agreement with the observed experimental outcomes. NPs produced by microfluidics were smaller than those prepared by the bulk method. The computational approach suggested that the size-determining factor in microfluidics is the boundary of solvents in the entrance region of the microchannel, explaining the size difference between the two experimental methods. Therefore, this computational approach can be a powerful tool to gain a deeper understanding and optimize NP synthesis.

Molecular insight into COF monolayers for urea sorption in artificial kidneys.

Urea removal from an aqueous solution is considered a challenge in the biological process. The state of complete kidney destruction is known as an end-stage renal disease (ESRD). Kidney transplant and hemodialysis are the most common methods for confronting ESRD. More recently, wearable artificial kidney (WAK) devices have shown a significant improvement in urea removal performance. However, low efficiency in physical adsorbents is a barrier in developing them. For the first time, the urea adsorption capacity of five types of last-generation covalent organic framework (COF) nanosheets (NSs) was investigated in this study by applying molecular dynamics (MD) simulation tools. To this end, different analyses have been performed to evaluate the performance of each nanoparticle. The MD all-atom (AA) results demonstrated that all introduced COF NSs had urea removal capacity. Among the five NSs, TPA-COF was shown to have the best outcomes. Moreover, coarse-grained (CG) and density functional theory (DFT) simulations were conducted, and the results show that the TPA-COF nanoparticle modified with -OH functional group has even better properties for urea adsorption. The present molecular study sheds new light on COF NSs as an adsorbent for urea removal.

ß-Amyloid Targeting with Two-Dimensional Covalent Organic Frameworks: Multi-Scale In-Silico Dissection of Nano-Biointerface.

Cytotoxic aggregation of misfolded ß-amyloid (Aß) proteins is the main culprit suspected to be behind the development of Alzheimer's disease (AD). In this study, Aß interactions with the novel two-dimensional (2D) covalent organic frameworks (COFs) as therapeutic options for avoiding ß-amyloid aggregation have been investigated. The results from multi-scale atomistic simulations suggest that amine-functionalized COFs with a large surface area (more than 1000 m2 /gr) have the potential to prevent Aß aggregation. Gibb's free energy analysis confirmed that COFs could prevent protofibril self-assembly in addition to inhibiting ß-amyloid aggregation. Additionally, it was observed that the amine functional group and high contact area could improve the inhibitory effect of COFs on Aß aggregation and enhance the diffusivity of COFs through the blood-brain barrier (BBB). In addition, microsecond coarse-grained (CG) simulations with three hundred amyloids reveal that the presence of COFs creates instability in the structure of amyloids and consequently prevents the fibrillation. These results suggest promising applications of engineered COFs in the treatment of AD and provide a new perspective on future experimental research.

Molecular insight into optimizing the N- and P-doped fullerenes for urea removal in wearable artificial kidneys.

Urea is the result of the breakdown of proteins in the liver, the excess of which circulates in the blood and is adsorbed by the kidneys. However, in the case of kidney diseases, some products, specifically urea, cannot be removed from the blood by the kidneys and causes serious health problems. The end-stage renal disease (ESRD) patients are not able to purify their blood, which endangers their life. ESRD patients require dialysis, a costly and difficult method of urea removal from the blood. Wearable artificial kidneys (WAKs) are consequently designed to remove the waste from blood. Regarding the great amount of daily urea production in the body, WAKs should contain strong and selective urea adsorbents. Fullerenes-which possess fascinating chemical properties-have been considered herein to develop novel urea removal adsorbents. Molecular dynamics (MD) has enabled researchers to study the interaction of different materials and can pave the way toward facilitating the development of wearable devices. In this study, urea adsorption by N-doped fullerenes and P-doped fullerenes were assessed through MD simulations. The urea adsorption was simulated by five samples of fullerenes, with phosphorous and different nitrogen dopant contents. For comparing the urea adsorption capacity in the performed simulations, detailed characteristics-including the energy analysis, radius of gyration, radial distribution function (RDF), root-mean-square fluctuation (RMSD), and H-bond analyses were investigated. It had been determined that the fullerene containing 8% nitrogen-with the highest reduction in the radius of gyration, the maximum RDF, a high adsorption energy, and a high number of hydrogen bonds-adsorbs urea more efficiently.

Shedding Light on Miniaturized Dialysis Using MXene 2D Materials: A Computational Chemistry Approach.

Materials science can pave the way toward developing novel devices at the service of human life. In recent years, computational materials engineering has been promising in predicting material performance prior to the experiments. Herein, this capability has been carefully employed to tackle severe problems associated with kidney diseases through proposing novel nanolayers to adsorb urea and accordingly causing the wearable artificial kidney (WAK) to be viable. The two-dimensional metal carbide and nitride (MXene) nanosheets can leverage the performance of various devices since they are highly tunable along with fascinating surface chemistry properties. In this study, molecular dynamics (MD) simulations were exploited to investigate the interactions between urea and different MXene nanosheets. To this end, detailed analyses were performed that clarify the suitability of these nanostructures in urea adsorption. The atomistic simulations were carried out on Mn2C, Cd2C, Cu2C, Ti2C, W2C, Ta2C, and urea to determine the most appropriate urea-removing adsorbent. It was found that Cd2C was more efficient followed by Mn2C, which can be effectively exploited in WAK devices at the service of human health.

Potential treatment of Parkinson's disease using new-generation carbon nanotubes: a biomolecular in silico study.

Background: One of the underlying mechanisms of Parkinson's disease is the aggregation of α-synuclein proteins, including amyloids and Lewy bodies in the brain. Aim: To study the inhibitory effect of doped carbon nanotubes (CNTs) on amyloid aggregation. Materials & methods: Molecular dynamics tools were utilized to simulate the influence of CNTs doped with phosphorus, nitrogen and bromine and nitrogen on the formation of α-synuclein amyloid. Results: The CNTs exhibited strong interactions with α-synuclein, with phosphorus-doped CNTs having the most substantial interactions. Conclusion: Doped-CNTs, especially phosphorus-doped carbon nanotube could effectively prevent α-synuclein amyloid formation, thus, it could be considered as a potential treatment for Parkinson's disease. However, further in vitro and clinical investigations are required.

Molecular Tuning of the Nano-Bio Interface: Alpha-Synuclein's Surface Targeting with Doped Carbon Nanostructures.

Carbon nanoparticles are becoming promising agents in treating Parkinson's disease (PD) by preventing the folding and aggregation of α-synuclein, i.e., amyloid formation. Herein, for the first time, highly tunable graphene and carbon nanotubes (CNTs) have been doped using biocompatible silicon atoms for preventing Parkinson's disease. In this study, the conformational changes induced by these nanoparticles, the compactness of nanoparticles, the number of hydrogen bonds, the stability of α-synuclein in the presence of nanoparticles, and the interaction energies between α-synuclein and nanoparticles were investigated using microsecond coarse-grained and all-molecular-atom simulations. Although the nanoparticles considered in this study could induce desirable changes in α-synuclein conformations, Si-graphene (silicon-doped graphene) demonstrated the best performance. Si-graphene showed the highest interaction energy with α-synuclein compared to other nanoparticles, induced the most hydrogen bonds, was the least compact, and showed the most unstable α-synuclein conformation, resulting in the highest capability to prevent the folding and aggregation of α-synuclein. Our results displayed that 2D hexagonal structures, such as graphene and Si-graphene, possess better performance than tubular structures in inducing conformational changes in the α-synuclein protein. Furthermore, it was observed that the doping of silicon in graphene and CNT results in better folding and aggregation of α-synuclein prevention. This molecular investigation offers a nanostructure method in PD treatment.

Graphene-Based Nanoparticles as Potential Treatment Options for Parkinson's Disease: A Molecular Dynamics Study.

INTRODUCTION: The study of abnormal aggregation of proteins in different tissues of the body has recently earned great attention from researchers in various fields of science. Concerning neurological diseases, for instance, the accumulation of amyloid fibrils can contribute to Parkinson's disease, a progressively severe neurodegenerative disorder. The most prominent features of this disease are the degeneration of neurons in the substantia nigra and accumulation of α-synuclein aggregates, especially in the brainstem, spinal cord, and cortical areas. Dopamine replacement therapies and other medications have reduced motor impairment and had positive consequences on patients' quality of life. However, if these medications are stopped, symptoms of the disease will recur even more severely. Therefore, the improvement of therapies targeting more basic mechanisms like prevention of amyloid formation seems to be critical. It has been shown that the interactions between monolayers like graphene and amyloids could prevent their fibrillation. METHODS: For the first time, the impact of four types of last-generation graphene-based nanostructures on the prevention of α-synuclein amyloid fibrillation was investigated in this study by using molecular dynamics simulation tools. RESULTS: Although all monolayers were shown to prevent amyloid fibrillation, nitrogen-doped graphene (N-Graphene) caused the most instability in the secondary structure of α-synuclein amyloids. Moreover, among the four monolayers, N-Graphene was shown to present the highest absolute value of interaction energy, the lowest contact level of amyloid particles, the highest number of hydrogen bonds between water and amyloid molecules, the highest instability caused in α-synuclein particles, and the most significant decrease in the compactness of α-synuclein protein. DISCUSSION: Ultimately, it was concluded that N-Graphene could be the most effective monolayer to disrupt amyloid fibrillation, and consequently, prevent the progression of Parkinson's disease.

An insight into the role of riboflavin ligand in the self-assembly of poly(lactic-co-glycolic acid)-based nanoparticles - a molecular simulation and experimental approach.

Nanoparticles (NPs) used for targeted delivery purposes are rapidly gaining importance in diagnostic and therapeutic fields. These agents have been studied extensively so far to reveal their optimal physicochemical properties including the effects of ligands and their density on the surface of NPs. This article was conducted through a computational approach (all-atom molecular dynamics simulations) to predict the stability of NPs based on a poly-lactic-co-glycolic acid (PLGA) hydrophobic core with a poly-ethylene glycol (PEG) hydrophilic shell and varying numbers of riboflavin (RF) molecules as ligands. Depending on the molecular weight of the polymers, the most stable composition of NPs was achieved at 20 wt% and 10 wt% PLGA-PEG-RF for PLGA3kDa-PEG2kDa and PLGA4.5kDa-PEG2kDa polymers, respectively. According to the simulations, riboflavin molecules were located on the surface of the NPs, which would indicate that riboflavin-bound PLGA-PEG NPs could be efficiently utilized for active targeting purposes. To scrutinize the simulation results, NPs with riboflavin ligands were synthesized and put into in vitro experiments. Outstandingly, the empirical outcomes revealed that the hydrodynamic sizes of NPs also met minimum points at 20 and 10 wt% for PLGA3kDa-PEG2kDa and PLGA4.5kDa-PEG2kDa, respectively. Moreover, similar trends in the gyration radius as a function of riboflavin content were observed in the simulation analysis and the experimental results, which would indicate that the method of molecular dynamics (MD) simulation is a reliable mathematical technique and could be applied for predicting the physicochemical properties of NPs.

Molecular engineering of the last-generation CNTs in smart cancer therapy by grafting PEG-PLGA-riboflavin.

In this work, the effect of environment and additives on the self-assembly and delivery of doxorubicin (DOX) have been studied. A microfluidic system with better control over molecular interactions and high surface to volume ratio has superior performance in comparison to the bulk system. Moreover, carbon nanotube (CNT) and CNT-doped structures have a high surface area to incorporate the DOX molecules into a polymer and the presence of functional groups can influence the polymer-drug interactions. In this work, the interactions of DOX with both the polymeric complex and the nanotube structure have been investigated. For quantification of the interactions, H-bonding, gyration radius, root-mean-square deviation (RMSD), Gibbs free energy, radial distribution function (RDF), energy, and Solvent Accessible Surface Area (SASA) analyses have been performed. The most stable micelle-DOX interaction is attributed to the presence of BCN in the microfluidic system according to the gyration radius and RMSD. Meanwhile, for DOX-doped CNT interaction the phosphorus-doped CNT in the microfluidic system is more stable. The highest electrostatic interaction can be seen between polymeric micelles and DOX in the presence of BCN. For nanotube-drug interaction, phosphorus-doped carbon nanotubes in the microfluidic system have the largest electrostatic interaction with the DOX. RDF results show that in the microfluidic system, nanotube-DOX affinity is larger than that of nanotube-micelle.