Targeted drug delivery to the inferior meatus cavity of the nasal airway using a nasal spray device with angled tip.

BACKGROUND AND OBJECTIVE: Nowadays, by advancement in computational tools, Computational Fluid and Particle Dynamics (CFPD) technique can be used more than ever. The main aim of this study is using a nasal spray device with angled tip to deliver drug particles to the inferior meatus cavity for treatment purposes. In the present study, the drug delivery to the lower regions of the nasal cavity will be improved that has been considered less in the literature. METHODS: For this purpose, a spray with an angled tip was used, and the deposition of sprayed particles was compared with a spray with a straight tip. Based on the objectives presented above, a realistic model of the nasal route, including facial geometry, and paranasal sinuses obtained from a series of Computed tomography (CT) scan images, as well as the geometry of a nasal spray with two types of tip were developed. RESULTS: It is observed that by using the spray with the straight tip, particles were mainly deposited in the middle and superior regions of the nasal cavity and no particles entered the inferior meatus airway. The results proved that the spray with the angled tip improved the regional deposition percentage in the inferior meatus cavity up to 2.4% of the total sprayed particles and 1 mg drug mass delivered to this region. The majority of these particles had a diameter between 15-55 µm and that could be considered by spray designers to produce more compatible sprays with the targeted region. Also, most particles were deposited near the inferior meatus cavity and so there is a strong chance to be absorbed and delivered to this region. CONCLUSION: The deposition pattern and particle size contour due to the spray with the angled tip can give sight to the designers and producers of nasal sprays to build more efficient types for better targeted drug delivery purposes. With this spray type, deposited particles were observed in the inferior meatus that never happened with the straight type. Also, the angled tip of the nasal spray shows the benefit of the ease of use for the user.

Dynamics and energetics of water transport through aquaporin mutants causing nephrogenic diabetes insipidus (NDI): A molecular dynamics study.

Human aquaporin-2 (AQP2) is the principal water channel in the human kidney. Any alteration of its physiological functioning may lead to the water imbalance and consequently diseases in humans, especially nephrogenic diabetes insipidus (NDI). Although many of the mutations associated with NDI are experimentally discovered and examined, a molecular level characterization of the structure and transport mechanism is still missing. In this paper, the gating effects of selectivity filter (SF) as wide/narrow states on the mechanism and dynamics of water permeation within the wild-type AQP2 and two NDI causing mutants as AQP2-V168M and AQP2-G64R are studied for the first time. The analysis of the 200 ns trajectory shows that the SF region in AQP2 is not only a selectivity filter, as previously reported but also it performs as a gating site depending on the side-chain conformation of His172. The assignment of the wide/narrow states of SF is supported by computing the free energy and permeability through the AQP2. Moreover, by exploring the effects of V168M and G64R mutants on the AQP2 structure during 200 ns trajectories, remarkable increases of energy barriers are observed in the middle and cytoplasmic side of the pore, respectively. Interestingly, it is found that due to the variable conformations of the SF region as wide/narrow, the effect of the NDI causing mutants on the average water permeability can be revealed with notably better accuracy by finding the wide states in the wild-type and mutated types of AQP2 and comparing the osmotic permeabilities for this state.Communicated by Ramaswamy H. Sarma.

Non-equilibrium molecular dynamics study of human aquaporin-2 in the static external electric fields.

In this paper, non-equilibrium MD simulations (NEMD) of human aquaporin-2 (AQP2) in the presence of an external static electric field have been performed along + z and - z directions of the pore axis. The impacts of the electric field direction on the gating mechanism corresponding to the selectivity filter (SF) region of AQP2 have been studied. Besides, the effects of applied external electric field on the PMF profile of water molecules translocation, water permeability, and molecules dipole orientation are investigated. Our results showed that when the external electric field is implemented along the + z direction of the channels, the selectivity filter region is kept in the wide conformation for the majority of the time. Therefore, a remarkable increase in the overall water permeability can be seen compared to the case without any external electric field. This is in contrast to the effects of - z-directed electric field on the conformations of the selectivity filter, which induces mostly narrow conformations in this constriction region. A substantial higher energy barrier emerged in the middle of the AQP2's pores under the effect of -z-directed electric field in comparison with the zero and + z-directed electric field strengths, which is mainly ascribed to the deviation from bipolar dipole orientation within the AQP2's pores.Communicated by Ramaswamy H. Sarma.

Molecular dynamics study of water transport through AQP5-R188C mutant causing palmoplantar keratoderma (PPK) using the gating mechanism concept.

It is widely known that any disruption to the water regulation in aquaporins (AQPs) leads to numerous important diseases. However, studies of dynamics and energetics of disease-causing mutations in the aquaporins on the molecular level are still limited. In the present work, the effects of a skin disease-causing mutant, R188C, on the structure of AQP5 and water transport mechanism within this mutated aquaporin are investigated using the concept of gating mechanism. Our results have revealed that the R188C mutation causes a remarkable increase in the pore radius inside the selectivity filter (SF) region facilitating the passage of water molecules. This observation is supported by plotting the free energy profiles of water molecules transport and calculating permeability values through AQP5-R188C, such that the energy barrier in the SF region of the pores was substantially reduced by this mutation, and therefore, the translocation of water molecules was improved. The total averaged osmotic permeability for R188C has been computed as about 11-fold of the wild-type permeability. However, a comparison between the osmotic permeability values related to the open conformation of CE revealed that this coefficient for AQP5-R188C is about 6.5 times larger than that of wt-AQP5, which can be a more accurate value according to the gating mechanism associated with the constriction region of the aquaporin.

Investigation of the aquaporin-2 gating mechanism with molecular dynamics simulations.

Aquaporin-2 plays a vital role in the human kidney as a water passage channel. Any disorder with its function can cause water imbalance and consequently disease in humans, especially nephrogenic diabetes insipidus (NDI). For this reason, an accurate understanding of its performance can be useful for therapeutic purposes. In this article, we investigate the gating mechanism induced by spontaneous fluctuations in aquaporin-2's (AQP2) channels in the palmitoyl-oleoyl-phosphatidyl-ethanolamine lipid bilayer by molecular dynamics. Our results show that the selectivity filter (SF) in AQP2 is also a gating site depending on the side-chain conformation of His172. The important role of His172 in modulating the wide and narrow conformations has been further investigated by the simulation of the H172G mutant. The osmotic permeability values of all four monomers are in the range of wide state and the average is very close to that of the wide channel formed by wild-type AQP2. Moreover, by calculating the osmotic permeability and the potential of mean force of each of the AQP2 monomers for wide/narrow states of the SF, it is seen that the SF at its narrow conformation can induce a much larger energy barrier for water molecules permeation, hindering the transport of water molecules remarkably. The reason for the discrepancy among osmotic permeabilities of different monomers of aquaporins is revealed by investigating the osmotic permeability of each monomer through the wide/narrow states of their SF.

Magnetic particle targeting for diagnosis and therapy of lung cancers.

Over the past decade, the growing interest in targeted lung cancer therapy has guided researchers toward the cutting edge of controlled drug delivery, particularly magnetic particle targeting. Targeting of tissues by magnetic particles has tackled several limitations of traditional drug delivery methods for both cancer detection (e.g., using magnetic resonance imaging) and therapy. Delivery of magnetic particles offers the key advantage of high efficiency in the local deposition of drugs in the target tissue with the least harmful effect on other healthy tissues. This review first overviews clinical aspects of lung morphology and pathogenesis as well as clinical features of lung cancer. It is followed by reviewing the advances in using magnetic particles for diagnosis and therapy of lung cancers: (i) a combination of magnetic particle targeting with MRI imaging for diagnosis and screening of lung cancers, (ii) magnetic drug targeting (MDT) through either intravenous injection and pulmonary delivery for lung cancer therapy, and (iii) computational simulations that models new and effective approaches for magnetic particle drug delivery to the lung, all supporting improved lung cancer treatment. The review further discusses future opportunities to improve the clinical performance of MDT for diagnosis and treatment of lung cancer and highlights clinical therapy application of the MDT as a new horizon to cure with minimal side effects a wide variety of lung diseases and possibly other acute respiratory syndromes (COVID-19, MERS, and SARS).

A novel molecular dynamics study of CO2 permeation through aquaporin-5.

Aquaporins (AQPs) are protein channels which facilitate rapid water permeation across cell membrane. The AQPs are very vital for biological organs, as their malfunction causes severe diseases in human body. A particular family of AQPs, that is AQP5, has a significant role in lung fluid transport due to submucosal glands structure. However, it has not been yet well understood whether these protein channels can conduct gas molecules. Here, Molecular Dynamics (MD) simulations are used to investigate the CO2 permeability and diffusion in AQP5 during a 40-nanosecond period. For the first time, equilibrium and Steered MD (SMD) are used to simulate self and force-induced diffusion of CO2 molecules across AQP5 and POPE lipid bilayer. According to PMFs profile associated to CO2 permeation, the hydrophobic central pore provides a more suitable pathway for gas molecules compared to other AQP5 channels. Although CO2 molecules can also permeate across AQP5 water channels, the rate of CO2 permeation through four channels of the AQP5 monomers is much lower than the central pore. The rate of CO2 permeation through four AQP5 water channels is even lower than CO2 diffusion through POPE lipid membrane. The results reported in this investigation demonstrate that MD simulations of human AQP5 provide valuable insights into the gas permeation mechanism for both the equilibrium self-diffusion, and quasi-equilibrium condition.

Magnetic aerosol drug targeting in lung cancer therapy using permanent magnet.

Primary bronchial cancer accounts for almost 20% of all cancer death worldwide. One of the emerging techniques with tremendous power for lung cancer therapy is magnetic aerosol drug targeting (MADT). The use of a permanent magnet for effective drug delivery in a desired location throughout the lung requires extensive optimization, but it has not been addressed yet. In the present study, the possibility of using a permanent magnet for trapping the particles on a lung tumor is evaluated numerically in the Weibel's model from G0 to G3. The effect of different parameters is considered on the efficiency of particle deposition in a tumor located on a distant position of the lung bronchi and bronchioles. Also, the effective position of the magnetic source, tumor size, and location are the objectives for particle deposition. The results show that a limited particle deposition occurs on the lung branches in passive targeting. However, the incorporation of a permanent magnet next to the tumor enhanced the particle deposition fraction on G2 to up to 49% for the particles of 7 µm diameter. Optimizing the magnet size could also improve the particle deposition fraction by 68%. It was also shown that the utilization of MADT is essential for effective drug delivery to the tumors located on the lower wall of airway branches given the dominance of the air velocity and resultant drag force in this region. The results demonstrated the high competence and necessity of MADT as a noninvasive drug delivery method for lung cancer therapy.

Maximum Spreading and Rebound of a Droplet Impacting onto a Spherical Surface at Low Weber Numbers.

The spreading and rebound patterns of low-viscous droplets upon impacting spherical solid surfaces are investigated numerically. The studied cases consider a droplet impinging onto hydrophobic and superhydrophobic surfaces with various parameters varied throughout the study, and their effects on the postimpingement behavior are discussed. These parameters include impact Weber number (through varying the surface tension and impingement velocity), the size ratio of the droplet to the solid surface, and the surface contact angle. According to the findings, the maximum spreading diameter increases with the impact velocity, with an increase of the sphere diameter, with a lower surface wettability, and with a lower surface tension. Typical outcomes of the impact include (1) complete rebound, (2) splash, and (3) a final deposition stage after a series of spreading and recoiling phases. Finally, a novel, practical model is proposed, which can reasonably predict the maximum deformation of low Reynolds number impact of droplets onto hydrophobic or superhydrophobic spherical solid surfaces.

Forced diffusion of water molecules through aquaporin-5 biomembrane; a molecular dynamics study.

Aquaporins (AQPs) are protein channels located across the cell membrane which conduct the water permeation through the cell membrane. Different types of AQPs exist in human organs and play vital roles, as the malfunction of such protein membranes can lead to life-threatening conditions. A specific type of AQP, identified as AQP5, is particularly essential to the generation of saliva, tears and pulmonary secretions. We have adopted Molecular Dynamics (MD) simulation to analyze the water permeation and diffusion in AQP5 structure in a 0.5 microsecond simulation time window. The MD numerical simulation shows the water permeability of the human AQP5 is in the nominal range for other members of human aquaporins family. In addition, we have considered the effect of the osmotic water diffusion and the diffusion occurred by pressure gradient on the protein membrane. The water permeability grows monotonically as the applied pressure on the solvent increases. Furthermore, the forced diffusion increases the minimum radius of Selectivity Filter (SF) region of region AQP5 up to 20% and consequently the permeability coefficients enhance enormously compared to osmotic self-diffusion in AQP5 tetramer. Finally, it is revealed that the MD simulation of human AQP5 provides useful insights into the mechanisms of water regulation through alveolar cells under the different physical conditions; osmotic self-diffusion and forced diffusion condition.

Delivery of magnetic micro/nanoparticles and magnetic-based drug/cargo into arterial flow for targeted therapy.

Magnetic drug targeting (MDT) and magnetic-based drug/cargo delivery are emerging treatment methods which attracting the attention of many researchers for curing different cancers and artery diseases such as atherosclerosis. Herein, computational studies are accomplished by utilizing magnetic approaches for cancer and artery atherosclerosis drug delivery, including nanomagnetic drug delivery and magnetic-based drug/cargo delivery. For the first time, the four-layer structural model of the artery tissue and its porosity parameters are modeled in this study which enables the interaction of particles with the tissue walls in blood flow. The effects of parameters, including magnetic field strength (MFS), magnet size, particle size, the initial position of particles, and the relative magnetic permeability of particles, on the efficacy of MDT through the artery walls are characterized. The magnetic particle penetration into artery layers and fibrous cap (the covering layer over the inflamed part of the artery) is further simulated. The MDT in healthy and diseased arteries demonstrates that some of the particles stuck in these tissues due to the collision of particles or blood flow deviation in the vicinity of the inflamed part of the artery. Therefore the geometry of artery and porosity of its layers should be considered to show the real interaction of particles with the artery walls. Also, the results show that increasing the particles/drug/cargo size and MFS leads to more particles/drug/cargo retention within the tissue. The present work provides insights into the decisive factors in arterial MDT with an obvious impact on locoregional cancer treatment, tissue engineering, and regenerative medicine.

Missed Opportunity to Deprescribe: Docusate for Constipation in Medical Inpatients.

BACKGROUND: Hospital admissions provide an opportunity to deprescribe ineffective medications and reduce pill burden. Docusate sodium is a stool softener that is frequently prescribed to treat constipation despite poor evidence for efficacy, thus providing a good target for deprescription. The aims of this study were to characterize rates of use and discontinuation of docusate among internal medicine inpatients, as well as use of other laxatives. METHODS: We conducted a retrospective observational study over 1 year on all patients admitted to internal medicine at 2 urban academic hospitals to determine rates of docusate use. We also evaluated laxative and opioid medication use on a random sample of 500 inpatients who received docusate to characterize patterns of prescription and deprescription. RESULTS: Fifteen percent (1169/7581) of all admitted patients received 1 or more doses of docusate. Among our random sample, 53% (238/452) received docusate before admission, and only 13% (31/238) had docusate deprescribed. Among patients not receiving docusate before admission, 33.2% (71/214) received a new prescription for docusate on discharge. Patients receiving opioids were frequently prescribed no laxatives or given docusate monotherapy (28%, 51/185). CONCLUSIONS: Docusate was frequently prescribed to medical inpatients despite its known ineffectiveness, with low deprescription and high numbers of new prescriptions. Docusate use was common even among patients at high risk of constipation. One third of patients not receiving docusate before admission were prescribed docusate on discharge, potentially exacerbating polypharmacy. Among patients already receiving docusate, 80% had it continued on discharge, indicating significant missed opportunities for deprescribing. Given the availability of effective alternatives, our results suggest that quality-improvement initiatives are needed to promote evidence-based laxative use in hospitalized patients.

Numerical investigation of molecular nano-array in potential-energy profile for a single dsDNA.

A Rigorous numerical investigation on dsDNA translocation in quasi-2-dimensional nano-array filter is performed using Molecular Dynamics (MD) method. Various dsDNA molecules with different sizes are chosen in order to model Ogston sieving in a nano-array filter. The radius of gyration of dsDNA molecule is less than the characteristic length of the shallow region in nano-array. The dsDNA molecule is assumed to be in the 0.05M NaCl electrolyte. MD shows acceptable results for potential-energy profile for nano-array filter. According to the MD outcomes, the dsDNA electrophoretic mobility decreases almost linearly with dsDNA size and show the same trend as Ogston sieving for gel electrophoresis. In addition, different shapes for nano-array filter are studied for a unique dsDNA molecule. It is concluded that steeping the nano-array wall can cause the retardation of dsDNA translocation and decreases dsDNA electrophoretic mobility.

Rigorous study of molecular dynamics of a single dsDNA confined in a nanochannel: Introduction of a critical mobility behaviour.

The essential and effective characteristics of a double-stranded DNA (dsDNA) confined in a nanochannel is revisited by employing the rigorous full numerical approach of Molecular Dynamics (MD). The deformation of dsDNA and wall-biomolecule interaction which is critical in highly confined regime has been precisely imposed in numerical simulations. The numerical approach has been justified against available theoretical outcomes. A new and general expression for DNA electrophoretic mobility versus DNA length is extracted from numerical simulation which is out of reach of experimental methods due to practical shortcomings. The newly derived expression suggests an essential correction in the previously proposed expression for the critical case of small DNA molecules and reveals an astonishingly unbeknown trend of small DNA's mobility. Sub-molecular phenomenon of dsDNA melting under the condition of large external force is also studied. Assuming strong electric field exertion, the MD approach aptly demonstrates the elaborate melting phenomenon for dsDNA in sub-molecular scale.