Efficient Drug Delivery System Research Articles

Cholesterol concentration effect on bilayer membranes and its role in designing efficient liposomal drug delivery systems.

Liposomal drug delivery systems provide a versatile therapeutic platform for treating numerous diseases. Cholesterol, as a common component of many liposomal drug delivery systems, plays a crucial role in enhancing mechanical strength and decreasing the permeability of biomembranes. However, the ratio required for a proper formulation is poorly recognized. In this study, all-atom molecular dynamics simulations are performed to characterize the effect of cholesterol concentration in bilayers. To prepare liposomes, we simulate DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine) phospholipid combined with different molar ratios of cholesterol (100, 80-20, 70-30, and 60-40%) in both planar and spherical bilayers. Furthermore, it has been quantified how a range of bilayer properties, including area per lipid, leaflet interdigitation, membrane thickness, and lipid Scd order parameters, are altered by variation in concentrations of lipid and cholesterol. Therefore, the most suitable amount of cholesterol and lipid to prepare stable and controlled drug release vehicles is obtained by screening the lipid and cholesterol ratio arrangement. Compared to membranes without cholesterol, the influence of cholesterol on lipid bilayers is revealed. These results provide a better understanding of the fundamental characteristics of the structure and dynamics of cholesterol-containing membranes. By revealing molecular details of interactions between cholesterol and phospholipids, these simulations accurately represent atomic-level characteristics of the planar and spherical bilayers. The simulations presented here shed light on the workings and limitations of liposomal drug delivery technology and establish a computational framework for the rational design of liposomes in drug delivery systems.

Hyperbranched Nanostructure Drug Delivery Carrier: Dendrimer

Abstract: Dendrimers are nanosized macromolecules with a hyperbranched globular shape that are commonly employed for drug delivery. They have shown to be both complex and valuable due to their high level of surface functioning, adaptability, and unique features. Furthermore, dendrimers have a wide range of applications in supramolecular chemistry, mainly in self-assembly processes. The potential of this macromolecule to construct a definite architectural design in terms of size, shape, branching length, density, and its well-defined molecular structure and segmented spherical construction has sparked a wide range of research on the interactions that occur between biological organisms. Dendrimers are "grown" from a central core in a repetitive divergent manufacturing process, with each succeeding step representing a new "generation" of the dendrimer. In comparison to linear polymers, dendrimers have more precisely controlled structures, globular in shape, and have a specific molecular weight rather than a range of molecular weights. The divergence in dendritic structure customization provides a one-of-a-kind framework for drug delivery to acute and chronic diseases. The development of efficient drug delivery systems based on dendrimers has attracted much interest in recent years. This review aims to discuss some important perspectives and recent patents regarding dendrimers.

Application of zinc oxide nano-tube as drug-delivery vehicles of anticancer drug

Zinc oxide nano-tube (ZnONT) nano-structures, which possess chemical stability and non-toxicity in the human body, are considered promising for delivering different drugs. Within this work, we scrutinized the drug delivery capability of the ZnONT and its adsorptional properties as a drug delivery vehicle (DDV) for hydroxyurea (HU) as an anti-cancer drug through density functional theory along with the solvent impacts. Based on the optimized structures, it can be suggested that Zn atoms of ZnONT are the ideal sites on this nano-tube for the adsorption of HU. HU had a strong physical adsorption through the O atom of carbonyl groups onto the local pyramidal site of the ZnONT. At 1.96 Å and Ead of -39.28 kcal/mol, in the configuration which was favorable in terms of energy, there was an interaction between the O atoms of -C=O group of the drug and a Zn atom of the ZnONT. In order to scrutinize the excited state properties of the HU-ZnONT complex, we also examined the UV/Vis data of the HU/ZnONT interaction system. Following the adsorption of HU onto the surface of the ZnONT, there was a significant red-shift based on the maximum absorption wavelength, showing that the ZnONT is an ideal candidate for optic sensors in order to detect and monitor the drug molecule. HU could be released in the cancer tissues where pH was low based on the drug release mechanism. The current work thoroughly investigated the mechanism of interaction between the ZnONT and HU, showing that ZnONT can be used for the smart drug delivery of HU. Overall, the findings suggest that ZnONT could be used as an efficient drug-delivery system for the HU drug to treat various types of cancer. In this work we used B3LYP-gCP-D3 functional and the basis set LANL2DZ on the transition metal (Zn) and the basis set cc-pVDZ on the others. GAMESS software program was employed for performing the calculations. we performed analyses, including charge transport, molecular electrostatic potential surface (MEP), energetic, electronic, natural bond orbitals (NBOs), and structural optimizations.

Trend in biodegradable porous nanomaterials for anticancer drug delivery.

In recent years, biodegradable nanomaterials have exhibited remarkable promise for drug administration to tumors due to their high drug-loading capacity, biocompatibility, biodegradability, and clearance. This review will discuss and summarize the trends in utilizing biodegradable nanomaterials for anticancer drug delivery, including biodegradable periodic mesoporous organosilicas (BPMOs) and metal-organic frameworks (MOFs). The distinct structure and features of BPMOs and MOFs will be initially evaluated, as well as their use as delivery vehicles for anticancer drug delivery applications. Then, the themes for the development of each material will be utilized to illustrate their drug delivery performance. Finally, the current obstacles and potential for future development as efficient drug delivery systems will be thoroughly reviewed. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

Computational Study of the Interaction of C12P12 and C12N12 Nanocages with Alendronate Drug Molecule

AbstractThe utilization of nanomaterials as efficient delivery systems to specific metabolic sites is essential for harnessing the utmost therapeutic potency of drugs leading to a tremendous quest in the design of efficient drug delivery systems. In this present study, appropriate level of quantum chemical calculation by applying DFT/ωB97XD/6‐311G+ (d, p) method was utilized to investigate the effectiveness of C12N12, and C12P12 nanocages as delivery systems for alendronate drug. The properties of an ideal nano‐delivery system with regards to potential constraints during fabrication are being considered. The highest adsorption energy in C12N12 was observed in interaction site CN_CH −7.355 eV while interaction site CP_CH was observed with the highest Eads −3.518 eV for C12P12. These interaction sites in studied nanocages are suitable for the delivery of alendronate to target site. Our results for energy gap show that studied nanocages are good for the delivery of alendronate drug. The natural bond orbital analysis confirms nanocages and various interactions to be stable. Non‐covalent interaction and quantum theory of atoms in molecules were used to probe the effectiveness of the nanomaterials as delivery materials and confirms strong interaction between drug alendronate and nanocages.

Rational design of magnetoliposomes for enhanced interaction with bacterial membrane models

There is a growing need for alternatives to target and treat bacterial infection. Thus, the present work aims to develop and optimize the production of PEGylated magnetoliposomes (MLPs@PEG), by encapsulating superparamagnetic iron oxide nanoparticles (SPIONs) within fusogenic liposomes. A Box–Behnken design was applied to modulate size distribution variables, using lipid concentration, SPIONs amount and ultrasonication time as independent variables. As a result of the optimization, it was possible to obtain MLPs@PEG with a mean size of 182 nm, with polydispersity index (PDI) of 0.19, and SPIONs encapsulation efficiency (%EE) around 76%. Cytocompatibility assays showed that no toxicity was observed in fibroblasts, for iron concentrations up to 400μg/ml. Also, for safe lipid and iron concentrations, no hemolytic effect was detected. The fusogenicity of the nanosystems was first evaluated through lipid mixing assays, based on Förster resonance energy transfer (FRET), using liposomal membrane models, mimicking bacterial cytoplasmic membrane and eukaryotic plasma membrane. It was shown that the hybrid nanosystems preferentially interact with the bacterial membrane model. Confocal microscopy and fluorescence lifetime measurements, using giant unilamellar vesicles (GUVs), validated these results. Overall, the developed hybrid nanosystem may represent an efficient drug delivery system with improved targetability for bacterial membrane.

Changes in Membrane Lipid Order of Cells by Optimized Microplasma Irradiation for High-Molecule Drug Absorption

Microplasma-based drug delivery, particularly transdermal drug delivery, has emerged as a promising alternatives to conventional methods due to its unique advantages. In this system, plasma components interact not only with the stratum corneum but also with the cells beneath it. Cell membranes mainly comprise lipids which are highly susceptible to plasma components, including reactive oxygen and nitrogen species. However, the effects of microplasma irradiation on cell membrane lipids are largely unexplored. In this context, the current study investigated an important physical property of cell membranes, membrane lipid order, in small intestinal epithelial cells after microplasma irradiation. First, the microplasma irradiation condition was optimized for the intracellular delivery of high molecular weight molecules, namely fluorescein isothiocyanate-dextran (FD-150 and FD-2000). Air microplasma discharge was applied at varying voltages (i.e., 3.5, 4.0, and 4.5 kV), and the efficiency of drug absorption was evaluated using a microplate reader and a fluorescence microscope. The cell viability was calculated using an automated cell counter. The most favorable outcomes in terms of both drug absorption and cell viability were achieved at 4 kV. Next, the membrane lipid order of cells was investigated using a solvatochromic dye after microplasma irradiation at 4 kV. Interestingly, non-irradiated cells exclusively manifested the liquid-ordered phase, whereas irradiated cells displayed a dual-phased composition comprising both liquid-ordered and liquid-disordered phases. In addition, live-cell imaging unveiled that alterations in membrane lipid order commenced as early as 4 min post-irradiation. This evidence points to a significant reduction in lipid packing and membrane thickness induced by microplasma irradiation. The findings shed light on the intricate mechanism underlying cellular drug absorption facilitated by microplasma irradiation. The insights gained into the impact on membrane lipid properties will contribute to developing safe and efficient drug delivery systems while minimizing side effects.

Biomaterial-based strategies for immunomodulation in IBD: current and future scenarios.

Instinctive gastrointestinal inflammatory conditions with persistent intestinal inflammation are known as "inflammatory bowel diseases" (IBDs). IBDs are growing progressively common throughout the world although it is still unclear what causes them. IBDs that cause recurrent, intermittent, and disburse inflammatory responses, may also have systemic symptoms such as ulcerative colitis and Crohn's disease. It has been discovered that a number of medications, including antibiotics, corticosteroids, and immune-suppressants, can promote mucous and damaged epithelial restoration. The incidences of general and specific therapy failure in IBD continue to climb, even though the availability of advanced biologics including anti-interleukins, anti-integrins, anti-tumor necrosis factor (anti-TNF), and small molecules such as tofacitinib exist. Management therapies that are currently being researched include specifically JAK (janus kinase) inhibitors, anti-IL (anti-interleukin) (IL-12, IL23), and leukocyte inhibitors such as sphingosine-1-phosphate receptors. Clinical treatments can have various adverse effects. In order to give pharmacological drugs to the disease-specific sites with improved efficacy and fewer complications, innovative frameworks centered on biomaterials are needed. We provide an outlook on the current state of several biomaterials used to treat IBD. This article comprehensively addresses numerous microparticles, nanoparticles, and hydrogels that have recently been made from natural bio-polymers and lipids. To support colon-specific target delivery and steady release of medications during IBD therapies, these various biomaterial-based monotherapies could be employed as efficient drug delivery systems.

Probing the Synergistic Effect of Antibacterial Drug and Oleic Acid in Lipid-based Gastroretentive Matrices by Melt Molding Method.

Clarithromycin (antibiotic), due to its narrow absorption window in the gastrointestinal tract, was taken as a model drug. Focusing on the efficient drug delivery system, floating tablets that remain buoyant over gastric fluid for 24 hrs were produced by adopting the melt mold method using beeswax, gelucire, and oleic acid. To modulate the release pattern, a different concentration of 48/16 of beeswax and gelucire was used. To evaluate and characterize the final product, several tests, including the percentage recovery, in-vitro release studies, clarithromycin loading, scanning electron microscopy, differential scanning calorimeter, X-ray powder diffractometry, fourier transform infrared spectroscopy, weight variation, hardness, and friability, were carried out. Regarding the results, the encapsulation efficiency of the floating tablets was 39.5% to 59%, having weight variation with and without gelucire as 48/16 0.09525±0.0032g, and 0.09527±0.00286g to 0.0957±0.00321g, respectively. Clarithromycin release was controlled by using hydrophobic beeswax and hydrophilic gelucire 48/16. X-ray powder diffractometry, differential scanning calorimeter, and fourier transform infrared spectroscopy confirmed the absence of drug-polymer interaction, and exhibited amorphous and crystalline form of the drug after encapsulation. Drug release kinetics was determined by applying different models, such as zero-order, first-order model, Higuchi, and Korsemeyer-Pappas model. All formulations followed the Korsmeyer- Peppas model at 1.2 pH. Gastroretentive drug delivery systems were produced by using melt molding technique. In vitro dissolution represents the sustained release of the drug from the formulation.

Adsorption of Favipiravir on pristine graphene nanosheets as a drug delivery system: a DFT study.

The efficiency of pristine graphene (GN) in the delivery process of the Favipiravir (FPV) anti-COVID-19 drug was herein revealed within the FPV⋯GN complexes in perpendicular and parallel configurations in terms of the density functional theory (DFT) method. Adsorption energy findings unveiled that the parallel configuration of FPV⋯GN complexes showed higher desirability than the perpendicular one, giving adsorption energy up to -15.95 kcal mol-1. This favorability could be interpreted as a consequence of the contribution of π-π stacking to the overall strength of the adsorption process in the parallel configuration. Frontier molecular orbitals (FMO) findings demonstrated the ability of the GN nanosheet to adsorb the FPV drug by the alteration in the EHOMO, ELUMO, and Egap values before and after the adsorption process. Based on Bader charge results, the FPV drug and GN sheet exhibited electron-donating and -accepting characters, respectively, which was confirmed by the negative sign of the computed charge transfer (Qt) values. The FPV(R)⋯T@GN complex showed the most desirable Qt value of -0.0377e, which was in synoptic with the adsorption energy pattern. Electronic properties of GN were also altered after the adsorption of the FPV drug in both configurations, with more observable changes in the parallel one. Interestingly, the Dirac point of the GN sheet coincided with the Fermi level after the adsorption process, indicating that the adsorption process unaffected the presence of the Dirac point. The occurrence of the adsorption process was also noticed by the existence of new bands and peaks in the band structure and DOS plots, respectively. Short recovery time rendered the GN nanosheet an efficient FPV drug delivery system. The obtained findings provide new insight into the biomedical applications of the GN sheet as a promising drug delivery system.

Design and fabrication of intracellular therapeutic cargo delivery systems based on nanomaterials: current status and future perspectives.

Intracellular cargo delivery, the introduction of small molecules, proteins, and nucleic acids into a specific targeted site in a biological system, is an important strategy for deciphering cell function, directing cell fate, and reprogramming cell behavior. With the advancement of nanotechnology, many researchers use nanoparticles (NPs) to break through biological barriers to achieving efficient targeted delivery in biological systems, bringing a new way to realize efficient targeted drug delivery in biological systems. With a similar size to many biomolecules, NPs possess excellent physical and chemical properties and a certain targeting ability after functional modification on the surface of NPs. Currently, intracellular cargo delivery based on NPs has emerged as an important strategy for genome editing regimens and cell therapy. Although researchers can successfully deliver NPs into biological systems, many of them are delivered very inefficiently and are not specifically targeted. Hence, the development of efficient, target-capable, and safe nanoscale drug delivery systems to deliver therapeutic substances to cells or organs is a major challenge today. In this review, on the basis of describing the research overview and classification of NPs, we focused on the current research status of intracellular cargo delivery based on NPs in biological systems, and discuss the current problems and challenges in the delivery process of NPs in biological systems.

Microstructured drug-delivery systems as solid dispersions using peg 6000 and polysorbate 80 containing hydrochlorothiazide: development, synthesis, and physicochemical and morphological characterization

Bioavailability indicates the speed of dissolution and absorption of the drug by its active site, characterization of the potential pharmacological effect, dosage of a medication, and the effectiveness of treatment. Microstructured systems make it possible to increase the efficiency of drug release and absorption processes that have low solubility in physiological media and are extremely important in the area of ​​drug development and new pharmaceutical forms. The drug containing hydrochlorothiazide, distributed by RENAME and widely used for the treatment of arterial hypertension is classified as poorly permeable and poorly soluble, thus having low absorption and bioavailability, which requires administration of high doses to generate side effects. and lack of treatment adherence. The application of a microstructured drug-delivery system in the form of a solid dispersion containing hydrochlorothiazide, a lipophilic drug, dispersed in a solid matrix found by the hydrophilic carriers PEG 6000 (polyethylene glycol) and polysorbate80, given the increased solubility, dissolution profile and consequently the bioavailability of the drug. The system was extended physically-chemically and morphologically utilizing testicles such as scanning electron microscopy (SEM), in addition to thermogravimetry (TGA), differential scanning calorimetry (DSC), and infrared absorption spectroscopy, with satisfactory results in that region. formation of an efficient and innovative drug delivery system.

Tailoring Lipid-Based Drug Delivery Nanosystems by Synchrotron Small Angle X-ray Scattering.

Thanks to specific physico-chemical properties, drug delivery systems based on nanoparticles have proven to effectively transport delicate molecules for therapeutic purposes, protecting them from degradation, increasing their stability in the blood circulation and allowing to convey and release the transported substances in specific areas of the body. Nanoparticles obtained from biopolymers for applications in medicine and pharmaceutics have become particularly popular in recent years due to the enormous research effort in the field of vaccines to respond to the pandemic emergency. Among the various types of biopolymers used to produce nanoparticles for therapeutics, lipids have characteristics that make them biocompatible, with low toxicity and ease of clearance. They can be synthesized by designing their characteristics according to the foreseen administration path, or to the target of the transported drug. The analytical methods mostly used to evaluate the characteristics of lipid nanosytems for drug delivery involve studying their effects on cells, in vitro and in vivo. Although it is often considered a "niche technique" for research in the bio-related sciences, Small Angle X-ray Scattering (SAXS) is a versatile tool to study the structure of nanosystems based on lipids, both ex situ and in situ. Therefore, it allows to evaluate both the effect of the different synthesis parameters and of the exposure of lipid nanoparticles to physiological conditions, which is of fundamental importance to design efficient drug delivery systems. In this mini-review, we will report some recent examples of characterization and design of nanoparticles based on lipids, where SAXS has been a fundamental step both to guide the synthesis of nanomaterials with tailored characteristics, and to understand the interaction between nanomaterials and cells.

Insights into Drug-Loading Capacity of Bio-Zirconium Metal-Organic Frameworks Nanoparticles for Tetracycline Hydrochloride

The discovery of a highly efficient drug delivery system with high biocompatibility and good loading/release properties is a key challenging issue. In the past decade, metal-organic frameworks (MOFs) have shown great interest as drug delivery systems (DDSs), due to their high porosity, tunable functionality, and large drug loading capacities. Herein, we report the potential use of a new family of biocompatible MOFs called bio-MOFs synthesized from bio-based ligands and water-based synthesis for drug delivery. We propose a facile method to synthesize MIP-202 (bio-based Zr-MOF) built from Zr metal nodes and aspartic acid as an amino acid ligand. The efficiency of loading tetracycline hydrochloride drug onto MIP-202 and UiO-66-NH2 has been carefully studied. Characterization techniques such as powder X-ray diffraction, and transmission electron microscopy have been used for structural and morphological confirmation. The loading capacity of tetracycline hydrochloride on UiO-66-NH2 was determined to be higher than MIP-202 reaching up to 50.3%. The results provide an investigated insight into the utilization of bio-based MOFs as drug carriers for tetracycline hydrochloride.

Tumor microenvironment penetrating chitosan nanoparticles for elimination of cancer relapse and minimal residual disease.

Chitosan and its derivatives are among biomaterials with numerous medical applications, especially in cancer. Chitosan is amenable to forming innumerable shapes such as micelles, niosomes, hydrogels, nanoparticles, and scaffolds, among others. Chitosan derivatives can also bring unprecedented potential to cross numerous biological barriers. Combined with other biomaterials, hybrid and multitasking chitosan-based systems can be realized for many applications. These include controlled drug release, targeted drug delivery, post-surgery implants (immunovaccines), theranostics, biosensing of tumor-derived circulating materials, multimodal systems, and combination therapy platforms with the potential to eliminate bulk tumors as well as lingering tumor cells to treat minimal residual disease (MRD) and recurrent cancer. We first introduce different formats, derivatives, and properties of chitosan. Next, given the barriers to therapeutic efficacy in solid tumors, we review advanced formulations of chitosan modules as efficient drug delivery systems to overcome tumor heterogeneity, multi-drug resistance, MRD, and metastasis. Finally, we discuss chitosan NPs for clinical translation and treatment of recurrent cancer and their future perspective.

NMR Studies on the Interaction of Anticancer Drug Doxorubicin with Membrane Mimetic SDS.

In the formulation of efficient drug delivery systems, it is essential to unravel the structural and dynamical aspects of the drug's interaction with biological membranes. This has been done for the anticancer drug-membrane system comprising doxorubicin hydrochloride (DOX), a water-soluble anticancer drug, and the micellar sodium dodecyl sulfate (SDS), the latter serving as a useful mimic for membrane proteins. Using a multimodal NMR approach involving 1H, 2H, and 13C as probe nuclei and through the determination of chemical shifts, spin-relaxation, nuclear Overhauser enhancements (NOE), and translational self-diffusion (SD), the binding characteristics of the DOX with SDS have been determined. The perturbation to 13C chemical shifts of SDS indicate the penetration of DOX into the SDS micelle, which is further revealed by 1H-1H NOESY and SD measurements. 2H spin-relaxation measurements and their analysis using a two-step model show DOX induced SDS micellar volume changes, which determine the correlation times involved in the DOX-SDS mobility.

Development of a Eudragit-Chitosan Nanosystem for the pH-Dependent Transport of Duloxetine to the Brain: Synthesis, Characterization and In Silico Modeling Analysis

The purpose of this study was to synthesize duloxetine (DLX)- loaded Eudragit-Chitosan (Eud-CHT) nanoparticles enclosed in an oral gelatin capsule and to evaluate the potential to transport DLX to the blood-brain barrier (BBB)for improved neuro-availability. The utilization of Eudragit® with chitosan offers a pH-dependent controlled drug release. The physicochemical properties of the formulated DLX-loaded Eud-CHT nanosystem were confirmed using various characterization techniques. SEM confirmed the nanoparticle morphology and pore size distribution. The particle size was 100 ± 73,41 nm, with a polydispersity index (PDI) of 0,283 and zeta potential of 16±2,79 mV. Drug entrapment efficacy (DEE) of 72% was attained, and molecular modelling predicted an efficient and controllable drug delivery system. The release of DLX from the nanosystem was evaluated at pH1.2, pH 6.8 and pH 7.4. At a pH of 6.8, 40 % of DLX was released, with only 20 % at pH 1.2 and 35% at pH 7.4. This demonstrated DLX's pH-dependent release and the Eud-CHT nanosystem's shielding effect at gastric pH. In addition, HEK 293 neural cells confirmed the non-toxicity of the DLX-Eud-CHT nanosystem. In silico modelling revealed a DLX-Eud-CHT composite with an outer cationic surface attributable to the EUD moieties on nanoparticles for preferential cell recognition and uptake at the anionic cell interface. The combined trials and results from the synthesis of DLX-Eud-CHT nanoparticles showed that these nanoparticles could be utilized as a potentially invaluable formulation for oral drug delivery of duloxetine with improved neuro-availability.

In Vivo Evaluation of the Anti-Schistosomal Potential of Ginger-Loaded Chitosan Nanoparticles on Schistosoma mansoni: Histopathological, Ultrastructural, and Immunological Changes.

Chemotherapy is the most widely advocated method of Schistosome control. However, repeated chemotherapy leads to the emergence of drug-resistant Schistosoma strains. Therefore, efforts to find alternative drugs, especially those of natural origin, have risen globally. Nanoparticles (NPs) have received special interest as efficient drug delivery systems. This work aimed to investigate the anti-schistosomal potential of Zingiber officinale (ginger, Zingiberaceae)-loaded chitosan nanoparticles (GCsNPs) on Schistosoma mansoni experimentally infected mice that were exposed to 80 ± 10 cercariae/mouse. The study groups are: (G1) negative control; (G2) positive control; (G3) praziquantel in a dose of 500 mg/kg/day for two consecutive days; (G4) ginger in a dose of 500 mg/kg treated; (G5) chitosan nanoparticles in a dose 3 mg/kg (G6) GCsNPs in a dose 250 mg/kg; and (G7) GCsNPs in a dose 500 mg/kg. The anti-schistosome potential was assessed using histopathological scanning electron microscopically and immunological parameters. The results showed that there was a significant decrease in cellular granuloma count (p < 0.05) and granuloma diameter (p < 0.001) in all infected treated mice groups, in comparison to the infected non-treated group with the highest reduction in both G3 and G7. SEM of S. mansoni adult worm recovered from G3 showed mild edema of oral and ventral suckers with some peeling and blebs around them, while that recovered from G7 showed abnormal oedematous oral and retracted ventral sucker, edema of the tegument, rupture of many tubercles with vacuolation and complete loss of spines. All infected treated mice groups, in comparison to positive control G2, showed a significant reduction in IL-4, IL-10, and TNF-α levels (p-value < 0.001), especially groups G6 and G7 (p-value < 0.05); both G6 and G7 values were nearer to the normal that indicated recovery of the liver tissue.

Molecular Docking and Intracellular Translocation of Extracellular Vesicles for Efficient Drug Delivery.

Extracellular vesicles (EVs), including exosomes, mediate intercellular communication by delivering their contents, such as nucleic acids, proteins, and lipids, to distant target cells. EVs play a role in the progression of several diseases. In particular, programmed death-ligand 1 (PD-L1) levels in exosomes are associated with cancer progression. Furthermore, exosomes are being used for new drug-delivery systems by modifying their membrane peptides to promote their intracellular transduction via micropinocytosis. In this review, we aim to show that an efficient drug-delivery system and a useful therapeutic strategy can be established by controlling the molecular docking and intracellular translocation of exosomes. We summarise the mechanisms of molecular docking of exosomes, the biological effects of exosomes transmitted into target cells, and the current state of exosomes as drug delivery systems.

Quantitative Model Analysis and Simulation of Pharmacokinetics and Metastasis-Associated Lung Adenocarcinoma 1 RNA Knockdown Effect After Systemic Administration of Cholesterol-Conjugated DNA/RNA Heteroduplex Oligonucleotide Crossing Blood-Brain Barrier of Mice.

The cholesterol-conjugated heteroduplex oligonucleotide (Chol-HDO) is a double-stranded complex; it comprises an antisense oligonucleotide (ASO) and its complementary strand with a cholesterol ligand. Chol-HDO is a powerful tool for achieving target RNA knockdown in the brains of mice after systemic injection. Here, a quantitative model analysis was conducted to characterize the relationship between the pharmacokinetics (PK) and pharmacodynamics (PD), non-coding RNA metastasis-associated lung adenocarcinoma 1 (Malat1) RNA, of Chol-HDO, in a time-dependent manner. The established PK model could describe regional differences in the observed brain concentration-time profiles. Incorporating the PD model enabled the unique knockdown profiles in the brain to be explained in terms of the time delay after single dosing and enhancement following repeated dosing. Moreover, sensitivity analysis of PK exposure/persistency, target RNA turnover, and knockdown potency identified key factors for the efficient and sustained target RNA knockdown in the brain. The simulation of an adequate dosing regimen quantitatively supported the benefit of Chol-HDO in terms of achieving a suitable dosing interval. This was achieved via sufficient and sustained brain exposure and subsequent strong and sustained target RNA knockdown in the brain, even after systemic injection. The present study provides new insights into drug discoveries and development strategies for HDO in patients with neurogenic disorders. SIGNIFICANCE STATEMENT: The quantitative model analysis presented here characterized the PK/PD relationship of Chol-HDO, enabled its simulation under various conditions or assumptions, and identified key factors for efficient and sustained RNA knockdown, such as PK exposure and persistency. Chol-HDO appears to be an efficient drug delivery system for the systemic administration of desired drugs to brain targets.