Thermosensitive multivesicular liposomal hydrogel: a potential platform for loco-regional drug delivery in the treatment of osteomyelitis caused by antibiotic-resistant biofilm-forming bacteria.

Biofilm-mediated osteomyelitis presents significant therapeutic challenges. Given the limitations of existing osteomyelitis treatment approaches, there is a distinct need to develop a localized drug delivery system that is biocompatible, biodegradable, and capable of controlled antibiotic release. Multivesicular liposomes (MVLs), characterized by their non-concentric vesicular structure, distinct composition, and enhanced stability, serve as the system for a robust sustained-release drug delivery platform. In this study, various hydrogel formulations composed of poloxamer 407 and other hydrogels, incorporating vancomycin hydrochloride (VAN HL) -loaded MVLs (VAN HL-MVL), were prepared and evaluated. The optimized VAN HL-MVL sol-gel system, consisting of poloxamer 407 and hyaluronic acid, successfully maintained drug release for up to three weeks and exhibited shear-thinning behavior at 37°C. While complete drug release from MVLs alone took place in 312 hours, the hydrogel formulation extended this release to 504 hours. The released drug effectively inhibited the Staphylococcus aureus biofilms growth within 24 hours and methicillin-resistant Staphylococcus aureus biofilms within 72 hours. It also eradicated pre-formed biofilms of Staphylococcus aureus and methicillin-resistant Staphylococcus aureus in 96 and 120 hours, respectively. This injectable in situ gel system incorporating VAN HL-MVLs holds potential as an alternative to undergoing multiple surgeries for osteomyelitis treatment and warrants further studies.

Preparation of multivesicular liposomes for the loco-regional delivery of Vancomycin hydrochloride using active loading method: drug release and antimicrobial properties.

Over the last few years, among controlled-release delivery systems, multivesicular liposomes (MVLs) have attracted attention due to their unique benefits as a loco-regional drug delivery system. Considering the clinical limitations of the current treatment strategies for osteomyelitis, MVLs can be a suitable carrier for the local delivery of effective antibiotics. This study aimed to prepare vancomycin hydrochloride (VAN HL) loaded MVLs using the active loading method which to the best of our knowledge has not been previously reported. Empty MVLS were prepared by the double emulsion (w/o/w) method and VAN HL was loaded into the prepared liposomes by the ammonium gradient method. After full characterization, the release profile of VAN HL from MVLs was assessed at two different pH values (5.5 and 7.4), and compared with the release profile of the free drug and also passively loaded MVLs. In vitro antimicrobial activities were evaluated using the disc diffusion method. Our results demonstrated that the encapsulation efficiency was higher than 90% in the optimum actively loaded MVL. The free VAN HL was released within 6-8 h, while the passively loaded MVLs and the optimum actively loaded MVL formulation released the drug in 6 days and up to 19 days, respectively. The released drug showed effective antibacterial activity against osteomyelitis-causing pathogens. In conclusion, the prepared formulation offered the advantages of sustained-release properties, appropriate particle size as well as being composed of biocompatible materials, and thus could be a promising candidate for the loco-regional delivery of VAN HL and the management of osteomyelitis.

Recombinant human epidermal growth factor-loaded liposomes and transferosomes for dermal delivery: Development, characterization, and cytotoxicity evaluation.

Recombinant human epidermal growth factor (rhEGF) is widely utilized as an antiaging compound in wound-healing therapies and cosmetic purposes. However, topical administration of rhEGF has limited treatment outcomes because of its poor percutaneous penetration and rapid proteinase degradation. To overcome these obstacles, this study aims to develop and characterize rhEGF-containing conventional liposomes (rhEGF-CLs) and transferosomes (rhEGF-TFs) as efficient dermal carriers. Physicochemical characterization such as particle size, zeta potential (ZP), morphology, encapsulation efficiency (EE%), and release properties of nanocarriers as well as in vitro cytotoxicity in human dermal fibroblast (HDF) and human embryonic kidney (HEK293) cell lines were investigated. rhEGF-TFs at the rhEGF concentration ranging from 0.05 to 1.0 µg/mL were chosen as the optimum formulation due to the desired release profile, acceptable EE%, optimal cell proliferation, and minimal cytotoxicity compared to the control and free rhEGF. However, higher concentrations caused a decrease in cell viability. The ratio 20:80 of Tween 80 to lipid was optimal for rhEGF-TFs-2, which had an average diameter of 233.23 ± 2.64 nm, polydispersity index of 0.33 ± 0.05, ZP of -15.46 ± 0.29 mV, and EE% of 60.50 ± 1.91. The formulations remained stable at 5°C for at least 1 month. TEM and SEM microscopy revealed that rhEGF-TFs-2 had a regular shape and unilamellar structure. In vitro drug release studies confirmed the superiority of rhEGF-TFs-2 in terms of optimal cumulative release of rhEGF approximately 82% within 24 h. Franz diffusion cell study showed higher rhEGF-TFs-2 skin permeation compared to free rhEGF solution. Taken together, we concluded that rhEGF-TFs can be used as a promising formulation for wound healing and skin regeneration products.

Bile salt-enriched vs. non-enriched nanoparticles: comparison of their physicochemical characteristics and release pattern.

Bile salts were first used in the preparation of nanoparticles due to their stabilizing effects. As time went by, they attracted much attention and were increasingly employed in fabricating nanoparticles. It is well accepted that the physicochemical properties of nanoparticles are influential factors in their permeation, distribution, elimination and degree of effectiveness as well as toxicity. The review of articles shows that the use of bile salts in the structure of nanocarriers may cause significant changes in their physicochemical properties. Hence, having information about the effect of bile salts on the properties of nanoparticles could be valuable in the design of optimal carriers. Herein, we review studies in which bile salts were used in preparing liposomes, niosomes and other nanocarriers. Furthermore, the effects of bile salts on entrapment efficiency, particle size, polydispersity index, zeta potential, release profile and stability of nanoparticles are pointed out. Finally, we debate how to take advantage of bile salts potential for preparing desirable nanocarriers.

Extracellular vesicle-based formulation of doxorubicin: drug loading optimization, characterization, and cytotoxicity evaluation in tumor spheroids.

Doxorubicin (DOX) is a chemotherapeutic with considerable efficacy, but its application is limited due to cardiotoxicity. Nanoparticles can improve DOX efficacy and prevent its adverse effects. Herein, DOX-loaded extracellular vesicles (DOX-EVs) were prepared using different loading methods including incubation, electroporation, and sonication in different hydration buffers to permeabilize nanostructures or desalinize DOX for improved entrapment. Different protein:drug (µg:µg) ratios of 1:10, 1:5, and 1:2, and incubation parameters were also investigated. The optimal formulation was characterized by western blotting, electron microscopy, Zetasizer, infrared spectroscopy, and release study. The cellular uptake and efficacy were investigated in MCF-7 spheroids via MTS assay, spheroid formation assay (SFA), confocal microscopy, and flow cytometry. The percentage of entrapment efficiency (EE) of formulations was improved from 1.0 ± 0.1 to 22.0 ± 1.4 using a protein:drug ratio of 1:2 and sonication in Tween 80 (0.1%w/v) containing buffer. Characterization studies verified the vesicles' identity, spherical morphology, and controlled drug release properties. Cellular studies revealed the accumulation and cytotoxicity of DOX-EVs in the spheroids, and SFA and confocal microscopy confirmed the efficacy and cellular localization. Flow cytometry results revealed a comparable and amplified efficacy for DOX-EV formulations with different cell origins. Overall, the EV formulation of DOX can be applied as a promising alternative with potential advantages.

Piperine liposome-embedded in hyaluronan hydrogel as an effective platform for prevention of postoperative peritoneal adhesion.

This study aimed to prepare piperine (PIP) loaded liposomes in hyaluronic acid (HA) hydrogel to provide a hybrid superstructure for postoperative adhesion prevention. Liposomes were prepared using thin-film hydration method. The optimised formulation was characterised by size, SEM, TEM, FTIR, encapsulation efficiency (EE)% (w/w), and release pattern. Liposome-in-hydrogel formulation was investigated by rheology, SEM, and release studies. The efficacy was evaluated in a rat peritoneal abrasion model. EE% (w/w) increased with increasing lipid concentration from 10 to 30; however, a higher percentage of Chol reduced EE% (w/w). The optimised liposome (EE: 68.10 ± 1.71% (w/w), average diameter: 513 ± 8 nm, PDI: 0.15 ± 0.04) was used for hydrogel embedding. No sign of adhesion in 5/8 rats and no collagen deposition confirmed the in vivo effectiveness of the optimised formulation. Overall, providing a sustained delivery of PIP, the developed liposome-in-hydrogel formulation can be a promising carrier to prevent postoperative adhesion.

Sirolimus-exuding core-shell nanofibers as an implantable carrier for breast cancer therapy: preparation, characterization, in vitro cell studies, and in vivo anti-tumor activity.

OBJECTIVE: Breast cancer accounts for significant mortality worldwide. Here, we develop a localized, sustained-release delivery system for breast cancer therapy. METHODS: Sirolimus (SIR) core-shell nanofibers (NFs) are fabricated by coaxial electrospinning with poly(ε-caprolactone) (PCL) for the core and chitosan and PCL for the shell. The NFs were characterized by SEM, AFM, TEM, XRD, FTIR, water uptake, water contact angle, mechanical properties, drug content, and in vitro release. In vitro and in vivo anticancer effects were investigated. RESULTS: A sustained release behavior is observed during 480 h that is more extended compared to monoaxial NFs. In vitro cytotoxicity and Annexin V/propidium iodide assays indicate that SIR-loaded coaxial NFs are effective in inhibiting proliferation of 4T1 and MCF-7 cells. Implantation of SIR NFs in 4T1 breast tumor-bearing mice inhibits tumor growth significantly compared to free drug. Histopathological examination shows that suppression of tumor growth by SIR NFs is associated with apoptotic cell death. Furthermore, anti-cancer effects are also confirmed by decreased expression levels of Ki-67, MMP-2, and MMP-9. Histological observation of organs, serological analyses, and the lack of body weight changes indicate in vivo safety of SIR NFs. CONCLUSIONS: Altogether, we show here that incorporation of SIR into core-shell NFs could act as an effective drug release depot and induce a sustained antitumor response.

Fabrication, in Vitro, and in Vivo Characterization of Mucoadhesive Berberine-Loaded Blended Wafers for Treatment of Chemotherapy-Induced Oral Mucositis.

This study aims to design and characterize berberine-loaded wafers for the treatment of chemotherapy-induced oral mucositis. Wafers were prepared by lyophilization of hydrogels of various ratios of chitosan (CS)/sodium alginate (SA) as well as CS/hydroxypropyl methylcellulose (HPMC). In vitro release, in vitro mucoadhesion, porosity, and swelling studies were conducted to select the optimized formulations. Moreover, scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), and mechanical properties studies were also performed for further characterization. The efficacy of optimized berberine-loaded wafers in the treatment of oral mucositis was investigated in a 5FU-induced oral mucositis rat model. F2-CS-SA and F6-CS-HPMC wafers exhibited sustained release profile and excellent mucoadhesion strength. Therefore, these wafers were selected as the optimized formulations. SEM confirmed the porous structure of these wafers and is in agreement with the results of porosity and swelling studies. XRD and FTIR studies indicated that berberine was incorporated into the wafer matrix in the amorphous form. In vivo studies demonstrated that topical application of berberine-loaded optimized wafers reduced significantly the severity of 5FU-induced oral mucositis and decreased the expression of inflammatory markers (TNF-α and IL-1ß). The results of in vitro and in vivo studies revealed that berberine-loaded F2-CS-SA and F6-CS-HPMC wafers can be effective in the treatment of chemotherapy-related oral mucositis.

Multivesicular liposomal depot system for sustained delivery of risperidone: development, characterization, and toxicity assessment.

OBJECTIVE: Considering the limitations of conventional risperidone (RSP) therapies, the present research characterizes the usefulness of multivesicular liposomes (MVLs) as an efficient controlled-release carrier for this widely used antipsychotic drug, to be employed for the treatment of schizophrenia. METHODS: A 23 full factorial design based on three independent variables was implemented to plan the experiments: the molar ratios of lipid to the drug, triolein to phospholipid, and cholesterol to phospholipid. The impacts of these parameters on the risperidone encapsulation efficiency and its release pattern within the first 24 and 48 h were investigated as dependent variables. Then, the optimized liposomal system was further in-depth analyzed in terms of size, morphological and structural features, release profile over 15 days, biocompatibility, and stability. RESULTS: Optimized formulation parameters gave rise to MVLs possessing a spherical morphology with a median diameter of about 8 µm, a relatively narrow size distribution (span value of 1.49), and an encapsulation efficiency of 57.6%. These carriers not only exhibited a sustained-release behavior in vitro, lasting until the end of the 15 days but also underwent a negligible change in their size and RSP incorporation over two months at refrigerator condition. Furthermore, in vitro cytotoxicity and hemolysis assessments revealed that the optimized MVL formulation is biocompatible. CONCLUSION: This study revealed the potential of MVLs as a promising system for the delivery of RSP and could open a new vista for the successful management of schizophrenia.

Tuning the Physicochemical Characteristics of Particle-Based Carriers for Intraperitoneal Local Chemotherapy.

Over the last few decades, intraperitoneal (IP) local drug delivery, providing high drug concentrations with prolonged retention in the peritoneal cavity, has opened a new horizon for the management of life-threatening peritoneal disorders, such as peritoneal carcinomatosis (PC). However, clinical translation of this strategy is hampered by several hurdles, namely premature clearance of small-sized molecules from the peritoneum, limited distribution within the peritoneal space and inadequate penetration into the target tissues. To address these challenges, incorporation of therapeutic agents into the particulate-based drug delivery systems has brought new hope in this direction. Nonetheless, as yet, there has been no formulation specifically approved for IP delivery. To gain this goal, it is crucial to have a detailed understanding of the correlation between the physicochemical characteristics of particle-based carriers and their biological fate and anticancer efficacy after IP administration. The main focus of this review, therefore, concerns the significance of these characteristics, namely composition, particle size, charge, coating and presence of targeting moieties in the design of carriers for successful IP delivery. Graphical Abstract Physicochemical characteristics of particle-based carriers influence their peritoneal residence time, biological fate and anticancer efficacy after intraperitoneal administration.

Pharmacokinetics, Tissue Distribution and Excretion of Ag2S Quantum Dots in Mice and Rats: the Effects of Injection Dose, Particle Size and Surface Charge.

PURPOSE: We systematically investigated the effects of injection dose, particle size and surface charge on the pharmacokinetics, tissue distribution and excretion of Ag2S quantum dots (Qds) in rats and mice. METHODS: Three different doses of Ag2S Qds with similar size and composition were administrated to rats and mice. The effect of size and surface charge was investigated with the injection of three sizes (5, 15 and 25 nm) of Ag2S Qds possessing similar surface charge, as well as 5 nm Qds with a positive surface charge. RESULTS: Results indicated that pharmacokinetics and biodistribution of Ag2S Qds were strongly dose, particle size and surface charge dependent. By increasing the dose from 0.5 to 4.0 mg/kg, mean residence time (MRT) and apparent volume of distribution at steady state (Vss) were increased while clearance (CL) was decreased. Qds with a negative surface charge had significantly larger MRT and Vss values than positively charged particles, but their CL was about 50% lower than that of positively charged ones. By increasing Qds size from 5 to 25 nm, CL was increased while MRT and AUC were decreased. CONCLUSIONS: This study establishes comprehensive principles for the rational design and tailoring of Ag2S Qds for biomedical applications. Graphical Abstract The effects of injection dose, particle size and surface charge on pharmacokinetics and tissue distribution of Ag2S Qds after intravenous injection into rats and mice were investigated.

Labrasol-Enriched Nanoliposomal Formulation: Novel Approach to Improve Oral Absorption of Water-Insoluble Drug, Carvedilol.

The purpose of the current study was to develop a novel liposomal formulation to improve the oral bioavailability of carvedilol, a Biopharmaceutics Classification System class II with poor aqueous solubility and extensive presystemic metabolism. Conventional and various surfactant-enriched carvedilol-loaded liposomes were prepared by thin film hydration technique and physicochemical properties of liposomes (including size, encapsulation efficiency, release behavior, and morphology) were evaluated. To assess the oral bioavailability, in vivo studies were carried out in eight groups of male Wistar rats (n = 6) and the drug plasma concentration was determined. Conventional and surfactant containing liposomes showed average particle size of 76-104 nm with a narrow size distribution, high encapsulation efficiency (80%≤) and a sustained release profile in simulated intestinal fluid. Compared to the suspension, conventional and Labrasol containing liposomes significantly improved the oral bioavailability and peak plasma concentration of carvedilol. Biocompatibility studies (cell cytotoxicity and histopathological analyses) showed that the enhancing effect might be achieved without any apparent toxicity in the intestine. Decreased oral absorption of carvedilol nanovesicles by using a chylomicron flow blocker indicated contribution of lymphatic transport in nanocapsules absorption. The results reported the successful development of biocompatible Labrasol-enriched carvedilol nanoliposomal formulation with a significant oral enhancement capability. Graphical Abstract ᅟ.

Radiolabeling of Preformed Niosomes with [99mTc]: In Vitro Stability, Biodistribution, and In Vivo Performance.

Nanocarriers radiolabeled with [99mTc] can be used for diagnostic imaging and radionuclide therapy, as well as tracking their pharmacokinetic and biodistribution characteristics. Due to the advantages of niosomes as an ideal drug delivery system, in this study, the radiolabeling procedure of niosomes by [99mTc]-HMPAO complexes was investigated and optimized. Glutathione (GSH)-loaded niosomes were prepared using a thin-film hydration method. To label the niosomes with [99mTc], the preformed GSH-loaded niosomes were incubated with the [99mTc]-HMPAO complex and were characterized for particle size, size distribution, zeta potential, morphology, and radiolabeling efficiency (RE). The effects of GSH concentration, incubation time, incubation temperature, and niosomal composition on RE were investigated. The biodistribution profile and in vivo SPECT/CT imaging of the niosomes and free [99mTc]-HMPAO were also studied. Based on the results, all vesicles had nano-sized structure (160-235 nm) and negative surface charge. Among the different experimental conditions that were tested, including various incubation times, incubation temperatures, and GSH concentrations, the optimum condition that resulted in a RE of 92% was 200-mM GSH and 15-min incubation at 40°C. The in vitro release study in plasma showed that about 20% of radioactivity was released after 24 h, indicating an acceptable radiolabeling stability in plasma. The biodistribution of niosomes was clearly different from the free radiolabel. Niosomes carrying radionuclide were successfully used for tracking the in vivo disposition of these carriers and SPECT/CT imaging in rats. Furthermore, biodistribution studies in tumor-bearing mice revealed higher tumor accumulation of the niosomal formulation as compared with [99mTc]-HMPAO.

Sirolimus-loaded exosomes as a promising vascular delivery system for the prevention of post-angioplasty restenosis.

Restenosis remains the main reason for treatment failure of arterial disease. Sirolimus (SIR) as a potent anti-proliferative agent is believed to prevent the phenomenon. The application of exosomes provides an extended-release delivery platform for SIR intramural administration. Herein, SIR was loaded into fibroblast-derived exosomes isolated by ultracentrifugation. Different parameters affecting drug loading were optimized, and exosome samples were characterized regarding physicochemical, pharmaceutical, and biological properties. Cytotoxicity, scratch wound assays, and quantitative real-time PCR for inflammation- and migration-associated genes were performed. Restenosis was induced by carotid injury in a rat carotid model and then exosomes were locally administered. After 14 days, animals were investigated by computed tomography (CT) angiography, morphometric, and immunohistochemical analyses. Western blotting confirmed the presence of specific protein markers in exosomes. Characterization of empty and SIR-loaded exosomes verified round and nanoscale structure of vesicles. Among prepared formulations, desired entrapment efficiency (EE) of 76% was achieved by protein:drug proportion of 2:1 and simple incubation for 30 min at 37 °C. Also, the optimal formulation released about 30% of the drug content during the first 24 h, followed by a prolonged release for several days. In vitro studies revealed the uptake and functional efficacy of the optimized formulation. In vivo studies revealed that %restenosis was in the following order: saline > empty exosomes > SIR-loaded exosomes. Furthermore, Ki67, alpha smooth muscle actin (α-SMA), and matrix metalloproteinase (MMP) markers were less expressed in the SIR-exosomes-treated arteries. These findings confirmed that exosomal SIR could be a hopeful strategy for the prevention of restenosis.

Exploring the vast potentials and probable limitations of novel and nanostructured implantable drug delivery systems for cancer treatment.

Conventional cancer chemotherapy regimens, albeit successful to some extent, suffer from some significant drawbacks, such as high-dose requirements, limited bioavailability, low therapeutic indices, emergence of multiple drug resistance, off-target distribution, and adverse effects. The main goal of developing implantable drug delivery systems (IDDS) is to address these challenges and maintain anti-cancer drugs directly at the intended sites of therapeutic action while minimizing inevitable side effects. IDDS possess numerous advantages over conventional drug delivery, including controlled drug release patterns, one-time drug administration, as well as loading and stabilizing poorly water-soluble chemotherapy drugs. Here, we summarized conventional and novel (three-dimensional (3D) printing and microfluidic) preparation techniques of different IDDS, including nanofibers, films, hydrogels, wafers, sponges, and osmotic pumps. These systems could be designed with high biocompatibility and biodegradability features using a wide variety of natural and synthetic polymers. We also reviewed the published data on these systems in cancer therapy with a particular focus on their release behavior. Various release profiles could be attained in IDDS, which enable predictable, adjustable, and sustained drug releases. Furthermore, multi-step or stimuli-responsive drug release could be obtained in these systems. The studies mentioned in this article have proven the effectiveness of IDDS for treating different cancer types with high prevalence, including breast cancer, and aggressive cancer types, such as glioblastoma and liver cancer. Additionally, the challenges in applying IDDS for efficacious cancer therapy and their potential future developments are also discussed. Considering the high potential of IDDS for further advancements, such as programmable release and degradation features, further clinical trials are needed to ensure their efficiency. The overall goal of this review is to expand our understanding of the behavior of commonly investigated IDDS and to identify the barriers that should be addressed in the pursuit of more efficient therapies for cancer. See also the graphical abstract(Fig. 1).

Design and Characterization of an Osmotic Pump System for Optimal Feeding and pH Control in E. coli Culture to Increase Biomass.

Background: Batch cultures used for various purposes, such as expression screening and recombinant protein production in laboratories, usually have some drawbacks due to the bolus addition of carbon sources, such as glucose and buffers, that lead to overflow metabolism, decreased pH, high osmolality, low biomass yield, and low protein production. Objectives: This study aimed to overcome the problems of batch culture using the controlled release concept by a controlled porosity osmotic pump (CPOP) system. Methods: The CPOP was formulated with glucose as a carbon source feeding and sodium carbonate as a pH modifier in the core of the tablet that was coated with a semipermeable membrane containing cellulose acetate and polyethylene glycol (PEG) 400. The release rate was regulated with Eudragit L100 as a retardant agent in the core and PEG 400 as a pore-former agent in the coating membrane. Fourier-transform infrared spectroscopy (FT-IR) and scanning electron microscopy (SEM) were used to elucidate compatibility between components and release mechanism, respectively. The in-vitro release of glucose and Na2CO3 studies were performed for 24 hours in a mineral culture medium (M9). Then, the effectiveness of CPOP in the growth of Escherichia coli (E. coli BL21) as a microorganism model was evaluated. Glucose consumption, changes in medium's pH, and acetate concentration as a by-product were also monitored during the bacterial growth. Results: Fourier-transform infrared spectroscopy confirmed the compatibility between the components in the osmotic pump, and SEM elucidated the release mechanism due to in-situ delivery pores created by dissolving soluble components (PEG 400) on the coated membrane upon contact with the dissolution medium. The in-vitro release studies indicated that the osmotic pump was able to deliver glucose and sodium carbonate in a zero-order manner. The use of CPOP in E. coli (BL21) cultivation resulted in a statistically significant improvement in biomass (over 80%), maintaining the pH of the medium (above 6.8) during the exponential phase, and reducing metabolic by-product formation (acetate), compared to bolus feeding (P < 0.05). Conclusions: The use of CPOP, which is capable of controlled release of glucose as a carbon source and sodium carbonate as a pH modifier, can overcome the drawbacks of bolus feeding, such as decreased pH, increased acetate concentration, and low productivity. It has a good potential for commercialization.

Crocin-Phospholipid Complex: Molecular Docking, Molecular Dynamics Simulation, Preparation, Characterization, and Antioxidant Activity.

Background: Crocin is a water-soluble carotenoid compound present in saffron (Crocus sativus L.), known for its wide range of pharmacological activities, including cardioprotective, hepatoprotective, anti-tumorigenic, anti-atherosclerosis, and anti-inflammatory effects. Objectives: The instability of crocin, its low miscibility with oils, and poor bioavailability pose challenges for its pharmaceutical applications. This study aimed to design and prepare a crocin-phospholipid complex (CPC) and assess its physicochemical properties. Methods: The study investigated the formation of the complex and its binding affinity through molecular docking. Molecular dynamics (MD) simulations were conducted to find the optimal molar ratio of crocin to phospholipid for the complex's preparation. The CPC was produced using the solvent evaporation method. Techniques such as X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR), field-emission scanning electron microscopy (FE-SEM), nuclear magnetic resonance (NMR), and solubility studies were utilized to characterize and confirm the formation of CPC. Additionally, the in vitro antioxidant activity of crocin and CPC was evaluated. Results: Molecular dynamic simulations explored molar ratios of 1: 1, 1: 1.5, and 1: 2 for crocin to phospholipid. The ratio of 1: 2 was found to be the most stable, exhibiting the highest probability of hydrogen bond formation. Molecular docking, FTIR, and NMR studies indicated hydrogen bond interactions between crocin and phospholipid, confirming CPC's formation. XRD and FE-SEM analyses showed a decrease in crocin's crystallinity within the phospholipid complex. Furthermore, the solubility of crocin in n-octanol was enhanced post-complexation, indicating an increase in crocin's lipophilic nature. Conclusions: Phospholipid complexation emerges as a promising technique for enhancing the physicochemical characteristics of crocin.

Liposomal factor VIII as an efficient pharmaceutical system for the treatment of hemophilia.

Objectives: Currently, the most important treatment approach for hemophilia type A is recombinant Factor VIII. However, due to its low retention time in the blood, the patients usually need successive injections. In addition, neutralization of injected proteins by antibodies complicates treatment. We examined the prolongation of the persistence time of injectable FVIII in the blood and the potential effects on survival using promising PEGylated liposomes (PEGLip) utilizing hydrogenated soy phosphatidylcholine (HSPC, Tm= 54.5 ºC) and 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPC, Tm= - 2 ºC). Materials and Methods: Nanoliposomes with different percentages of PEG (3% and 5%) were obtained via the thin film hydration procedure and extrusion. Liposomal FVIII formulation was prepared and characterization was done. Results: The results revealed that the formulations are in the 80-120 nm range with uniform dispersion, which was confirmed using transmission electron microscopy (TEM) imaging. The phase transition temperature (Tm) of the liposomes was obtained by differential scanning calorimetry (DSC). With an attachment efficacy of approximately 87%, proteins bind non-covalently yet with a strong affinity to the exterior of PEGLip. The final formulations underwent additional examination. No significant change was observed in size, charge, and PDI between the FVIII-conjugated liposomal formulations and their liposomal nanoparticles. The selected formulations were injected into BALB/c mice. The circulation time and potential clotting effectiveness of PEGLip-FVIII are vastly improved over free protein, in non-hemophilic mice. Conclusion: The obtained results showed that using phospholipids with high Tm (HSPC) can improve the hemostatic efficiency of liposomes more than phospholipids with low Tm (POPC).

Oral delivery of posaconazole-loaded phospholipid-based nanoformulation: Preparation and optimization using design of experiments, machine learning, and TOPSIS.

Phospholipid-based nanosystems show promising potentials for oral administration of hydrophobic drugs. The study introduced a novel approach to optimize posaconazole-loaded phospholipid-based nanoformulation using the design of experiments, machine learning, and Technique for Order of Preference by Similarity to the Ideal Solution. These approaches were used to investigate the impact of various variables on the encapsulation efficiency (EE), particle size, and polydispersity index (PDI). The optimized formulation, with %EE of âˆ¼ 74 %, demonstrated a particle size and PDI of 107.7 nm and 0.174, respectively. The oral pharmacokinetic profiles of the posaconazole suspension, empty nanoformulation + drug suspension, and drug-loaded nanoformulation were evaluated. The nanoformulation significantly increased maximum plasma concentration and the area under the drug plasma concentration-time curve (∼3.9- and 6.2-fold, respectively) and could be administered without regard to meals. MTT and histopathological examinations were carried out to evaluate the safety of the nanoformulation and results exhibited no significant toxicity. Lymphatic transport was found to be the main mechanism of oral delivery. Caco-2 cell studies demonstrated that the mechanism of delivery was not based on an increase in cellular uptake. Our study represents a promising strategy for the development of phospholipid-based nanoformulations as efficient and safe oral delivery systems.

Bile salt integrated cerasomes: A potential nanocarrier for enhancement of the oral bioavailability of idarubicin hydrochloride.

Cerasomes are a modified form of liposomes containing both inorganic and organic parts and due to their strong polyorganosiloxane surface have remarkably high morphological stability and provide easier functionalization compared with conventional liposomes. To investigate the potential of these nanocarriers for oral delivery, bile salt integrated cerasomes (named bilocerasomes) encapsulating idarubicin hydrochloride (IDA) were prepared and characterized. The optimum formulation showed excellent stability in the simulated gastrointestinal fluids as well as under storage conditions. The oral pharmacokinetics of the IDA solution, empty nanocarrier + drug solution, and IDA-loaded bilocerasome were evaluated. The nanoformulation significantly increased the area under the drug concentration-time curve and the mean residence time (∼14.3- and 9-fold, respectively). The results obtained from cell uptake and chylomicron flow blocking approach revealed that bilocerasomes are absorbed into the intestinal cells via a clathrin/caveolin-independent endocytosis pathway and transported to the systemic circulation extensively via the intestinal lymphatic vessels. Considering the high stability of the prepared bilocerasome, noticeable participation of lymphatic transport in its systemic absorption and marked enhancement in the oral absorption of IDA, bilocerasomes can be introduced as a capable carrier for improving the oral bioavailability of drugs, particularly those that hepatic first-pass metabolism seriously limits their oral absorption.