Drug Diffusion Research Articles

Comprehensive Review on Phytoconstituents-based Nanomedicine for the Treatment of Atopic Dermatitis.

Atopic dermatitis (AD) is known as a chronic disease characterized by eczematous and pruritus skin lesions. The pathology behind atopic dermatitis etiology is loss of epidermal barrier, which prevents the production of protein filaggrin that can induce T-cell infiltration and inflammation. Treatment of AD is majorly based on limiting skin repair as well as reducing inflammation and itching. There are several remedies available for the treatment of AD, such as Janus kinase and calcineurin inhibitors, topical corticosteroids, and phosphodiesterase-4 inhibitors. The conventional formulations in the market have limited safety and efficacy. Hence, effective treatment of atopic dermatitis requires the development of novel, efficacious, reliable, and specific therapies. Recent research data have revealed that some naturally occurring medicinal plants have potential applications in the management of AD through different mechanisms. The nanotechnology-based therapeutics have gained a lot of attention in the last decade for the improvement in the activity of drugs having low absorption due to poor solubility, thus leading to lesser bioavailability. Therapies based on nanotechnology can be an effective way to overcome these obstacles. Due to their effective propensity to provide better drug diffusion and bioavailability as well as drug targeting potential at the desired site of action, these approaches may have decreased adverse drug effects, better penetration, and enhanced therapeutic efficacy. Hence, this review highlights the potential of phytoconstituents-based novel formulations for the treatment of atopic dermatitis. Furthermore, recent patents on therapeutic approaches to atopic dermatitis have also been briefly described.

Effects of buoyancy on the dispersion of drugs released intrathecally in the spinal canal.

This paper investigates the transport of drugs delivered by direct injection into the cerebrospinal fluid (CSF) that fills the intrathecal space surrounding the spinal cord. Because of the small drug diffusivity, the dispersion of neutrally buoyant drugs has been shown in previous work to rely mainly on the mean Lagrangian flow associated with the CSF oscillatory motion. Attention is given here to effects of buoyancy, arising when the drug density differs from the CSF density. For the typical density differences found in applications, the associated Richardson number is shown to be of order unity, so that the Lagrangian drift includes a buoyancy-induced component that depends on the spatial distribution of the drug, resulting in a slowly evolving cycle-averaged flow problem that can be analysed with two-time scale methods. The asymptotic analysis leads to a nonlinear integro-differential equation for the spatiotemporal solute evolution that describes accurately drug dispersion at a fraction of the cost involved in direct numerical simulations of the oscillatory flow. The model equation is used to predict drug dispersion of positively and negatively buoyant drugs in an anatomically correct spinal canal, with separate attention given to drug delivery via bolus injection and constant infusion.

POLYSACCHARIDE BASED CONTROLLED RELEASE MUCOADHESIVE DRUG DELIVERY SYSTEM FOR PAIN MANAGEMENT

Mucoadhesion is one of the most extensively studied methods for the administration of medication for faster onset of action with enhanced bioavailability. Present investigation was concerned with the development and characterization of controlled release muco-adhesive drug delivery system for the drug Tramadol Hydrochloride (TRD) to extend the duration of analgesia for patients suffering from acute to chronic pain. Formulations were made using the solvent casting technique, incorporating natural polymers like Guar Gum, Xanthum Gum and Chitosan in conjunction with HPMC (hydroxy propyl methyl cellulose) to modify the drug release. The compatibility of film components were validated by Fourier Transform Infra- Red (FTIR) spectroscopy and subjected to physico-chemical evaluation parameters and ex-vivo drug diffusion study. Optimized formulation was tested for analgesic efficacy in vivo to determine extent of their suitability in therapeutic use. All the prepared formulations exhibited superior pharmaceutical qualities with respect to drug content, folding endurance, swelling index and mucoadhesion time. In ex-vivo drug diffusion study, all the films displayed a controlled release lasting longer than eight hours. Formulations containing Chitosan in combination with HPMC (F6) showed better controlled drug release over other combinations. The formulation F6 bring out remarkable in vivo analgesic efficacy with 58.10 % analgesia in contrast to the standard (61.16%). It was deduced that Tramadol hydrochloride mucoadhesive films were found to be an effective treatment for moderate to severe pain with a quick onset and a lengthy half-life.

Innovative transdermal doxorubicin patches prepared using greenly synthesized iron oxide nanoparticles for breast cancer treatment

ABSTRACT An innovative strategy was formulated to overcome the challenges in delivering doxorubicin (DOX) for breast cancer treatment. Transdermal patches were prepared using carbopol 971 (CP) and polyvinyl alcohol (PVA) loaded with starch-coated iron oxide nanoparticles conjugated to DOX (DOX@St-IONPs). The patches’ physicochemical properties, in vitro drug diffusion, alongside the physical properties of DOX@St-IONPs, and their impact on breast cancer cell lines’ viability were examined. The M1 patch, with a 1:1 CP:PVA ratio and DOX@St-IONPs, showed unique properties, indicating effective delivery. It maintained consistent thickness, weight, and 97% DOX loading. Demonstrated flexibility and acceptable surface pH. M1 displayed fivefold increased drug penetration compared to free DOX patches (flux of 14.85 µg/cm2/h and permeability of 0.95 cm/h), with higher cytotoxicity against triple-negative breast cancer. These results propose promising non-invasive DOX delivery through the developed patches.

Optimizing fluconazole-embedded transfersomal gel for enhanced antifungal activity and compatibility studies.

Fungal infections are of major concern all over the globe, and fluconazole is the most prevalently used drug to treat it. The goal of this research work was to formulate a fluconazole-embedded transfersomal gel for the treatment of fungal infections. A compatibility study between fluconazole and soya lecithin was performed by differential scanning calorimetry (DSC). Transfersomes were formulated by a thin-film hydration technique using soya lecithin and Span 80. A central composite design was adopted to prepare different formulations. Soya lecithin and Span 80 were chosen as independent variables, and the effect of these variables was studied on in vitro drug diffusion. Formulations were evaluated for entrapment efficiency and in vitro drug diffusion. The results of in vitro drug diffusion were analyzed using the analysis of variance (ANOVA) test. Optimized formulation was prepared based on the overlay plot and evaluated by scanning electron microscopy, DSC, vesicle size, polydispersity index (PDI), zeta potential, and in vitro drug diffusion studies. An optimized formulation was loaded into xanthan gum gel base and evaluated for pH, viscosity, in vitro and ex vivo drug diffusion, and antifungal activity. DSC studies revealed compatibility between fluconazole and soya lecithin. Entrapment efficiency and in vitro drug diffusion of various formulations ranged between 89.92% ± 0.20% to 97.28% ± 0.42% and 64% ± 1.56% to 85% ± 2.05%, respectively. A positive correlation was observed between in vitro drug diffusion and Span 80; conversely, a negative correlation was noted with soya lecithin. Entrapment efficiency, particle size, zeta potential, PDI, and drug diffusion of optimized formulation were 95.0% ± 2.2%, 397 ± 2nm, -38 ± 5mV, 0.43%, and 81 % ± 2%, respectively. SEM images showed well-distributed spherical-shaped transfersomes. In vitro, ex vivo drug diffusion and antifungal studies were conclusive of better diffusion and enhanced antifungal potential fluconazole in transfersomal formulation.

Pullulan-Based Spray-Dried Mucoadhesive Microparticles for Sustained Oromucosal Drug Delivery.

Mucoadhesive microparticles for oromucosal drug delivery offer several advantages, including intimate contact with the mucosa, delivery to less accessible regions, extended residence time, sustained drug release, reduced irritation, and improved patient compliance. In this study, pullulan was used to prepare mucoadhesive spray-dried microparticles for delivering benzydamine hydrochloride (BZH) to oral mucosa. The BZH-pullulan spray-dried microparticles had a mean size of <25 μm with an angle of repose values between 25.8-36.6°. Pullulan markedly extended drug-release time to >180 min, ~9 times greater than the duration (i.e., 20 min) reportedly achieved by chitosan. Kinetic analysis showed the drug-release rate was concentration dependent and jointly controlled by drug diffusion and polymer chain relaxation. Further, pullulan was mucoadhesive and was able to retain up to 78.8% w/w of microencapsulated gold nanoparticle probes at the mucosal membrane. These data strongly suggest that BZH-pullulan microparticles have great potential for oromucosal drug delivery, by providing elongated residence time in situ and sustained drug release for the treatment of local diseases.

Effect of Caffeine in the Diffusion Behaviour of Analgesic Drugs in Aqueous Solutions

The aim of the study was to examine the effect of caffeine on the diffusion of two pain-relieving drugs, namely paracetamol and sodium salicylate, in aqueous solutions at a temperature of 25.00ºC, using the Taylor dispersion method to determine the mutual diffusion coefficients for these ternary aqueous solutions. Ternary mutual diffusion coefficients are reported for aqueous solutions of paracetamol + caffeine, and sodium salicylate + caffeine, at 25.00ºC, and concentrations up to 0.050mol·dm-3. The data indicate that the presence of caffeine affects the diffusion of analgesic drugs. For example, a coupled diffusion of these drugs with caffeine was observed through the non-zero values of the cross-diffusion coefficients. Support for this came from the good agreement between our data and the predicted by a model of the diffusion that includes 1:1 complex, being obtained the association constants for systems [(caffeine and paracetamol) and (caffeine and salicylate sodium)], K=70mol-1·dm3 and K=80, respectively. These data provide us with a better understanding of the mechanisms of mass transport through diffusion in biological systems, as well as the structure of these systems.

Abstract 914: Combination analysis of tumor-associated collagen frameworks and tumor immune phenotype of lung carcinomas using virtual staining

Abstract An emerging predictive parameter of immunotherapy response is the patient’s tumor immune status, generally classified as “inflamed”, "immune excluded” and “desert”. Historically, classification was performed semi-quantitatively with somewhat subjective parameters as evidenced by the recent Delphi Workshop consensus. There are a variety of approaches to classifying immune status, most based upon analysis of H&amp;E images (counting tumor infiltrating lymphocytes, TILs), or counting subpopulations of immune cells using immunologic staining. However, use of multiplexed or multiple stains has recently been explored to better quantify the counts and types of immune cells in individual tissue compartments. While the immune microenvironment represents an important parameter in predicting patient response, other regions such as the extracellular matrix (ECM) may yield complementary information, as collagen-rich ECMs may present a barrier to drug diffusion and the orientation of fibers may direct the migration of malignant cells. Here we present a proof of concept virtual staining enhanced image analysis pipeline, which converts autofluorescence signals from a single tissue section into virtual H&amp;E and Masson’s Trichrome along with virtual detection of pan cytokeratin (AE1/AE3/PCK26) and CD45 (LCA) positive cells. We apply image analysis to the panel of virtual stains to study the spatial and case-by-case heterogeneity of tumor collagen frameworks and immune phenotype. Using a standard slide scanner (Axio Scan Z1, Zeiss), multiple autofluorescence images were captured from unstained sections (4-6um thick) of lung tissue. The virtual staining was performed by four deep neural networks trained in a supervised learning fashion. Select chemical stains were performed on previously scanned tissues and reviewed by pathologists side-by-side with virtual stains to ensure consistency and quality control. Four perfectly registered WSI virtual stain images were generated from each tissue section. The multi-stain results were rendered from a variety of lung cancers, including tissue microarray slides. Image analysis was performed using HALO (Indica Labs) and custom python scripts. We identified unique areas of tumor and adjacent stroma with heterogeneous immune phenotype and collagen characteristics, suggesting that an interplay might exist that could be utilized to improve patient selection or prognosis when deploying advanced AI tools. Future work includes applying this virtual stain technique retrospectively to cases with known immunotherapy treatment responses to determine the prognostic significance of the combined immune/ECM phenotype. Citation Format: Serge Alexanian, Yair Rivenson, Ning Xuan, Brian Cone, Zihang Fang, Sean Meyering, Luis A. Carvalho, David Palacios, Raymond Kozikowski. Combination analysis of tumor-associated collagen frameworks and tumor immune phenotype of lung carcinomas using virtual staining [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 914.

Chitosan hydrogels enriched with bioactive phloroglucinol for controlled drug diffusion and potential wound healing

We report a facile strategy to prepare chitosan (CS) hydrogels that eliminates the need for chemical crosslinking for advanced biomedical therapies. This approach gives controlled properties to the hydrogels by incorporating a natural bioactive phenolic compound, phloroglucinol (PG), into their microstructure. The adsorption of PG onto CS chains enhanced the hydrogels' antioxidant activity by up to 25 % and resulted in a denser, more entangled structure, reducing the pore size by 59 μm while maintaining porosity above 94 %. This allowed us to finely adjust pore size and swelling capacity. These structural properties make these hydrogels well-suited for wound healing dressings, promoting fibroblast proliferation and exhibiting excellent hemocompatibility. Furthermore, to ensure the versatility of these hydrogels, herein, we demonstrate their potential as drug delivery systems, particularly for dermal infections. The drug release can be controlled by a combination of drug diffusion through the swollen hydrogel and relaxation of the CS chains. In summary, our hydrogels leverage the synergistic effects of CS's antibacterial and antifungal properties with PG's antimicrobial and anti-inflammatory attributes, positioning them as promising candidates for biomedical and pharmaceutical applications, more specifically in advanced wound healing therapies with local drug delivery.

Formulation and Optimization of Intra Nasal Niosomal Gel of Kynurenic Acid: In Vitro in Vivo Characterization

Kynurenic acid's (KNA) inability to cross the blood brain barrier (BBB) severely limits its usage as a neuroprotective drug, despite the fact that it may have significant therapeutic effects in neurological illnesses. Drug delivery devices are one of the new avenues we're exploring as a means for KNA to enter the brain. Due to its low absorption when taken orally, medication formulation faces a significant hurdle. Here, nasal drug delivery has emerged as a popular alternate method for increasing medication bioavailability. In light of this, the current investigation set out to increase KNA bioavailability by means of an intranasal formulation based on niosomal technology. Rapid onset and evasion of first-pass metabolism are both offered by the nasal route, whereas niosomes protect hydrophilic medicines inside their core. For the purpose of determining entrapment efficiency, particle size, and in vitro drug release, niosomes were synthesized by combining lipid, nonionic surfactant, and cholesterol in distinct ratios. With a vesicle size of 248.51±1.54nm, the optimized niosomal formulation demonstrated a superior drug content (DC) of 98216±0.11% and an entrapment efficiency (EE) of 89.23±0.35. The formulation also contained cholesterol in an equal proportion (1:1). A value of 24 minutes was shown in the in vitro drug diffusion testing, indicating that the formulation exhibited prolonged activity. Gelation occurred at 37 ⁰C, which is the body's physiological temperature, and the optimum in situ gel, which contained 1:2 carbopol 934 and benzalkonium chloride, had a t90 value of 24 hours, indicating prolonged activity. In comparison to KNA oral suspension, the results showed that the KNA-loaded niosomal gel had a much higher relative bioavailability and improved drug penetration through the nasal mucosa

Unlocking new dimensions in long-acting injectables using lipid mesophase-based beads

In this study, we explored the use of lipid mesophases (LMPs) as a biocompatible and biodegradable material for sustained drug delivery. Our hypothesis centered on leveraging the high surface-to-volume ratio of LMP-based beads to enhance strength, stability, and surface interaction compared to the LMP bulk gel. To modulate drug release, we introduced antioxidant vitamin E into the beads, influencing mesophase topologies and controlling drug diffusion coefficients. Four drugs with distinct chemical properties and intended for three different pathologies and administration routes were successfully loaded into the beads with a drug entrapment efficiency exceeding 80 %. Notably, our findings revealed sustained drug release, irrespective of the drugs' chemical properties, culminating in the development of an injectable formulation. This formulation allows direct administration into the target site, minimizing systemic exposure, and thereby mitigating adverse effects. Our approach demonstrates the potential of LMP-based beads for tailored drug delivery systems with broad applications in diverse therapeutic scenarios.

SYNERGISTIC DRUG COMPATIBILITY OF SUMATRIPTAN SUCCINATE AND METOCLOPRAMIDE HYDROCHLORIDE (IN SITU GEL FORMULATIONS) FOR NASAL DRUG RELEASE OPTIMIZATION

Objective: Migraine is a prevalent neurological condition that causes lifelong tenacious headaches and significantly impacts the daily lives of individuals. Despite being frequently underestimated or neglected, it affects the individual’s routine activities, performance, self-confidence, and identity. Treatment often involves the administration of painkillers, which can lead to various complications. This study aimed to develop and characterize an in situ nasal formulation of sumatriptan succinate and metoclopramide hydrochloride to enhance drug residence time in the nasal cavity and improve drug bioavailability. Methods: Eight formulations of intranasal in situ gels were prepared using the “Cold Method” and evaluated for various parameters, including appearance, texture, viscosity, pH, gel strength, gelation temperature, drug content, and in vitro/ex vivo drug diffusion. FT-IR studies confirmed no interactions between sumatriptan succinate, metoclopramide hydrochloride, and the excipients. Simultaneous estimation method was used to evaluate drug content, in vitro and ex vivo drug diffusion. Results: Among the formulations, “Sumatriptan Succinate Metoclopramide Hydrochloride Polymer (SMP8)” exhibited the most favorable characteristics. The percent cumulative drug release was determined to be 96.803±0.0015 for sumatriptan succinate and 92.569±0.0028 for metoclopramide hydrochloride, aligning with the Higuchi model kinetics. In vitro and ex vivo diffusion studies demonstrated that SMP8 provided sustained drug release for up to 9 h, making it the optimal dosage formulation for nasal drug delivery in the treatment of migraine. Conclusion: This study’s findings suggest that the developed intranasal in situ gel formulation, SMP8, effectively releases sumatriptan succinate and metoclopramide hydrochloride over an extended period. By improving drug residence time and bioavailability, this formulation has the potential to enhance the therapeutic efficacy and patient compliance in the management of migraine.

Oncolytic Virus‐Like Nanoparticles for Tumor‐Specific Gene Delivery

AbstractNucleic acid drugs are widely used in biomedical fields. However, one of the main challenges in vivo is to selectively deliver nucleic acid drugs to subcellular compartments. To solve this problem, an oncolytic virus‐like nanoparticle, OV@FN, is constructed that can directly deliver nucleic acids to the cytoplasm through membrane fusion in response to the slightly acidic environment of the tumor. OV@FN is composed of a nano‐core (NA‐Zn@G) that can accurately release nucleic acids in response to high concentrations of glutathione in the cytoplasm of tumor cells and a hybrid membrane vesicle (FN) expressing oncolytic virus fusion membrane glycoprotein (mVSV‐G). The study findings suggest that OV@FN efficiently and selectively delivers nucleic acids to the cytoplasm of tumor cells, as compared to normal cells. Importantly, FN effectively induces tumor cells to form a syncytium, thus promoting intracellular drug diffusion, and enhancing the gene therapy effect. In vivo gene silencing test shows that OVsiR@FN has a significant nucleic acid delivery performance. In the melanoma model, the OV3pdsR@FN shows remarkable tumor ablation ability and improves the immunosuppressive microenvironment of the tumor site. OV@FN offers a novel approach to designing gene delivery and tumor therapy platforms.

Drug delivery with melt-spun liquid-core fibers

Conventional local drug delivery systems often encounter issues such as burst-release, limited drug reservoirs, rigidity, and low mechanical performance. We present an innovative approach to local drug delivery utilizing melt-spun drug-loaded liquid-core filaments (LiCoFs). LiCoFs were produced, incorporating fluorescein sodium salt as the model drug, dissolved in various liquid core materials, and enveloped by poly(ε-caprolactone) as the sheath material. We assessed thermal, mechanical, and structural properties of LiCoFs and have conducted extensive drug diffusion trials. Some trials involved pre-exchange of the liquid core with ibuprofen, bovine serum albumin–fluorescein isothiocyanate and methylene blue solutions using a pumping device. It was observed that diffusion mechanisms and diffusion rates depend on temperature, core size/sheath thickness, sheath permeability, carrier liquid type, drug molecule properties, and the drug's affinity to the sheath polymer. These drug-loaded LiCoFs pave the way towards a new generation of medical textiles facilitating controlled, local drug delivery.

Zn-MOF as a tumor responsive carrier for combination therapy

Combination therapy is considered as a useful therapeutic strategy for tumor. Here, Zn-based MOF Zn-TPN was prepared for combination with chemotherapy and chemodynamic therapy. Co-precipitation method was used to obtain the antitumor system DOX&Mn@Zn-TPN, which incorporated DOX (9.37 wt%) and Mn2+ (5.75 wt%). The Fenton-like reaction of Mn2+ provided positive chemodynamic therapy, and drug release exhibited responses to pH, temperature and glutathione (GSH), enabling specific therapeutic effects in the tumor environment. According to the Korsmeyer-Peppas model, DOX release was a result of drug diffusion. In vitro cell experiments confirmed that the system exhibited significant lethality against 4T1 cells while maintaining biocompatibility with L929 cells.

Optimization of ultrasound contrast agent and treatment duration for drug delivery to methicillin-resistant Staphylococcus aureus diabetic wound biofilms in mice

Chronic wounds are frequently infected with bacterial biofilms which pose a barrier to drug diffusion, drug uptake, and facilitate drug tolerance, thereby prolonging the healing process in chronic wounds and increasing the likelihood of relapse. A major contributor to relapse is persister cells, a subset resilient to high antibiotic doses. Previous work by our group showcased significantly improved gentamicin efficacy in a diabetic murine wound model using ultrasound, nanodroplets, and an anti-persister drug. Here, we aim to optimize nanodroplet formulation for persister cell targeting and treatment duration for clinical translation. In a methicillin-resistant Staphylococcus aureus (MRSA) diabetic wound model in SKH-1 hairless mice (n = 5), wounds were treated twice daily with gentamicin, ultrasound, and nanodroplets containing oxygen or palmitoleic acid (PA). These components aim to increase oxygenation and enhance persister uptake, respectively. Additionally, treatments with gentamicin, PA nanodroplets, and ultrasound for 2, 5, and 10 minutes were investigated (n = 3). Preliminary findings indicate PA most effectively potentiates antibiotic activity, 10- minute treatments improve efficacy by 1-log compared to 5-minutes, and 2-minute treatments achieve comparable efficacy to 5-minutes. These initial findings suggest a promising strategy for enhancing antibiotic efficacy and targeting persister cells in biofilms, with consideration for resource-efficient treatment times for clinical application.

Insights on Structure-Passive Permeability Relationship in Pyrrole and Furan-Containing Macrocycles.

Macrocycles have recognized therapeutic potential, but their limited cellular permeability can hinder their development as oral drugs. To better understand the structure-permeability relationship of heterocycle-containing, semipeptidic macrocycles, a library was synthesized. These compounds were created by developing two novel reactions described herein: the reduction of activated oximes by LiBH4 and the aqueous reductive mono-N-alkylation of aldehydes using catalytic SmI2 and stoichiometric Zn. The permeability of the macrocycles was evaluated through a parallel artificial membrane permeability assay (PAMPA), and the results indicated that macrocycles with a furan incorporated into the structure have better passive permeability than those with a pyrrole moiety. Compounds bearing a 2,5-disubstituted pyrrole (endo orientation) were shown to be implicated in intramolecular H-bonds, enhancing their permeability. This study highlighted the impact of heterocycles moieties in semipeptides, creating highly permeable macrocycles, thus showing promising avenues for passive diffusion of drugs beyond the rule-of-five chemical space.

Ivermectin-Loaded Mesoporous Silica and Polymeric Nanocapsules: Impact on Drug Loading, In Vitro Solubility Enhancement, and Release Performance.

Ivermectin (IVM), a widely used drug for parasitic infections, faces formulation and application challenges due to its poor water solubility and limited bioavailability. Pondering the impact of IVM's high partition coefficient value (log P) on its drug release performance, it is relevant to explore whether IVM nanoencapsulation in organic or inorganic nanoparticles would afford comparable enhanced aqueous solubility. To date, the use of inorganic nanoparticles remains an unexplored approach for delivering IVM. Therefore, here we loaded IVM in mesoporous silica particles (IVM-MCM), as inorganic nanomaterial, and in well-known poly(ε-caprolactone) nanocapsules (IVM-NC). IVM-MCM had a well-organized hexagonal mesoporous structure, reduced surface area, and high drug loading of 10% w/w. IVM-NC had a nanometric mean size (196 nm), high encapsulation efficiency (100%), physicochemical stability as an aqueous dispersion, and drug loading of 0.1% w/w. Despite differing characteristics, both nanoencapsulated forms enhance IVM's aqueous intrinsic solubility compared to a crystalline IVM: after 72 h, IVM-MCM and IVM-NC achieve 72% and 78% releases through a dialysis bag, whereas crystalline IVM dispersion achieves only 40% drug diffusion. These results show distinct controlled release profiles, where IVM-NC provides a deeper sustained controlled release over the whole experiment compared to the inorganic nanomaterial (IVM-MCM). Discussing differences, including drug loading and release kinetics, is crucial for optimizing IVM's therapeutic performance. The study design, combined with administration route plans and safety considerations for humans and animals, may expedite the rational optimization of IVM nanoformulations for swift clinical translation.

Numerical investigation of the heat flux frequency effect on the doxorubicin absorption by Bio MOF11 carrier: A molecular dynamics approach

The present study investigated the effect of heat flux frequency on doxorubicin adsorption by bio MOF11 biocarrier using molecular dynamics simulation. This simulation examined the effect of several heat flux frequencies (0.001, 0.002, 0.005, and 0.010 1/fs) on the quantity of drug particles absorbed, mean square displacement (MSD), diffusion coefficient, and interaction energy. The present outputs of simulations predicted the structural stability of the modeled MOF-drug system in 300 K. Also, simulation outputs predicted by frequency optimization, the adsorption of target drug inside MOF11 maximized, and efficiency of this sample in actual clinical applications, such as drug delivery process increased. Numerically, the optimum value of frequency was estimated to be 0.005 1/fs. Using this heat setting, the interaction energy between MOF 11 and the doxorubicin drug increased to −929.05 kcal/mol, and the number of penetrated drug particles inside MOF11 converged to 207 atoms. The results reveal that the MSD parameter reached 64.82 Å2 after 100000-time steps. By increasing frequency to 0.005 fs−1, this increased to 78.05 Å2. By increasing MSD parameter, the drug diffusion process effectively occurred, and the diffusion coefficient increased from 67.29 to 82.47 nm2/ns. It is expected that the findings of present investigation guide the design of more efficient drug delivery platforms, enhance drug-carrier interactions, improve manufacturing processes, and aid in developing novel nanomaterials with enhanced adsorption properties for various applications.

Diverse mutant selection windows shape spatial heterogeneity in evolving populations.

Mutant selection windows (MSWs), the range of drug concentrations that select for drug-resistant mutants, have long been used as a model for predicting drug resistance and designing optimal dosing strategies in infectious disease. The canonical MSW model offers comparisons between two subtypes at a time: drug-sensitive and drug-resistant. In contrast, the fitness landscape model with N alleles, which maps genotype to fitness, allows comparisons between N genotypes simultaneously, but does not encode continuous drug response data. In clinical settings, there may be a wide range of drug concentrations selecting for a variety of genotypes in both cancer and infectious diseases. Therefore, there is a need for a more robust model of the pathogen response to therapy to predict resistance and design new therapeutic approaches. Fitness seascapes, which model genotype-by-environment interactions, permit multiple MSW comparisons simultaneously by encoding genotype-specific dose-response data. By comparing dose-response curves, one can visualize the range of drug concentrations where one genotype is selected over another. In this work, we show how N-allele fitness seascapes allow for N * 2N-1 unique MSW comparisons. In spatial drug diffusion models, we demonstrate how fitness seascapes reveal spatially heterogeneous MSWs, extending the MSW model to more fully reflect the selection of drug resistant genotypes. Furthermore, using synthetic data and empirical dose-response data in cancer, we find that the spatial structure of MSWs shapes the evolution of drug resistance in an agent-based model. By simulating a tumor treated with cyclic drug therapy, we find that mutant selection windows introduced by drug diffusion promote the proliferation of drug resistant cells. Our work highlights the importance and utility of considering dose-dependent fitness seascapes in evolutionary medicine.