Drug Diffusion Research Articles

Gas-propelled anti-hair follicle aging microneedle patch for the treatment of androgenetic alopecia.

Existing treatments for androgenetic alopecia (AGA) are unsatisfactory, owing to the two major reasons: (1) Oxidative stress and vascularization deficiency in the perifollicular microenvironment provoke the premature senescence of hair follicles, limiting the transformation of hair growth cycle from the telogen to the anagen phase; (2) The amount of drug delivered to the perifollicular region located in the deep dermis is very limited for passive drug delivery systems. Herein, we developed a gas-propelled microneedle patch integrated with ferrum-chelated puerarin/quercetin nanoparticles (PQFN) to increase drug accumulation in hair follicles and reshape the perifollicular microenvironment for improved hair-regenerating effects. PQFN can rejuvenate testosterone (Tes)-induced senescence of dermal papilla cells by scavenging ROS, restoring mitochondrial function, regulating signaling pathways related to hair regeneration, and upregulating hair growth-promoting genes. PQFN more efficiently promoted endothelial cell proliferation, migration, and tube formation than ferrum-chelated quercetin nanoparticles (QFN) because of puerarin's proangiogenic effects. Compared with passive MNs, gas-propelled MNs promoted drug diffusion and permeation into deeper skin layers, resulting in significantly higher drug accumulation in hair follicles. Pharmacodynamic studies on an AGA mouse model further showed that PQFN-loaded active MNs achieved higher hair coverage by alleviating oxidative stress, promoting angiogenesis, and rejuvenating senescent cells. Therefore, this study presents a novel "anti-hair follicle aging" treatment strategy for AGA.

Formulation, development and in vivo characterization of selegiline hydrochloride nanostructured lipid nanocarrier loaded microneedle array patch for depression.

Depression is a common mental condition causing depressed mood and loss of pleasure. The primary treatment approach for the management of depression consists of the use of selegiline (MAO-B) inhibitor compound. The present work aimed to develop and optimize selegiline-loaded nanostructured lipid carriers for transdermal application, utilizing a 23 full factorial design approach. The optimized nanostructured lipid carriers formulation (Batch B7) demonstrated a particle size of 158.71±0.56nm, a narrow size distribution (0.266±0.006), high entrapment efficiency (59.60±0.34%), and a zeta potential of -23.2±2.21mV. Furthermore, x-ray diffraction and differential scanning calorimetry studies revealed the amorphous transformation of selegiline within the nanostructured lipid carrier. Transmission Electron Microscopy study has shown that nanostructured lipid carrier particles had a spherical shape with a smooth surface. These optimized nanostructured lipid carriers were then incorporated into a microneedle array patch for transdermal delivery. The selegiline-loaded nanostructured lipid carrier microneedle array patch exhibited no skin irritation in a rabbit model. It enhanced drug diffusion ex vivo (1.13-fold compared to pure selegiline-loaded microneedle array patch) with 90% drug release in 12h. The pharmacokinetic study demonstrated a steady and controlled release profile with a half-life of 29.9±0.14h and AUC0-t (26.57±0.51 μg/ml*h) of selegiline loaded nanostructured lipid carrier microneedle array patch. On the contrary, a pure selegiline-loaded microneedle array patch showed a short half-life of 6.5±0.26h and AUC0-t (20.90±0.31μg/ml*h). The sustained release profile and prolonged half-life in plasma and the brain suggest improved therapeutic efficacy. Histopathology analysis revealed no significant toxicity to vital organs. Thus, a selegiline nanostructured lipid carrier-loaded microneedle array patch can increase brain bioavailability compared to a pure selegiline-loaded microneedle array patch for managing depression.

Enhancement of Transdermal Drug Delivery: Integrating Microneedles with Biodegradable Microparticles.

This investigation aimed to enhance transdermal methotrexate delivery through human skin by employing Dr. Pen microneedles and poly(d,l-lactide-co-glycolide) acid microparticles formulated from eight polymer grades (Expansorb DLG 95-4A, DLG 75-5A, DLG 50-2A, DLG 50-5A, DLG 50-8A, DLG 50-6P, DLG 50-7P, and DLL 10-15A). A comprehensive characterization of the microparticles was performed, encompassing various parameters such as size, charge, morphology, microencapsulation efficiency, yield, release kinetics, and chemical composition. The efficacy of microneedles in disrupting skin integrity was demonstrated by scanning electron microscopy, dye binding, histological examination, confocal laser microscopy, and pore size analysis. Microneedle-mediated skin microporation led to a substantial reduction in skin electrical resistance and a concomitant increase in transepidermal water loss. In vitro permeation experiments using human skin delivered microparticles into microporated skin and demonstrated a considerable difference in methotrexate delivery among the polymer groups. Microneedle treatment significantly amplified cumulative drug delivery, steady-state flux, diffusion coefficient, permeability coefficient, and drug concentration within skin layers while concurrently diminishing lag time (p < 0.05). Furthermore, a robust correlation was established between microparticle properties (cumulative release, release rate, encapsulation efficiency) and drug deposition in the skin. In conclusion, the synergistic combination of Dr. Pen microneedles and PLGA microparticles facilitated enhanced and regulated transdermal methotrexate delivery.

Drug-Loaded Hydrogel Microneedles for Sustainable Transdermal Delivery of Macromolecular Proteins.

Poly(methyl vinyl ether co-maleic acid) (PMVE/MA) hydrogel microneedles (HMN) are investigated for transdermal delivery of macromolecular drugs owing to their biocompatibility and super-swelling properties. However, the drug delivery efficacy reduces with increasing molecular weight due to the entrapment within the HMN matrices. Furthermore, integrating external drug reservoirs extends the drug diffusion path and reduces the efficiency of drug permeation. A direct drug loading approach in the HMN matrix was introduced in this work following a pH modification step. The effect of pH modification on the physicochemical properties of HMN was studied. Then, bovine serum albumin (BSA), a model protein, was loaded into the pH-modified HMN, and the morphological changes in HMN and protein stability were also assessed. Finally, the efficacy of BSA-loaded HMN in the transdermal delivery was evaluated ex vivo. A significant increase in swelling was recorded following the pH modification of HMN (p < 0.001). The structure of pH-modified hydrogel was highly porous, and ATR-FTIR spectra indicated a shift in the carboxylic peak. The secondary structure of BSA loaded in the pH-modified HMN was also preserved. The BSA-loaded HMN mediated a sustained ex-vivo drug release with a cumulative release of 64.70% (3.88 mg) in 24 h. Hence, the model drug-incorporated PMVE/MA HMN system shows potential for sustainable transdermal delivery of proteins.

Pioneering a New Era in Oral Cancer Treatment with Electrospun Nanofibers: A Comprehensive Insight.

Oral cancer, currently ranked 16th among the most prevalent malignancies worldwide according to GLOBOCAN, presents significant challenges to global oral health. Conventional treatment modalities such as surgery, radiation, and chemotherapy often have limitations, prompting the need for innovative therapeutic approaches. Tissue engineering has emerged as a promising solution aimed at developing biocompatible, functional, and biologically responsive tissue constructs. This approach involves the integration of cells, bioactive compounds, and scaffolds to enhance treatment efficacy. Electrospun nanofibers, mimicking the extracellular matrix, exhibit considerable potential in addressing complex oral health issues by influencing cellular behavior. The versatility of electrospinning technology allows for the fabrication of fiber scaffolds with high surface area, making them ideal for localized delivery of bioactive compounds or pharmaceuticals. Enhancing these electrospun scaffolds with growth factors, nanoparticles, and biologically active substances significantly increases their therapeutic appeal in oral cancer management. This review offers a comprehensive examination of the various applications of electrospun nanofibers in oral cancer therapy. Utilizing electronic databases such as PubMed, CrossREF, and Google Scholar, we conducted an extensive review of relevant literature concerning "electrospun nanofibers" and their therapeutic potential in oral cancer treatment. Key topics addressed include engineering methodologies, drug diffusion mechanisms, factors influencing nanofiber scaffold design, toxicity concerns, and clinical implications. The findings underscore the transformative potential of electrospun nanofibers in revolutionizing oral cancer therapy.

Evaluating the antioxidant, anti-inflammatory, and neuroprotective potential of fruiting body and mycelium extracts from edible yellow morel (Morchella esculenta L. Pers.).

This study aimed to assess the antioxidant, anti-inflammatory, and acetylcholinesterase activities of fruiting bodies (FB) and mycelium (M) extracts of Morchella esculenta L. collected from various regions of Pakistan. The samples included Skardu fruiting body (SKFB) and mycelia Skardu (SKM), Malam Jaba fruiting body (MJFB) and Malam Jaba mycelia (MJM), Krair Mansehra fruiting body (KMFB) and Krair Mansehra mycelia (KMM), and Thandiani fruiting body (TFB) and Thandiani mycelia (TM). The IC50 values for free radical scavenging activity of all samples revealed that fruiting body SKFB and MJFB of M. esculenta are significantly involved in relieving oxidative stress. Bovine serum albumin conformation destruction assay showed a significantly increased anti-inflammatory activity of SKFB with an IC50 value of 10.94±0.098 µg/mL. The human red blood cell protection assay showed that TFB has a lower EC50 value as compared to other samples. KMFB and KMM extracts of M. esculenta showed significantly higher anti-acetylcholinesterase activity compared to the standard drug, donepezil. The lower IC50 value of M. esculenta extracts suggested higher efficacy for acetylcholinesterase (AChE) inhibition. Enzyme kinetics results showed that KMFB of M. esculenta is a competitive inhibitor, while KMM and Donepezil are noncompetitive AChE inhibitors. Further, molecular docking, physicochemical properties and ADMET analysis of M. esculenta constituents showed smooth drug diffusion and protection against neurodegenerative disorders. This study indicates that M. esculenta extracts may hold significant therapeutic potential for neurodegenerative diseases, opening a path for potential therapeutic strategies.

Development of hyaluronic acid/β-cyclodextrin semi-interpenetrating network hydrogels for prolonged delivery of water-soluble sunitinib malate.

Sunitinib malate (SUM), widely used in cancer treatment for its anti-VEGF properties, has also been explored for ocular neovascular diseases. For ocular applications, sustained drug release is essential to reduce dosing frequency. Hyaluronic acid (HA)-based hydrogels are commonly used for controlled drug delivery, but their hydrophilicity leads to rapid drug diffusion, especially for water-soluble drugs like SUM. To address this, β-cyclodextrin (β-CD) polymers (2-300kDa) were incorporated into tyramine-conjugated HA (HA-TA) (200-400kDa) networks to extend drug release via the formation of host-guest inclusion complexes. SUM-CD intermolecular interactions were identified and characterised by 1H NMR and FTIR spectroscopies, and NOESY spectra further confirmed a 1 SUM: 2 β-CD inclusion complex. β-CD polymers (10% w/v) were integrated into HA-TA (0.25, 0.5, 1% w/v) networks enzymatically crosslinked using horseradish peroxidase and hydrogen peroxide, forming semi-interpenetrating polymer network hydrogels. These gels exhibited faster gelation, enhanced swelling behaviour, higher drug loading capacity, a denser matrix, and a longer SUM release duration compared to HA-TA hydrogels. In an in vitro flow model, post-gelation loading of SUM led to a longer release duration than pre-loading, with release continuing over 20days. The HA-CD semi-IPN hydrogel therefore warrants further exploration for its potential ocular applications.

Formulation and evaluation of novel vesicular nanoethosomal patches for transdermal delivery of zidovudine: In vitro, ex vivo, and in vivo pharmacokinetic investigations

Ethosomes are novel soft malleable nanovesicles composed mainly of phospholipids, ethanol (relatively high concentration), glycol, and water. They are used for enhanced drug delivery through the skin. These zidovudine (ZV) vesicles were formulated by cold technique using phospholipids, cholesterol, propylene glycol, and ethanol. The nanoethosomal dispersion was transformed to transethosomal patches using HPMC E15 and chitosan as polymers, a mixture of dichloromethane (DCM) and methanol (1:1 ratio) as solvent, triethyl citrate as plasticizer, and span 80 as permeation enhancer. The physical features of the prepared patches were found to be within acceptable limits. The in vitro study showed drug diffusion of 71.25 − 88.19% through the semipermeable egg membrane in 24 hours. The ex vivo study showed drug permeation of 78.35 − 91.45% through the goat ear membrane in 24 hours. The combination of HPMC and EP4 transdermal patch was determined to be the most effective formulation for transdermal drug administration with sustained drug release, outperforming all other formulations based on acceptable physicochemical parameters, in vitro and ex vivo evaluation studies. Compared with the other formulations, the EP4 formulation had superior penetration kinetics, as proven by its highest permeation co-efficient (2.56 mg/cm2/h), flux (0.494 mg/cm2/h), and enhancement ratio (2.43). Moreover, dermal irritation tests demonstrated that topical therapy did not cause any irritation, indicating its safety. The in vivo bioavailability studies revealed that the AUC showed good bioavailability, which was approximately 188.99 times greater than that of the marketed product. According to the in vitro–in vivo correlation, the ex vivo (in vitro) data can represent physiological conditions that are exact replicas of those found in vivo. Therefore, the ZV transdermal patches exhibit enhanced drug permeation and good bioavailability for better therapeutic outcomes.

Formulation and in-vitro permeation kinetic studies of &amp;beta;-cyclodextrin complexed ketoconazole drug capped silver nanoparticles

Background: Invasive fungal infections are a growing global crisis due to environmental shifts and growing vulnerable populations. Pathogenic fungi that infect humans are developing resistance against all approved systemic antifungal drugs. Topical drug delivery systems provide a non-invasive way to distribute therapeutic substances directly to the site of action. Ketoconazole (KZ) is a BCS Class II broad-spectrum drug that is used to treat and prevent fungal infections in which Trichophyton rubrum is the main causative agent.Materials and Methods: The present study utilizes an in-vitro model in which KZ is complexed with β-CD and then capped with AgNPs to formulate a cream and evaluated for the underlying mechanisms and amount of improved passive penetration. The formulated cream is characterized for physiochemical evaluation, Fourier transform infrared spectroscopy (FTIR), kinetic studies indicating the effective stability and encapsulation of the composite.Results: The prepared sample was evaluated in terms of its appearance, drug content, spreadability, and viscosity. Drug diffusion through the dialysis membrane, and the findings showed the β-CD-KZ-AgNPs formulation had a significantly higher permeability than KZ alone and followed first-order kinetics with an anomalous release pattern. The higher solubility and stability of β-CD and nano-sized AgNPs resulted in improved penetration. This study investigates that β-CD-capped AgNPs can significantly enhance KZ passive penetration and diffusion, providing a potentially useful nanocarrier technology for antifungal treatment.Conclusion: Enhancing the passive permeation and diffusion characteristics of KZ on β-Cyclodextrin (β-CD)-capped silver nanoparticles (AgNPs) presents a viable approach for enhancing drug delivery efficiency.

Experimental and Theoretical Design on the Development of Matrix Tablets with Multiple Drug Loadings Aimed at Optimizing Antidiabetic Medication.

Background: Diabetes is a growing global health crisis that requires effective therapeutic strategies to optimize treatment outcomes. This study aims to address this challenge by developing and characterizing extended-release polymeric matrix tablets containing metformin hydrochloride (M-HCl), a first-line treatment for type 2 diabetes, and honokiol (HNK), a bioactive compound with potential therapeutic benefits. The objective is to enhance glycemic control and overall therapeutic outcomes through an innovative dual-drug delivery system. Methods: The tablets were formulated using hydrophilic polymers, such as Carbopol® 71G NF and Noveon® AA-1. The release kinetics of M-HCl and HNK were investigated through advanced mathematical models, including fractal and multifractal dynamics, to capture the non-linear and time-dependent release processes. Traditional kinetic models (zero-order, first-order, Higuchi equations) were also evaluated for comparison. In vitro dissolution studies were conducted to determine the release profiles of the active ingredients under varying polymer concentrations. Results: The study revealed distinct release profiles for the two active ingredients. M-HCl exhibited a rapid release phase, with 80% of the drug released within 4-7 h depending on polymer concentration. In contrast, HNK demonstrated a slower release profile, achieving 80% release after 9-10 h, indicating a greater sensitivity to polymer concentration. At shorter intervals, drug release followed classical kinetic models, while multifractal dynamics dominated at longer intervals. Higher polymer concentrations resulted in slower drug release rates due to the formation of a gel-like structure upon hydration, which hindered drug diffusion. The mechanical properties and stability of the matrix tablets confirmed their suitability for extended-release applications. Mathematical modeling validated the experimental findings and provided insights into the structural and time-dependent factors influencing drug release. Conclusions: This study successfully developed dual-drug extended-release matrix tablets containing metformin hydrochloride and honokiol, highlighting the potential of hydrophilic polymers to regulate drug release. The findings emphasize the utility of advanced mathematical models for predicting release kinetics and underscore the potential of these formulations to improve patient compliance and therapeutic outcomes in diabetes management.

Topical felbinac loaded cubosomal hydrogel for promising treatment of inflammatory pain

An attempt was made to formulate felbinac-loaded cubosomes to treat inflammatory pain. Cubosomes were prepared by the emulsification method in two stages; formulation of cubosomes and then conversion to hydrogel. Optimization technique was applied to get cubosomes by considering independent variables namely, glyceryl monooleate (GMO) and Poloxamer 407, in the range of 1.5 to 2.5 g and 0.5 to 2 w/w %, respectively. The effect of these variables was studied on particle size and drug release. Further, formulations were also characterized to get drug content and entrapment efficiency. Optimized formulation was incorporated into Carbopol 934 gel base to generate hydrogel and evaluated for spreadability, in-vitro diffusion, and anti-inflammatory activity by using carrageenan-induced rat paw edema model. Drug release, entrapment efficiency and drug content of nine formulations ranged from 70.62 ± 1.28 to 93.55 ± 2.35% within 24 h, 91.17 ± 1.12 to 91.89 ± 2.11%, and 21.82 ± 1.21 to 38.81 ± 0.87%, respectively. Transmission electron microscopy revealed well discrete, cubic, and spherical-shaped cubosomes. The zeta potential and particle size of the optimized formulation were 50 ± 1.31 mV and 332.5 ± 13.65 nm respectively. The drug release of optimized formulation was 89.58 ± 2.36% within 24 h. Cubosome hydrogel exhibited good spreadability and slow drug diffusion (88.45 ± 2.28% within 24 h) owing to the viscous nature of the gel. The studies of anti-inflammatory activity suggestive of a notable decrease in paw edema observed after 1 h, which persisted for up to 24 h following treatment with cubosome hydrogel. Felbinac gel (without cubosomes) showed anti-inflammatory action till 6 h with comparatively less reduction in edema. Histopathology of cubogel revealed significant reduction in edema and polymorphonuclear infiltration. Cubogel demonstrated good anti-inflammatory effect and could be a good choice of topical formulation to treat inflammatory pain.

Precipitation Polymerization-Based Molecularly Imprinted Polymers: A Novel Approach for Transdermal Curcumin Delivery.

This research describes the synthesis and characterization of a molecularly imprinted polymer (MIP) as a candidate for the transdermal delivery of curcumin. The MIP was synthesized through precipitation polymerization using methacrylic acid as the functional monomer and ethylene glycol dimethacrylate as the cross-linking agent. MIP characterization studies were conducted using SEM-EDX and FTIR spectroscopy to determine the morphology and interaction between curcumin and polymers. The MIP obtained through precipitation polymerization was in the form of a fine powder with a surface morphology resembling a collection of small granules with a uniform shape. The adsorption capacity of the MIP follows the Langmuir adsorption isotherm model, with a maximum capacity of 4.239 mg/g, which is greater than that of the NIP (3.219 mg/g), resulting in an imprinting efficiency of 1.317. The percentage of curcumin released from the MIP after 8 h was 41.26%, which is lower than that from the NIP, at 51.50%. The drug release kinetics study follows the Higuchi model, indicating drug diffusion from the polymer matrix. Imprinting on the MIP can modify drug diffusion from the polymer matrix, resulting in a reduced release rate in the MIP. Therefore, the MIP can be considered a candidate for the controlled transdermal delivery of curcumin.

Green/red fluorescent protein disrupting drugs for real‐time permeability tracking in three‐dimensional tumor spheroids

AbstractThree‐dimensional (3D) spheroid models offer a more physiologically relevant and complex environment compared to traditional two‐dimensional cultures, making them a promising tool for studying tumor biology and drug response. However, these models often face challenges in real‐time monitoring of drug diffusion, penetration, and target engagement, limiting their predictive power for in vivo and clinical outcomes. This study introduces a novel approach for real‐time tracking of drug permeability using small molecule drugs with GFP/RFP‐disrupting properties that correlate with their efficacy. We developed a reproducible 3D spheroid model with various cancer cell lines expressing GFP/RFP for efficient drug screening. Through screening over 20 FDA‐approved enzyme inhibitors, we identified three covalent kinase inhibitors—osimertinib, afatinib, and neratinib—that irreversibly disrupt GFP and RFP fluorescence. Our results reveal distinct drug diffusion and penetration profiles within GFP/RFP‐expressing spheroids, varying with drug concentration and formulation, and correlating with clinical volume of distribution (Vd) values. Additionally, we demonstrate that our approach is useful for evaluating different drug formulations as well as screening penetration enhancers for solid tumors. These findings offer a valuable 3D model for studying kinetics of drug permeability and efficacy in tumor‐like environments, with potential implications for drug delivery research and formulation development.

Reversing protonation of weakly basic drugs greatly enhances intracellular diffusion and decreases lysosomal sequestration.

For drugs to be active they have to reach their targets. Within cells this requires crossing the cell membrane, and then free diffusion, distribution, and availability. Here, we explored the in-cell diffusion rates and distribution of a series of small molecular fluorescent drugs, in comparison to proteins, by microscopy and fluorescence recovery after photobleaching (FRAP). While all proteins diffused freely, we found a strong correlation between pKa and the intracellular diffusion and distribution of small molecule drugs. Weakly basic, small-molecule drugs displayed lower fractional recovery after photobleaching and 10- to-20-fold slower diffusion rates in cells than in aqueous solutions. As, more than half of pharmaceutical drugs are weakly basic, they, are protonated in the cell cytoplasm. Protonation, facilitates the formation of membrane impermeable ionic form of the weak base small molecules. This results in ion trapping, further reducing diffusion rates of weakly basic small molecule drugs under macromolecular crowding conditions where other nonspecific interactions become more relevant and dominant. Our imaging studies showed that acidic organelles, particularly the lysosome, captured these molecules. Surprisingly, blocking lysosomal import only slightly increased diffusion rates and fractional recovery. Conversely, blocking protonation by N-acetylated analogues, greatly enhanced their diffusion and fractional recovery after FRAP. Based on these results, N-acetylation of small molecule drugs may improve the intracellular availability and distribution of weakly basic, small molecule drugs within cells.

Transdermal Delivery of Azilsartan: Formulation Strategies and Performance Evaluation

Aims: Matrix-type systems were developed in the present study by using various polymers including sodium carboxymethyl cellulose and eudragits with various concentrations. Materials and Methods: In the present work, an attempt has been made to develop a matrix-type transdermal therapeutic system comprising of Azilsartan with different concentrations of sodium carboxyl methyl cellulose and Eudragit using solvent evaporation technique. The physicochemical compatibility of the drug and the polymers was studied by infrared spectroscopy. Results and Discussion: The results obtained showed no physical-chemical incompatibility between the drug and the polymers. The in vitro drug diffusion studies from the formulation were found to be a sustained release effect. All the evaluation parameters obtained from the best formulation were found to be satisfactory. Conclusion: The data obtained from the in vitro release studies were fitted to various kinetic models; it was found that drug release follows the Peppas model release by diffusion technique from the polymer.

Pickering emulsion with tumor vascular destruction and microenvironment modulation for transarterial embolization therapy.

In the clinic, Lipiodol chemotherapeutic emulsions remain a main choice for patients diagnosed with hepatocellular carcinoma (HCC) via the mini-invasive transarterial chemoembolization (TACE) therapy. However, the poor stability of conventional Lipiodol chemotherapeutic emulsions would result in the fast drug diffusion and incomplete embolization, inducing systemic toxicity and impairing the efficacy of TACE therapy. Therefore, it is of great importance to construct alternative formulations based on commercial Lipiodol to achieve the improved efficacy and safety of HCC treatment. Herein, calcium phosphate (CaP) nanoparticles-stabilized Lipiodol Pickering emulsion (CaP-LPE) with improved stability and pH-responsiveness is prepared and utilized for the encapsulation of combretastatin A4-phosphate (CA4P), a clinically approved vascular disrupting agent. The obtained CA4P-loaded CaP-LPE (CCaP-LPE) was shown to be enhanced stability compared to conventional Lipiodol emulsion and pH-responsive release of the encapsulated drugs. On one hand, the released CA4P could disrupt tumor vascular and cut off the blood supplying of tumor cells, thus starving cancer cells. Moreover, it was revealed that CCaP-LPE could reverse immunosuppressive tumor microenvironment (TME) by neutralizing tumor acidity, leading to the increased infiltration of CD8+ T cells and the decreased percentages of immunosuppressive cells. As the result, such CCaP-LPE could effectively shrink orthotopic N1S1 HCC tumors in rats by eliciting a potent antitumor immune response. Therefore, this study highlights a simple strategy to construct a novel LPE with the potencies of tumor vascular disruption and TME modulation, holding a great promise for TAE therapy of HCC.

Hyaluronic acid-based hydrogels as codelivery systems: The effect of intermolecular interactions investigated by HR-MAS and solid-state NMR Spectroscopy

Hydrogels based on hyaluronic acid and agarose-carbomer, due to their peculiar 3D architecture and biocompatibility, are promising candidates for pharmaceutical strategies based on the codelivery of drugs targeting different diseases. The successful development of these applications requires a precise understanding of drug-drug interactions and their effects on transport and release mechanisms. In this study, such an investigation is carried out on hydrogels loaded with ethosuximide and sodium salicylate at different concentrations. Intermolecular interactions and transport properties are characterized by means of High Resolution Magic Angle Spinning and solid-state Magic Angle Spinning NMR Spectroscopy.At variance with our previous findings on single-drug formulations, the two drugs exhibit closely similar diffusion patterns when co-loaded in the HA-based hydrogels, plausibly due to drug-drug intermolecular interactions. At the highest drug concentrations, where superdiffusion comes into play, we find a fraction of molecules with time-varying diffusion coefficients. A trapping-release mechanism is proposed to explain this observation, which also accounts for the role of drug-hydrogel interactions in drug diffusion motion. The effects of drug-drug interactions on release profiles are finally assessed by means of in vitro release experiments.

Fabrication and Characterizations of Microwave‐Assisted Gelatin Cross‐Linked LBG/Guar Gum–Based Super Porous Hydrogels With Metformin Hydrochloride for Open Incision Wound Healing

ABSTRACTThe goal of this study was to fabricate gelatin cross‐linked Locust bean gum (LBG)/guar gum–based hydrogels with microwave assistance for diabetic wound healing applications and evaluate it for physicochemical properties. In the last few years, microwave irradiation has gained acceptance as a reliable technique for quickening and streamlining chemically modified reactions. In order to achieve this, metformin‐loaded LBG and guar gum–based hydrogel were formulated employing microwave radiation. Moreover, the microwave‐assisted–based metformin hydrogel are microwave‐assisted reaction sudden increase in temperature may led to distortion of molecules, very vigorous and which may be hazardous, but environmental sustainability and friendly chemistry concepts are supported by microwave irradiation. The optimized formulation (F3) showed significantly improved physicochemical properties, with a swelling capacity of 480.4% ± 2.5%. The results indicate an appropriate duration for adequate drugs diffusion and nutrition exchange. Controlled disintegrate and sustained release of embedded drug molecules from F3 may have an impact on antibacterial activity. The study indicated that microwave‐assisted polymer blend hydrogels had adequately improved physical qualities, making them a promising candidate for improving diabetic wound healing and hastening skin tissue regeneration.

Study of squalene monooxygenase mutations in response to higher MIC range among four dermatophytes &amp; their phylogenetic relatedness to Tinea indotineae at Doon valley

Antifungals reserved to, moderate &amp; recurrent cases of mycosis. Allylamines considered as 1st line drugs &amp; interfere with the ergosterol biosynthesis with SQLE gene. Strikingly elevated MIC leads to pathogen reassessment. To find out species specific predominance, of dermatophytes, in demography of Uttarakhand. Their susceptibility range, molecular study; for mutations in squalene SQLE gene in relation to higher MIC &amp; to corelate their phylogeny with previously reported genera.Samples collected from public hospitals, including treatment failure &amp; fresh cases, cultured at PDA for 25 days &amp; identified under trinocular. Microdilution performed by EUCAST E.def 11 CLSI guidelines to calculate the MIC, further genera confirmed by multiplying ITS1, ITS4,18s &amp; 28s rRNA specific primers, followed by sequencing. Homology confirmed at NCBI-FASTA by preparing a cladogram by CLUSTAL W &amp; MEGA X.Compratively &amp; recovered in huge quantity from higher altitudes.Clinical break points for , &amp; subsequently for terbinafine (11.9-21.6µg/ml), for Itraconazole(0.22-1.25µl/ml) &amp; for Fluconazole (0.12-0.22µl/ml) found much multiplied than previously reported MIC, at all 3 altitudes. SQLE was modified at aa F397L, A448T in mentagrophyte &amp; L393F in rubrum rRNA. It is difficult to find out the impact of increased MIC directly but helpful in associated pharmacokinetics &amp; pharmacodynamics by calculating C/MIC, time of diffusion of drug &amp; AUC/MIC ratios.PK/PD index in serum for increased MIC of antifungals more precisely to optimize antifungal therapy.

EXTH-28. DEVELOPING A NOVEL INJECTABLE IMMUNOTHERAPEUTIC GEL FOR ENCAPSULATION OF NATURAL KILLER CELLS FOR POST-SURGICAL GLIOBLASTOMA TREATMENT

Abstract Malignant brain tumors are one of the leading causes of death among all cancers. Approximately 40,000 people are diagnosed with malignant brain tumors every year. Among these patients, 15,000 cases are glioblastoma (GBM) with a very poor prognosis; even after aggressive surgical resection and adjuvant chemo/radiotherapy, the median survival is only 14.6 months. The major reason for poor prognosis is the blood-brain barrier, which prevents therapeutic agents from reaching the target area. Therefore, there are only a few choices of drugs available for brain tumor treatment. To date, temozolomide (TMZ) and the Gliadel wafer have been clinically used as standard chemotherapy agents after brain tumor resection. However, drug resistance to TMZ and the poor drug diffusion rate of the Gliadel wafer still result in ineffective suppression of residual cancer cells. To overcome the above-mentioned difficulties in clinical brain tumor treatment, in situ self-crosslinking multifunctional hydrogels was developed to carry natural killer cells (NK cells) and radiosensitizers as a novel brain tumor treatment system. Unlike traditional hydrogels catalyzed by pH value or temperature, this new system is stable and consistent as an immune cell carrier. We used fibrinogen, thrombin, and alginic acid as the backbone of the in situ self-crosslinking hydrogel, tested the properties of the synthesized hydrogel, and analyzed the gel-formation time and swelling rate. The release rate of NK cells was also examined. In a brain tumor animal model, the use of hydrogel-NK cells significantly inhibited tumor proliferation and prolonged animal survival time. In conclusion, this therapeutic hydrogel carrying NK cells can serve as a novel post-operation adjuvant therapeutic tool for malignant brain tumors.