Nanofiber-based Delivery of Luliconazole: Fabrication, Characterization, and Therapeutic Performance Assessment.

This study introduces and assesses the potential of a Luliconazole-loaded nanofiber (LUL-NF) patch, fabricated through electrospinning, for enhancing topical drug delivery. The primary objectives involve evaluating the nanofiber structure, characterizing physical properties, determining drug loading and release kinetics, assessing antifungal efficacy, and establishing the long-term stability of the NF patch. LUL-NF patches were fabricated via electrospinning and observed by SEM at approximately 200 nm dimensions. The comprehensive analysis included physical properties (thickness, folding endurance, swelling ratio, weight, moisture content, and drug loading) and UV analysis for drug quantification. In vitro studies explored sustained drug release kinetics, while microbiological assays evaluated antifungal efficacy against Candida albicans and Aspergillus Niger. Stability studies confirmed long-term viability. Comparative analysis with the pure drug, placebo NF patch, LUL-NF patch, and Lulifod gel was conducted using agar diffusion, revealing enhanced performance of the LUL-NF patch. SEM analysis revealed well-defined LUL-NF patches (0.80 mm thickness) with exceptional folding endurance (> 200 folds) and a favorable swelling ratio (12.66 ± 0.73%). The patches exhibited low moisture uptake (3.4 ± 0.09%) and a moisture content of 11.78 ± 0.54%. Drug loading in 1 cm2 section was 1.904 ± 0.086 mg, showing uniform distribution and sustained release kinetics in vitro. The LUL-NF patch demonstrated potent antifungal activity. Stability studies affirmed long-term stability, and comparative analysis highlighted increased inhibition compared to a pure drug, LUL-NF patch, and a commercial gel. The electrospun LUL-NF patch enhances topical drug delivery, promising extended therapy through single-release, one-time application, and innovative drug delivery strategies, supported by thorough analysis.

Comparative evaluation of hesperetin-loaded graphene oxide nanosheets (Hsp-GO) as a drug delivery system for colon cancer: synthesis and anticancer efficiency assessment.

BACKGROUND: Graphene oxide nanosheets (GONS) are recognized for their role in enhancing drug delivery and effectiveness in cancer treatment. With colon cancer being a prevalent global issue and the significant side effects associated with chemotherapy, the primary treatment for colon cancer alongside surgery, there is a critical need for novel therapeutic strategies to support patients in combating this disease. Hesperetin (HSP), a natural compound found in specific fruits, exhibits anti-cancer properties. The aim of this study is to investigate the effect of GONS on the LS174t colon cancer cell line. METHODS: In this study, an anti-cancer nano-drug was synthesized by creating a hesperetin-graphene oxide nanocomposite (Hsp-GO), which was subsequently evaluated for its efficacy through in vitro cell toxicity assays. Three systems were investigated: HSP, GONS, and HSP-loaded GONS, to determine their cytotoxic and pro-apoptotic impacts on the LS174t colon cancer cell line, along with assessing the expression of BAX and BCL2. The morphology and properties of both GO and Hsp-GO were examined using scanning electron microscopy (SEM), X-ray diffraction, and Fourier transform infrared spectroscopy (FTIR). RESULTS: The Hsp-GO nanocomposite displayed potent cytotoxic and pro-apoptotic effects on LS174t colon cancer cells, outperforming individual treatments with HSP or GONS. Cell viability assays showed a significant decrease in cell viability with Hsp-GO treatment. Analysis of BAX and BCL2 expression revealed elevated BAX and reduced BCL2 levels in Hsp-GO treated cells, indicating enhanced apoptotic activity. Morphological analysis confirmed successful Hsp-GO synthesis, while structural integrity was supported by X-ray diffraction and FTIR analyses. CONCLUSIONS: These study highlight the potential of Hsp-GO as a promising anti-cancer nano-drug for colon cancer therapy.

Development of solid lipid microparticles (SLMs) containing asiatic acid for topical treatment of acne: Characterization, stability, in vitro and in vivo anti-acne assessment.

Solid lipid microparticles (SLMs) represent a promising approach for drug delivery in anti-acne applications. In this study, asiatic acid-loaded SLMs (AASLMs) were prepared by melt emulsification method in conjunction with freeze-drying. Comprehensive evaluations comprised particle size, %entrapment efficiency (%EE), %labeled amount (%LA), surface morphology, stability, %release, %skin permeation, and anti-acne activity. The AASLMs exhibited an average particle size ranging from 7.46 to 38.86 µm, with %EE and %LA falling within the range of 31.56 to 100.00 and 90.43 to 95.38, respectively. The AASLMs demonstrated a spherical shape under scanning electron microscopy, and maintained stability over a 3-month period. Notably, formulations with 10 % and 15 % cetyl alcohol stabilized with poloxamer-188 (specifically F6 and F12) displayed a minimum inhibitory concentration (MIC) value of 75 mg/ml against Cutibacterium acnes. Furthermore, F12 exhibited a higher %release and %skin permeation compared to F6 over 24 h. In a single-blind clinical trial involving fifteen participants with mild-to-moderate acne, F12 showcased its potential not only in reducing porphyrin intensity and enhancing skin barriers but also in significantly improving skin hydration and brightness. However, further investigations with larger subject cohorts encompassing diverse age groups and genders are necessary to thoroughly establish the performance of the developed AASLMs.

RNA therapeutics for the treatment of blood disorders.

Blood disorders are defined as diseases related to the structure, function, and formation of blood cells. These diseases lead to increased years of life loss, reduced quality of life, and increased financial burden for social security systems around the world. Common blood disorder treatments such as using chemical drugs, organ transplants, or stem cell therapy have not yet approached the best goals, and treatment costs are also very high. RNA with a research history dating back several decades has emerged as a potential method to treat hematological diseases. A number of clinical trials have been conducted to pave the way for the use of RNA molecules to cure blood disorders. This novel approach takes advantage of regulatory mechanisms and the versatility of RNA-based oligonucleotides to target genes and cellular pathways involved in the pathogenesis of specific diseases. Despite positive results, currently, there is no RNA drug to treat blood-related diseases approved or marketed. Before the clinical adoption of RNA-based therapies, challenges such as safe delivery of RNA molecules to the target site and off-target effects of injected RNA in the body need to be addressed. In brief, RNA-based therapies open novel avenues for the treatment of hematological diseases, and clinical trials for approval and practical use of RNA-targeted are crucial.

Assessment of x-ray efficacy for intraoperative microneedle retrieval using a cadaveric model.

INTRODUCTION: Institutional protocols often mandate the use of x-rays when a microneedle is lost intraoperatively. Although x-rays can reliably show a macroneedle, the benefit of x-rays in detecting microneedles in human tissues has not been established as available data on this topic are investigated in anthropometric models. The current study aims to evaluate whether x-rays can reliably detect retained microneedles in a human cadaveric model. We hypothesize that microneedles would be detected at a significantly lower rate than macroneedles by x-ray in human tissues. MATERIALS AND METHODS: Needles ranging from 4-0 to 10-0 were placed randomly throughout a cadaveric hand and foot. Each tissue sample was x-rayed using a Fexitron X-Ray machine, taking both anteroposterior and lateral views. A total of six x-ray images were then evaluated by 11 radiologists, independently. The radiologists circled over the area where they visualized a needle. The accuracy of detecting macroneedles (size 4-0 to 7-0) was compared with that of microneedles (size 8-0 to 10-0) using a chi-square test. RESULTS: The overall detection rate for the microneedles was significantly lower than the detection rate for macroneedles (13.5% vs 88.8%, p < .01). When subcategorized between the hand and the foot, the detection rate for microneedles was also significantly lower than the rate for macroneedles (hand: 7.6% for microneedles, 93.2% for macroneedles, p < .01; foot: 19.5% for microneedles, 84.4% for macroneedles, p < .01). The detection rate, in general, significantly decreased as the sizes of needles became smaller (7-0:70.5%, 8-0:18.2%, 9-0:16.7%, 10-0:2.3%, p < .01). CONCLUSION: X-rays, while useful in detecting macroneedles, had a significantly lower rate of detecting microneedles in a cadaveric model. The routine use of x-rays for a lost microneedle may not be beneficial. Further investigation with fresh tissue and similar intraoperative x-ray systems is warranted to corroborate and support these findings.

Toward the Scalable, Rapid, Reproducible, and Cost-Effective Synthesis of Personalized Nanomedicines at the Point of Care.

Organic nanoparticles are used in nanomedicine, including for cancer treatment and some types of COVID-19 vaccines. Here, we demonstrate the scalable, rapid, reproducible, and cost-effective synthesis of three model organic nanoparticle formulations relevant to nanomedicine applications. We employed a custom-made, low-cost fluid mixer device constructed from a commercially available three-dimensional printer. We investigated how systematically changing aqueous and organic volumetric flow rate ratios determined liposome, polymer nanoparticle, and solid lipid nanoparticle sizes, size distributions, and payload encapsulation efficiencies. By manipulating inlet volumes, we synthesized organic nanoparticles with encapsulation efficiencies approaching 100% for RNA-based payloads. The synthesized organic nanoparticles were safe and effective at the cell culture level, as demonstrated by various assays. Such cost-effective synthesis approaches could potentially increase the accessibility to clinically relevant organic nanoparticle formulations for personalized nanomedicine applications at the point of care, especially in nonhospital and low-resource settings.

Encapsulation and assessment of therapeutic cargo in engineered exosomes: a systematic review.

Exosomes are nanoscale extracellular vesicles secreted by cells and enclosed by a lipid bilayer membrane containing various biologically active cargoes such as proteins, lipids, and nucleic acids. Engineered exosomes generated through genetic modification of parent cells show promise as drug delivery vehicles, and they have been demonstrated to have great therapeutic potential for treating cancer, cardiovascular, neurological, and immune diseases, but systematic knowledge is lacking regarding optimization of drug loading and assessment of delivery efficacy. This review summarizes current approaches for engineering exosomes and evaluating their drug delivery effects, and current techniques for assessing exosome drug loading and release kinetics, cell targeting, biodistribution, pharmacokinetics, and therapeutic outcomes are critically examined. Additionally, this review synthesizes the latest applications of exosome engineering and drug delivery in clinical translation. The knowledge compiled in this review provides a framework for the rational design and rigorous assessment of exosomes as therapeutics. Continued advancement of robust characterization methods and reporting standards will accelerate the development of exosome engineering technologies and pave the way for clinical studies.

Development and characterization of novel surface engineered Depofoam: a QbD coupled failure modes and effects analysis risk assessment-based optimization studies.

This study aimed to design and develop novel surface-engineered Depofoam formulations to extend the drug delivery to the prescribed time. The objectives are to prevent the formulation from burst release, rapid clearance by tissue macrophages, and instability and to analyze the impact of process and material variables in the characteristics of formulations. This work employed a quality-by-design coupled failure modes and effects analysis (FMEA)-risk assessment strategy. The factors for the experimental designs were chosen based on the FMEA results. The formulations were prepared by the double emulsification method followed by surface modification and characterized in terms of critical quality attributes (CQAs). The experimental data for all these CQAs were validated and optimized using the Box-Behnken design. A comparative drug release experiment was studied by the modified dissolution method. Furthermore, the stability of the formulation was also assessed. In addition, the impact of critical material attributes and critical process parameters on CQAs was evaluated using FMEA risk assessment. The optimized formulation method yielded high encapsulation efficiency (86.24 ± 0.69%) and loading capacity (24.13 ± 0.54%) with an excellent zeta potential value (-35.6 ± 4.55mV). The comparative in vitro drug release studies showed that more than 90% of the drug's release time from the surface-engineered Depofoam was sustained for up to 168 h without burst release and ensured colloidal stability. These research findings revealed that Depofoam prepared with optimized formulation and operating conditions yielded stable formulation, protected the drug from burst release, provided a prolonged release, and sufficiently controlled the drug release rate.

Kinetic assessment of iontophoretic delivery efficiency of niosomal tetracycline hydrochloride incorporated in electroconductive gel.

The purpose of this study was to conduct the kinetic assessment of iontophoretic delivery of niosomal tetracycline-HCl formulated in an electroconductive gel. Tween-80 and Span-80 were used to obtain tetracycline-HCl niosomes with an average diameter of 101.9 ± 3.3 nm, a polydispersity index of 0.247 ± 0.004, a zeta potential of - 34.1 mV, and an entrapment efficiency of 70.08 ± 0.16%. Four different gel preparations, two of which contained niosomal tetracycline-HCl, were transdermally delivered using Franz diffusion cells under the trigger effect of iontophoresis, applied at 0.2, 0.5, and 1 mA/cm2 current density. The control group was the passive diffusion results of the preparation made using a tetracycline-HCl-based drug marketed in Turkey. The control group was compared with the groups that contained (a) tetracycline-HCl in an electroconductive gel, (b) the niosomal tetracycline-HCl formulation in water, and (c) the niosomal tetracycline-HCl formulation in the electroconductive gel. The group with the niosomal formulation in the electroconductive gel displayed the highest increase in iontophoretic transdermal delivery relative to the control group, displaying a 2-, 2.1-, and 2.2-fold increase, respectively, by current density. The experimental results of transdermal delivery using the synergistic effect of niosomal formulation in electroconductive gel and the trigger effect of iontophoresis appeared to divert slightly from zero-order kinetics, demonstrating a statistically significant increase in the rate of controlled transdermal drug delivery. Considering that about 20% of the formulation is transdermally delivered in the first half-hour, the iontophoretic transdermal delivery of niosomal tetracycline-HCl can be efficiently used in local iontophoretic therapy.

Computational Assessment of Unsteady Flow Effects on Magnetic Nanoparticle Targeting Efficiency in a Magnetic Stented Carotid Bifurcation Artery.

PURPOSE: Worldwide, cardiovascular disease is the leading cause of hospitalization and death. Recently, the use of magnetizable nanoparticles for medical drug delivery has received much attention for potential treatment of both cancer and cardiovascular disease. However, proper understanding of the interacting magnetic field forces and the hydrodynamics of blood flow is needed for effective implementation. This paper presents the computational results of simulated implant assisted medical drug targeting (IA-MDT) via induced magnetism intended for administering patient specific doses of therapeutic agents to specific sites in the cardiovascular system. The drug delivery scheme presented in this paper functions via placement of a faintly magnetizable stent at a diseased location in the carotid artery, followed by delivery of magnetically susceptible drug carriers guided by the local magnetic field. Using this method, the magnetic stent can apply high localized magnetic field gradients within the diseased artery, while only exposing the neighboring tissues, arteries, and organs to a modest magnetic field. The localized field gradients also produce the forces needed to attract and hold drug-containing magnetic nanoparticles at the implant site for delivering therapeutic agents to treat in-stent restenosis. METHODS: The multi-physics computational model used in this work is from our previous work and has been slightly modified for the case scenario presented in this paper. The computational model is used to analyze pulsatile blood flow, particle motion, and particle capture efficiency in a magnetic stented region using the magnetic properties of magnetite (Fe3O4) and equations describing the magnetic forces acting on particles produced by an external cylindrical electromagnetic coil. The electromagnetic coil produces a uniform magnetic field in the computational arterial flow model domain, while both the particles and the implanted stent are paramagnetic. A Eulerian-Lagrangian technique is adopted to resolve the hemodynamic flow and the motion of particles under the influence of a range of magnetic field strengths (Br = 2T, 4T, 6T, and 8T). Particle diameter sizes of 10 nm-4 µm in diameter were evaluated. Two dimensionless numbers were evaluated in this work to characterize relative effects of Brownian motion (BM), magnetic force induced particle motion, and convective blood flow on particle motion. RESULTS: The computational simulations demonstrate that the greatest particle capture efficiency results for particle diameters within the micron range of 0.7-4 µm, specifically in regions where flow separation and vortices are at a minimum. Similar to our previous work (which did not involve the use of a magnetic stent), it was also observed that the capture efficiency of particles decreases substantially with particle diameter, especially in the superparamagnetic regime. Contrary to our previous work, using a magnetic stent tripled the capture efficiency of superparamagnetic particles. The highest capture efficiency observed for superparamagnetic particles was 78% with an 8 T magnetic field strength and 65% with a 2 T magnetic field strength when analyzing 100 nm particles. For 10 nm particles and an 8 T magnetic field strength, the particle capture efficiency was 55% and for a 2 T magnetic field strength the particle capture efficiency was observed to be 43%. Furthermore, it was found that larger magnetic field strengths, large particle diameter sizes (1 µm and above), and slower blood flow velocity improves the particle capture efficiency. The distribution of captured particles on the vessel wall along the axial and azimuthal directions is also discussed. Results for captured particles on the vessel wall along the axial flow direction showed that the particle density decreased along the axial direction, especially after the stented region. For the entrance section of the stented region, the captured particle density distribution along the axial direction is large, corresponding to the center-symmetrical distribution of the magnetic force in that section. CONCLUSION: The simulation results presented in this work have shown to yield favorable capture efficiencies for micron range particles and superparamagnetic particles using magnetized implants such as the stent discussed in this work. The results presented in this work justify further investigation of MDT as a treatment technique for cardiovascular disease.

Preclinical Assessment of ADAM9-Responsive Mesoporous Silica Nanoparticles for the Treatment of Pancreatic Cancer.

Pancreatic adenocarcinoma (PDAC) remains largely refractory to chemotherapeutic treatment regimens and, consequently, has the worst survival rate of all cancers. The low efficacy of current treatments results largely from toxicity-dependent dose limitations and premature cessation of therapy. Recently, targeted delivery approaches that may reduce off-target toxicities have been developed. In this paper, we present a preclinical evaluation of a PDAC-specific drug delivery system based on mesoporous silica nanoparticles (MSNs) functionalized with a protease linker that is specifically cleaved by PDAC cells. Our previous work demonstrated that ADAM9 is a PDAC-enriched protease and that paclitaxel-loaded ADAM9-responsive MSNs effectively kill PDAC cells in vitro. Here, we show that paclitaxel-loaded ADAM9-MSNs result in off-target cytotoxicity in clinically relevant models, which spurred the development of optimized ADAM9-responsive MSNs (OPT-MSNs). We found that these OPT-MSNs still efficiently kill PDAC cells but, as opposed to free paclitaxel, do not induce death in neuronal or bone marrow cells. In line with these in vitro data, paclitaxel-loaded OPT-MSNs showed reduced organ damage and leukopenia in a preclinical PDAC xenograft model. However, no antitumor response was observed upon OPT-MSN administration in vivo. The poor in vivo antitumor activity of OPT-MSNs despite efficient antitumor effects in vitro highlights that although MSN-based tumor-targeting strategies may hold therapeutic potential, clinical translation does not seem as straightforward as anticipated.

Development of a Compensated Förster Resonance Energy Transfer Imaging for Improved Assessment of the Intrapulmonary Distribution of Polymeric Nanoparticles.

Inhalation-based drug delivery systems have gained attention as potential therapeutic options for various respiratory diseases. Among these systems, nanoparticles are being explored as drug carriers because of their ability to deliver therapeutic agents directly to the lungs. It is essential to accurately evaluate the intrapulmonary behavior of nanoparticles to optimize drug delivery and achieve selective targeting of lung lesions. Prior research used the Förster resonance energy transfer (FRET) phenomenon to study the in vivo behavior of nanoparticles as drug carriers. In this study, image reconstruction involving bleed-through compensation was used to quantitatively assess the behavior of FRET nanoparticles in the lungs. When the nanoparticles for FRET fluorescence imaging, which employed 1,1'-dioctadecyl-3,3,3',3'-tetramethylindodicarbocyanine, 4-chlorobenzenesulfonate salt (DiD) as the donor and as 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine iodide (DiR) the acceptor, were administered to mouse lungs, whole-body in vivo imaging could not compensate for the influence of respiration and heartbeat. However, ex vivo imaging of excised lungs enabled the quantitative evaluation of the time-concentration profiles and distribution of nanoparticles within the lungs. This imaging technique is particularly useful for the development of inhalable nanoparticles that specifically target the lesions and exhibit controlled-release capabilities within the lungs.

In vitro and in vivo assessment of structural integrity for HPCD complex@Liposome nanocomposites from ocular surface to the posterior segment of the eye.

Investigating the structural integrity of carriers in transit from ocular surface to ocular posterior segment is essential for an efficient topical drug delivery system. In this study, dual-carrier hydroxypropyl-ß-cyclodextrin complex@Liposome (HPCD@Lip) nanocomposites were developed for the efficient delivery of dexamethasone. Förster Resonance Energy Transfer with near-infrared I fluorescent dyes and in vivo imaging system were used to investigate the structural integrity of HPCD@Lip nanocomposites after crossing Human conjunctival epithelial cells (HConEpiC) monolayer and in ocular tissues. The structural integrity of inner HPCD complexes was monitored for the first time. The results suggested that 23.1 ± 6.4 % of nanocomposites and 41.2 ± 4.3 % of HPCD complexes could cross HConEpiC monolayer with an intact structure at 1 h. 15.3 ± 8.4 % of intact nanocomposites could reach at least sclera and 22.9 ± 1.2 % of intact HPCD complexes could reach choroid-retina after 60 min in vivo, which showed that the dual-carrier drug delivery system could successfully deliver intact cyclodextrin complexes to ocular posterior segment. In conclusion, in vivo assessment of structural integrity of nanocarriers is greatly significant for guiding the rational design, higher drug delivery efficiency and clinical transformation for topical drug delivery system to the posterior segment of the eye.

Self-Assembling Lecithin-Based Mixed Polymeric Micelles for Nose to Brain Delivery of Clozapine: In-vivo Assessment of Drug Efficacy via Radiobiological Evaluation.

Purpose: The research objective is to design intranasal brain targeted CLZ loaded lecithin based polymeric micelles (CLZ- LbPM) aiming to improve central systemic CLZ bioavailability. Methods: In our study, intranasal CLZ loaded lecithin based polymeric micelles (CLZ- LbPM) were formulated using soya phosphatidyl choline (SPC) and sodium deoxycholate (SDC) with different CLZ:SPC:SDC ratios via thin film hydration technique aiming to enhance drug solubility, bioavailability and nose to brain targeting efficiency. Optimization of the prepared CLZ-LbPM using Design-Expert® software was achieved showing that M6 which composed of (CLZ:SPC: SDC) in respective ratios of 1:3:10 was selected as the optimized formula. The optimized formula was subjected to further evaluation tests as, Differential Scanning Calorimetry (DSC), TEM, in vitro release profile, ex vivo intranasal permeation and in vivo biodistribution. Results: The optimized formula with the highest desirability exhibiting (0.845), small particle size (12.23±4.76 nm), Zeta potential of (-38 mV), percent entrapment efficiency of > 90% and percent drug loading of 6.47%. Ex vivo permeation test showed flux value of 27 µg/cm².h and the enhancement ratio was about 3 when compared to the drug suspension, without any histological alteration. The radioiodinated clozapine ([131I] iodo-CLZ) and radioiodinated optimized formula ([131I] iodo-CLZ-LbPM) were formulated in an excellent radioiodination yield more than 95%. In vivo biodistribution studies of [131I] iodo-CLZ-LbPM showed higher brain uptake (7.8%± 0.1%ID/g) for intranasal administration with rapid onset of action (at 0.25 h) than the intravenous formula. Its pharmacokinetic behavior showed relative bioavailability, direct transport percentage from nose to brain and drug targeting efficiency of 170.59%, 83.42% and 117% respectively. Conclusion: The intranasal self-assembling lecithin based mixed polymeric micelles could be an encouraging way for CLZ brain targeting.

Computational Assessment of Magnetic Nanoparticle Targeting Efficiency in a Simplified Circle of Willis Arterial Model.

This paper presents the methodology and computational results of simulated medical drug targeting (MDT) via induced magnetism intended for administering intravenous patient-specific doses of therapeutic agents in a Circle of Willis (CoW) model. The multi-physics computational model used in this work is from our previous works. The computational model is used to analyze pulsatile blood flow, particle motion, and particle capture efficiency in a magnetized region using the magnetic properties of magnetite (Fe3O4) and equations describing the magnetic forces acting on particles produced by an external cylindrical electromagnetic coil. A Eulerian-Lagrangian technique is implemented to resolve the hemodynamic flow and the motion of particles under the influence of a range of magnetic field strengths (Br = 2T, 4T, 6T, and 8T). Particle diameter sizes of 10 nm to 4 µm in diameter were assessed. Two dimensionless numbers are also investigated a priori in this study to characterize relative effects of Brownian motion (BM), magnetic force-induced particle motion, and convective blood flow on particle motion. Similar to our previous works, the computational simulations demonstrate that the greatest particle capture efficiency results for particle diameters within the micron range, specifically in regions where flow separation and vortices are at a minimum. Additionally, it was observed that the capture efficiency of particles decreases substantially with smaller particle diameters, especially in the superparamagnetic regime. The highest capture efficiency observed for superparamagnetic particles was 99% with an 8T magnetic field strength and 95% with a 2T magnetic field strength when analyzing 100 nm particles. For 10 nm particles and an 8T magnetic field strength, the particle capture efficiency was 48%, and for a 2T magnetic field strength the particle capture efficiency was 33%. Furthermore, it was found that larger magnetic field strengths, large particle diameter sizes (1 µm and above), and slower blood flow velocity increase the particle capture efficiency. The key finding in this work is that favorable capture efficiencies for superparamagnetic particles were observed in the CoW model for weak fields (Br < 4T) which demonstrates MDT as a possible viable treatment candidate for cardiovascular disease.

Assessment of formulation variables of poor water soluble diacerein for its improved loading and anti-inflammatory activity.

Dissolving microneedles have become a popular method for percutaneous administrationof drugs. However, loading poorly soluble drugs into water-based dissolving microneedles remains a challenge. In view of this, we aimed to improve Diacerein (DCN) solubility formulating dissolving microneedles. DCN microsuspension was created by high-speed homogenization with organic solvents or wet milling with Tween 80 as a stabilizer (LD1). They were analyzed for particle size and saturation solubility. Subsequently, the organic solvent-based microneedles were prepared under vacuum, whereas LD1 was mixed with HPMC (8% w/w) and PVP (30% w/w) matrix to concentrate the drug in acral fraction through centrifugation. DCN microsuspension in DMSO had the highest drug solubility with an average particle size of 6 µm, whereas LD1 had a particle size of 3.28 µm showing improved solubility. TD-3 had the highest drug loading and the least amount of drug migration into the blank baseplate. Within 5 min, these microneedles dissolved completely in an agarose-gel block. LD1 was likewise put in the baseplate to generate TD3-B. Within 24 h, 74.39% of the medication was released from TD3-B, with only a small amount remaining in the baseplate. TLC examination indicated the conversion of DCN to Rhein in the skin, whereas DSC and TGA studies revealed amorphous features. DCN microneedles showed no sign of skin irritancy but showed anti-inflammatory response on carrageenan-induced paw edema model. Microneedles remained stable during accelerated stability testing. Wet milling in the presence of a stabilizer can be an effective approach for enhancing DCN solubility for improved drug loading in dissolving microneedles. Improvement in solubility of Diacerein for subsequent loading in Dissolving Microneedle for percutaneous delivery.

Assessment of superiority of HSP70-targeting aptamer-functionalized drug-nanocarrier over non-targeted commercially available counterpart in HCC therapy: in vitro and in vivo investigations and molecular modeling.

AIMS: This research aims to compare the therapeutic potential of target-specific phosphorothioate backbone-modified aptamer L5 (TLS9a)-functionalized paclitaxel (PTX)-loaded nanocarrier (PTX-NPL5) that we formulated with that of non-targeted commercial formulation, protein albumin-bound nanoparticles of PTX, Abraxane® (CF) against hepatocellular carcinoma (HCC) through a myriad of preclinical investigations. MAIN METHODS: A variety of in vitro and in vivo assays have been executed to compare the therapeutic effects of the formulations under investigation, including the investigation of the degree of apoptosis induction and its mechanism, cell cycle analysis, the level of ROS production, and redox status, the morphological and histological characteristics of malignant livers, and in vivo imaging. The formulations were also compared concerning pharmacokinetic behaviors. Finally, in silico molecular docking has been performed to predict the possible interactions between aptamer and target(s). KEY FINDINGS: PTX-NPL5 exhibited therapeutic superiority over CF in terms of inducing apoptosis, cell cycle arrest, endorsing oxidative stress to neoplastic cells, and reducing hepatic cancerous lesions. Unlike CF, PTX-NPL5 did not exhibit any significant toxicity in healthy hepatocytes, proving enough impetus regarding the distinctive superiority of PTX-NPL5 over CF. The pharmacokinetic analysis further supported superior penetration and retention of PTX-NPL5 in neoplastic hepatocytes compared to CF. A molecular modeling study proposed possible interaction between aptamer L5 and heat shock protein 70 (HSP70). SIGNIFICANCE: The target-specificity of PTX-NPL5 towards neoplastic hepatocytes, probably achieved through HSP70 recognition, enhanced its therapeutic efficacy over CF, which may facilitate its real clinical deployment against HCC in the near future.

Development and optimization of transethosomal gel of apigenin for topical delivery: In-vitro, ex-vivo and cell line assessment.

The main aim of this study was to optimize the transethosomes of apigenin formulated by the thin film hydration method using surfactant Span 80. Response surface Box-Behnken design with three levels of three factors was used to design and optimize the formulations. The prepared transethosomal formulations were characterized for entrapment efficiency, vesicle size, and flux to obtain the optimized formulation batch. The optimized batch was further incorporated into the gel and characterized for the in-vitro, ex-vivo, and cytotoxic studies. The result showed the optimized transethosomes were smooth, nanosized, unilamellar, and spherical with an entrapment efficiency of 78.75 ± 3.14 %, a vesicle size of 108.75 ± 2.31 nm, and a flux of 4.10 ± 0.63 µg/cm2/h. In-vitro cumulative drug release of transethosomal gel of apigenin (TEL gel) and the conventional gel was 92.25 ± 3.5 % and 53.40 ± 3.10 %, respectively, after 24 h study. Ex-vivo permeation of TEL gel and conventional gel showed 86.20 ± 3.60 % and 51.20 ± 3.20 % permeation of apigenin at 24 h, respectively. A cytotoxic study confirmed that TEL gel significantly reduces cell viability compared to conventional gel. The results suggested that topical application of apigenin transethosomal gel may be a better treatment strategy for skin cancer because of the prolonged sustained release of the drug and the better permeability of apigenin through the skin.

Assessment of hydrophobic-ion paired insulin incorporated SMEDDS for the treatment of diabetes mellitus.

To overcome the low oral bioavailability of insulin, we hypothesized that the insulin-hydrophobic ion pairing (HIP) complex incorporated self-microemulsifying drug delivery system (SMEDDS) would be beneficial. In the present study, an oral insulin delivery system was developed and estimated using the HIP technique and SMEDDS. Further insulin-HIP complexes were characterized using various spectroscopical techniques. Additionally, insulin-HIP complexes were subjected to analysis of complexes' conformational stability in the real physiological solution using computational approaches. On the other hand, in vitro, and in vivo studies were carried out to investigate the permeability and hypoglycemic effect. Subsequently, in an in vitro non-everted gut sac study, the apparent permeability coefficient (Papp) was approximately 8-fold higher in the colon than in the jejunum, and the HIP-incorporated SMEDDS showed an approximately 3-fold higher Papp value than the insulin solution. The hypoglycemic effect after in situ colon instillation, the HIP complex between insulin and sodium docusate-incorporated SMEDDS showed a pharmacological availability of 2.52 ± 0.33 % compared to the subcutaneously administered insulin solution. Thus, based on these outcomes, it can be concluded that the selection of appropriate counterions is important in developing HIP-incorporated SMEDDS, wherein this system shows promise as a tool for oral peptide delivery systems.

Efficient delivery of abciximab using mesoporous silica nanoparticles: In-vitro assessment for targeted and improved antithrombotic activity.

Abciximab (ABX) is a chimeric monoclonal antibody reported for antithrombotic activity but their delivery remains challenging due to its poor stability in a biological system. The purpose of this research was to deliver ABX on the target efficiently using mesoporous silica nanoparticles (MSN). ABX coated mesoporous silica nanoparticles (MSN-ABX) were formulated and analyzed for particle size, shape, zeta-potential, surface morphology and surface chemistry. XPS analysis confirmed the presence of ABX on the surface of amino functionalized mesoporous silica nanoparticles (MSN-NH2). The degree of ABX attachment was 67.53 ± 5.81 % which was demonstrated by the Bradford assay. Furthermore, the targeting efficiency of the targeted nanoparticles has been evaluated by capturing the fluorescent images in-vitro which showed the significant accumulation of the ABX coated nanoparticles towards activated platelets. The significant (P < 0.05) increase in affinity of DiD dye loaded nanoparticles towards the activated platelets was confirmed by using an in-vitro imaging through photon imager optima. The hemolysis study of the nanoparticle formulations revealed that they were non-hemolytic for healthy human blood. The in-vitro antithrombotic effects of MSN-ABX were observed by blood clot assay which revealed its superior antithrombotic activity over clinical injection of ABX and could be a promising carrier for improved ABX targeted delivery.