Sustained Release Research Articles

Titanium Dioxide Nanomaterials: Progress in Synthesis and Application in Drug Delivery.

Background: Recent developments in nanotechnology have provided efficient and promising methods for the treatment of diseases to achieve better therapeutic results and lower side effects. Titanium dioxide (TiO2) nanomaterials are emerging inorganic nanomaterials with excellent properties such as low toxicity and easy functionalization. TiO2 with special nanostructures can be used as delivery vehicles for drugs, genes and antigens for various therapeutic options. The exploration of TiO2-based drug delivery systems shows great promise for translating nanotechnology into clinical applications; Methods: Comprehensive data on titanium dioxide were collected from reputable online databases including PubMed, GreenMedical, Web of Science, Google Scholar, China National Knowledge Infrastructure Database, and National Intellectual Property Administration; Results: In this review, we discuss the synthesis pathways and functionalization strategies of TiO2. Recent advances of TiO2 as a drug delivery system, including sustained and controlled drug release delivery systems were introduced. Rigorous long-term systematic toxicity assessment is an extremely critical step in application to the clinic, and toxicity is still a problem that needs to be closely monitored; Conclusions: Despite the great progress made in TiO2-based smart systems, there is still a great potential for development. Future research may focus on developing dual-reaction delivery systems and single-reaction delivery systems like redox and enzyme reactions. Undertaking thorough in vivo investigations is necessary prior to initiating human clinical trials. The high versatility of these smart drug delivery systems will drive the development of novel nanomedicines for personalized treatment and diagnosis of many diseases with poor prognosis.

Macroporous PEG-Alginate Hybrid Double-Network Cryogels with Tunable Degradation Rates Prepared via Radical-Free Cross-Linking for Cartilage Tissue Engineering.

Trauma or repeated damage to joints can result in focal cartilage defects, significantly elevating the risk of osteoarthritis. Damaged cartilage has an inherently limited self-healing capacity and remains an urgent unmet clinical need. Consequently, there is growing interest in biodegradable hydrogels as potential scaffolds for the repair or reconstruction of cartilage defects. Here, we developed a biodegradable and macroporous hybrid double-network (DN) cryogel by combining two independently cross-linked networks of multiarm polyethylene glycol (PEG) acrylate and alginate.Hybrid DN cryogels are formed using highly biocompatible click reactions for the PEG network and ionic bonding for the alginate network. By judicious selection of various structurally similar cross-linkers to form the PEG network, we can generate hybrid DN cryogels with customizable degradation kinetics. The resulting PEG-alginate hybrid DN cryogels have an interconnected macroporous structure, high mechanical strength, and rapid swelling kinetics. The interconnected macropores in the cryogels support efficient mesenchymal stem cell infiltration at a high density. Finally, we demonstrate that PEG-alginate hybrid DN cryogels allow sustained release of chondrogenic growth factors and support chondrogenic differentiation of mouse mesenchymal stem cells. This study provides a novel method to generate macroporous hybrid DN cryogels with customizable degradation rates and a potential scaffold for cartilage tissue engineering.

Synergistic Effects of Radical Distributions of Soluble and Insoluble Polymers within Electrospun Nanofibers for an Extending Release of Ferulic Acid.

Polymeric composites for manipulating the sustained release of an encapsulated active ingredient are highly sought after for many practical applications; particularly, water-insoluble polymers and core-shell structures are frequently explored to manipulate the release behaviors of drug molecules over an extended time period. In this study, electrospun core-shell nanostructures were utilized to develop a brand-new strategy to tailor the spatial distributions of both an insoluble polymer (ethylcellulose, EC) and soluble polymer (polyvinylpyrrolidone, PVP) within the nanofibers, thereby manipulating the extended-release behaviors of the loaded active ingredient, ferulic acid (FA). Scanning electron microscopy and transmission electron microscopy assessments revealed that all the prepared nanofibers had a linear morphology without beads or spindles, and those from the coaxial processes had an obvious core-shell structure. X-ray diffraction and attenuated total reflectance Fourier transform infrared spectroscopic tests confirmed that FA had fine compatibility with EC and PVP, and presented in all the nanofibers in an amorphous state. In vitro dissolution tests indicated that the radical distributions of EC (decreasing from shell to core) and PVP (increasing from shell to core) were able to play their important role in manipulating the release behaviors of FA elaborately. On one hand, the core-shell nanofibers F3 had the advantages of homogeneous composite nanofibers F1 with a higher content of EC prepared from the shell solutions to inhibit the initial burst release and provide a longer time period of sustained release. On the other hand, F3 had the advantages of nanofibers F2 with a higher content of PVP prepared from the core solutions to inhibit the negative tailing-off release. The key element was the water permeation rates, controlled by the ratios of soluble and insoluble polymers. The new strategy based on core-shell structure paves a way for developing a wide variety of polymeric composites with heterogeneous distributions for realizing the desired functional performances.

Cyclodextrin grafted chitosan thermosensitive hydrogel using dual gelling agents: Drug delivery and antibacterial materials

In this paper, three kinds of cyclodextrin-grafted-chitosan (CD-g-CS) were synthesized from chitosan (CS) and β-cyclodextrin (β-CD) with different ratios. And a series of hydrogel with good temperature sensitivity and injectability were prepared by using sodium glycerophosphate (GP) and ammonium hydrogen phosphate (AHP) as dual gelling agents. The gelation formation time of hydrogel was short, and the shortest time was 0.75 min. The FTIR spectrum and 1H-NMR spectrum showed the structure of the compounds and intermolecular interactions. The molecular docking technique probed the encapsulation mechanism of the drug with β-CD. The SEM results showed that the hydrogel had a highly interconnected three-dimensional spatial structure. The swelling ratio of hydrogel was not less than 150 % within 1 h and the degradation rate of hydrogel was not less than 75 % within 14 days. The in vitro drug release results showed that the hydrogel had optimal sustained release effect, and the cumulative release ratio was 58.3 % in 34 h. The release kinetics analysis exhibited that the hydrogel conformed to the Riter-Peppas model. The hemocompatibility test and cytotoxicity test proved that the hydrogel had good biocompatibility and biosafety. The antibacterial experiments showed that the hydrogel could inhibit the biological activity of Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). Therefore, the CD-g-CS/GP-AHP hydrogel has a broad application prospect in the biological fields of drug delivery and antibacterial materials.

Enhancment of zebrafish (Danio rerio) immune and antioxidant systems using medicinal plant extracts encapsulated in alginate-chitosan nanocapsules with slow sustained release.

This study aimed to screen 10 medicinal plant extracts on zebrafish (Danio rerio), evaluating their impact on the complement system, immunoglobulin M (IgM) levels, lysozyme, and peroxidase activity, while also enhancing their efficacy through the gradual release using alginate-chitosan nanocapsules. The prepared methanolic extracts were combined with fish feed. The fish were divided into 12 groups, including 10 treatment groups, a positive and a negative control group. Results showed varying impacts of the extracts on the immune and antioxidant systems, with Cinnamon (Cinnamon cassia) and Hypericum (Hypericum perforatum) extracts demonstrating the most significant effects. Subsequently, Cinnamon and Hypericum extract were encapsulated in alginate-chitosan nanocapsules to assess their impact on zebrafish immune parameters, separately and synergistically. Gradual release of the extracts from the nanocapsules was observed, with slower release at pH 2 compared to pH 7. Overall, Cinnamon and Hypericum extracts exhibited substantial immune system enhancement, and their encapsulation in nanocapsules improved their effects on zebrafish immune parameters. These findings suggest using these encapsulated extracts to enhance immune responses in aquatic organisms.

Formulation and Evaluation of Gastroretentive Bilayer Tablets

Gastroretentive bilayer tablets were designed to prolong the gastric residence time after oral administration and to achieve immediate release of lansoprazole and controlled release floating layer of clarithromycin to treat gastric ulcers. Instant release layer has a combination of super disintegrating agents. A combination of effervescent mechanism is used. HPMC K5 was used as swelling polymer and citric acid, sodium bicarbonate as gas generating agent to reduce the floating lag time. Bilayer floating tablets were prepared with varying proportions of instant layer and sustained release floating approaches. The prepared formulations were evaluated for various tablet and floating parameters. Tablet properties were found to be within the limits according to procedures prescribed in USP. They had a floating lag time around 3-7 seconds and floating time more than 24 hours. The cumulative % drug release in simulated gastric fluids after 10 hours was 70% - 95%. The mechanism of drug release was analyzed by fitting the release data into various kinetic models. It was found that all the formulations best fit the Higuchi’s model. Keywords: Gastroretentive drug delivery system; Bilayer tables, Instant release layer, Floating layer, Lansoprazole, Clarithromycin.

Preparation and In Vitro Characterization of Carbamazepine-Loaded Chitosan-Coated/Uncoated PLGA and Zein Nanoparticles

The aim of this study is to prepare CBZ-loaded chitosan (Ch)- coated/uncoated poly(lactic-co-glycolic acid) (PLGA) and Zein (using 20 mg or 40 mg Zein) nanoparticles (CBZ-PLGA-Zein-NPs or CBZ-PLGA-Zein-Ch-NPs) and to characterize (Particle size, PDI, zeta potential, percent encapsulation efficiency (EE%), FT-IR, DSC and XRD analyzes, and in vitro release study) them in vitro. These nanoparticles were prepared using a modified emulsification-solvent evaporation method. The particle sizes of CBZ-PLGA-Zein(20)-NPs, CBZ-PLGA-Zein(40)-NPs and CBZ-PLGA-Zein(20)-Ch-NPs were found to be about 222 nm, 245 nm and 221 nm, respectively. The PDI value of all NP formulations was below 0.3. This indicates a narrow particle size distribution. The EE% values of CBZ-PLGA-Zein(20)-NPs, CBZ-PLGA-Zein(40)-NPs and CBZ-PLGA-Zein(20)-Ch-NPs were determined as about 64%, 56% and 62%, respectively. The coating of the optimum formulation (containing 20 mg Zein) with chitosan did not lead to a significant difference in the particle size and EE% value of this formulation (P>0.05). A sustained release of CBZ from all prepared NPs formulations was achieved until 48th h. In conclusion, CBZ-PLGA-Zein(20 mg or 40 mg)-NPs and CBZ-PLGA-Zein(20 mg)-Ch-NPs were successfully prepared and characterized in vitro.

Novel inhalable nano-based/microparticles for enhanced sustained pulmonary delivery of remdesivir - A patient malleable treatment for coronaviruses infection: In vitro aerosolization, cytotoxicity assays and antiviral activity studies

Remdesivir (RDV) is an antiviral used in potential treatment of SARS-COV-2 infection during the COVID-19 pandemic worldwide. However, it is still limited to IV administration for hospitalized patients. Therefore, we report herein successful development of RDV-loaded nanosuspensions (NS) using polycaprolactone and pluronic® F127, for the first time. The optimized RDV-NS was further loaded into inhalable nano-based/microparticles (OLN-microparticles) via co-spray drying with hyaluronic acid and mannitol. OLN-microparticles exhibited high yield value ∼80.56 %, with satisfactory entrapment efficiency and drug loading percent ∼97.27 ± 1.84 % and 3.92 ± 0.07 %, respectively. Carr's index was equal to 22.7 ± 11.67 % indicating good flowability properties. Scanning electron microscopic analysis showed spherical-shaped particles. Transmission electron microscope demonstrated grape-shaped clumps surface porosity. OLN-microparticles exhibited excellent aerodynamic features including; emitted fraction ∼97.46 ± 1.70 %, respirable particle fraction 53.77 ± 0.2 %, effective inhalation index 72.39 ± 1.40 %, and mass median aerodynamic diameter 2.25 ± 0.01 μm. Compared to plain RDV, OLN-microparticles showed significantly enhanced sustained release (p < 0.0001) with 1.5 and 1.9 fold increase at 24 and 48 h, respectively in Gamble's solution. OLN-microparticles also showed favorable cytotoxic profile with CC50 ∼ 252.0 μg/mL, inhibitory concentration (IC50) 13.08 μg/mL, and safety index (SI) 19.26 which is 1.3 fold higher compared to plain RDV. The Optimal release profile of OLN-microparticles enabled controlled and sustained release with enhanced cellular uptake. Hence, OLN-microparticles represented an efficient alternative form of dry powder for inhalation for deep and targeted pulmonary delivery of RDV, outweighing limitations accompanied with IV administration. It can provide self-administered and malleable access of treatment for SARS-COV-2 infected patients.

Platelet-cloaked alginate-poly (β-amino ester) a novel platform bioinspired polyelectrolyte nanoparticle for targeted delivery of carboplatin in breast cancer: An in vitro/in vivo study

Triple-negative breast cancer (TNBC) has poor prognosis. Carboplatin (Crb) is a widely used chemotherapeutic agent, in TNBC but with serious systemic toxicity and poor tumor targeting. Bioinspired drug-loaded platelets (Plt) and Plt-coated nanocarriers evade macrophage phagocytosis by membrane proteins like CD47. The goal of this study was preparation of a novel alginate-poly (β-amino ester) (PβAE) nanoparticles (NPs) for targeted delivery of Crb to TNBC cells by developing and comparison of two bioinspired carriers of Plt membrane (PltM) coated Crb-loaded alginate-poly (β-amino ester) nanoparticles (PltM@Crb-PβAE-ALG NPs) and Plt loaded Crb (Plt@Crb). The NPs were prepared by ionic gelation and subsequently were coated by platelet membrane using ultra-sonication method. The loading efficiency, release profile, and in vitro cytotoxicity of both formulations were evaluated on HUVEC and 4 T1 cells. Additionally, the in vivo tumor targeting, therapeutic efficacy, and organ toxicity of the two formulations were assessed in a murine tumor model. Results showed both Plt@Crb and (PltM@Crb-PβAE-ALG NPs) exhibited high drug loading efficiency, sustained release, enhanced cytotoxicity against 4 T1 cells, and decreased cytotoxicity in normal cells (HUVEC) in vitro. In vivo studies revealed that although both formulations considerably improved tumor inhibition compared to free Crb, but the PltM@Crb-PβAE-ALG NPs demonstrated superior cytotoxicity and therapeutic efficacy, thanks to improved Crb’s internalization efficiency, enhanced stability, and controlled release properties.

Poly(lactic acid hydroxyacetic acid)-poly(ethylene glycol)-modified ginsenoside Rg3 nanomedicine enhances anti-tumor effect in hepatocellular carcinoma

Objective This research aims to improve the bioavailability and anti-hepatocellular carcinoma (HCC) efficacy of Ginsenoside Rg3 by modification with poly (lactic acid hydroxyacetic acid)-poly(ethylene glycol) (PLGA-PEG). Methods PLGA-PEG-Rg3 was obtained by emulsification and evaluated it physiochemical characterization by FTIR, SEM, laser particle-size analyzer and HPLC. The effect of the PLGA-PEG-Rg3 and Rg3 on HepG2 cells was compared in vitro studies, including cell proliferation, transwell and a series of apoptosis detection, and in-situ HCC model. Results The PLGA-PEG-Rg3 were 122 nm in size and 0.112 in polydispersity index with sustained release profile in vitro. Compared to Rg3, PLGA-PEG-Rg3 was more effective in suppressing HepG2 growth and inducing apoptosis by the mitochondrial apoptosis pathway in vitro. And PLGA-PEG modification enhanced the liver-targeting ability and drug circulation time of Rg3 in vivo, resulting in PLGA-PEG-Rg3 possessing superior performance in inhibiting tumor growth and prolonging the survival time of tumor-bearing mice than Rg3. Conclusions Overall, these results showed PLGA-PEG-Rg3 enhanced the anti-tumor effect of Rg3 in HCC.

Chitosan/Sodium Alginate Hydrogel for the Release of Berberine as an Algae Suppressant: RSM Optimization and Analysis of Sustained Release Characteristics.

In this study, we used chitosan/sodium alginate hydrogel as a carrier to prepare berberine sustained-release capsule materials that can inhibit algae for a long time and safely. The preparation conditions of the material were optimized by the response surface method, and the optimized capsule material was characterized and the sustained release characteristics were analyzed to study the change of the algae inhibition effect of the material within 30 days. The results showed that the optimum preparation parameters of the material were 0.54% chitosan content, 2.46% sodium alginate content and 1.09% anhydrous calcium chloride content by response surface optimization design, which was consistent with the parameters set by each factor at the central point. The algae inhibition rate of the material under this preparation condition was 93.75 ± 1.01%, which was similar to the predicted value. The release characteristics analysis showed that the material continuously released up to 90% of berberine within 24 days, and its release characteristics were sustained release after burst release, with good sustained release effect. The results of material characterization showed that chitosan/sodium alginate hydrogel could effectively load berberine and was beneficial to the loading and release of berberine. The results of algae inhibition experiments showed that low concentration materials could control the outbreak of cyanobacterial blooms in a short time, while under high concentration conditions, the materials could inhibit Microcystis aeruginosa efficiently and for a long time.

Development of dual drug loaded-hydrogel scaffold combining microfluidics and coaxial 3D-printing for intravitreal implantation

Treating diabetic retinopathy (DR) effectively is challenging, aiming for high efficacy with minimal discomfort. While intravitreal injection is the current standard, it has several disadvantages. Implantable systems offer an alternative, less invasive, with long-lasting effects drug delivery system (DDS). The current study aims to develop a soft, minimally invasive, biodegradable, and bioadhesive material-based hydrogel scaffold to prevent common issues with implants. A grid-shaped scaffold was created using coaxial 3D printing (3DP) to extrude two bioinks in a single filament. The scaffold comprises an inner core of curcumin-loaded liposomes (CUR-LPs) that prepared by microfluidics (MFs) embedded in a hydrogel of hydroxyethyl cellulose (HEC), and an outer layer of hyaluronic acid-chitosan matrix with free resveratrol (RSV), delivering two Sirt1 agonists synergistically activating Sirt1 downregulated in DR. Optimized liposomes, prepared via MFs, exhibit suitable properties for retinal delivery in terms of size (<200 nm), polydispersity index (PDI) (<0.3), neutral zeta potential (ZP), encapsulation efficiency (∼97 %), and stability up to 4 weeks. Mechanical studies confirm scaffold elasticity for easy implantation. The release profiles show sustained release of both molecules, with different patterns related to different localization of the molecules. RSV released initially after 30 min with a total release more than 90 % at 336 h. CUR release starts after 24 h with only 4.78 % of CUR released before and gradually released thanks to its internal localization in the scaffold. Liposomes and hydrogels can generate dual drug-loaded 3D structures with sustained release. Microscopic analysis confirms optimal distribution of liposomes within the hydrogel scaffold. The latter resulted compatible in vitro with human retinal microvascular endothelial cells up to 72 h of exposition. The hydrogel scaffold, composed of hyaluronic acid and chitosan, shows promise for prolonged treatment and minimally invasive surgery.

Engineered PLGA Core-Lipid Shell Hybrid Nanocarriers Improve the Efficacy and Safety of Irinotecan to Combat Colon Cancer.

Poly(lactide-co-glycolide) (PLGA) is a biocompatible and biodegradable copolymer that has gained high acceptance in biomedical applications. In the present study, PLGA (Mw = 13,900) was synthesized by ring-opening polymerization in the presence of a biocompatible zinc-proline initiator through a green route. Irinotecan (Ir) loaded with efficient PLGA core-lipid shell hybrid nanocarriers (lipomers, LPs) were formulated with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino (polyethylene glycol)-2000] (DSPE-PEG-2000), using soya lecithin, by a nanoprecipitation method, and the fabricated LPs were designated as P-DSPE-Ir and P-DSPE-PEG-Ir, respectively. The formulated LPs were further validated for their physicochemical properties and biological potential for colon cancer application. The potential delivery of a poorly water-soluble chemotherapeutic drug (Ir) was studied for the treatment of colon cancer. LPs were successfully prepared, providing controlled size (80-120 nm) and surface charge (∼ -35 mV), and the sustained release properties and cytotoxicity against CT-26 colon cancer cells were studied. The in vivo biodistribution and tumor site retention in CT-26 xenograft tumor-bearing Balb/C mice showed promising results for tumor uptake and retention for a prolonged time period. Unlike P-DSPE-Ir, the P-DSPE-PEG-Ir LP exhibited significant tumor growth delay as compared to untreated and blank formulation-treated groups in CT-26 (subcutaneous tumor model) after 4 treatments of 10 mg irinotecan/kg dose. The biocompatibility and safety of the LPs were confirmed by an acute toxicity study of the optimized formulation. Overall, this proof-of-concept study demonstrates that the PLGA-based LPs improve the efficacy and bioavailability and decrease neutropenia of Ir to combat colon cancer.

Microparticle Mediated Delivery of Apelin Improves Heart Function in Post Myocardial Infarction Mice.

Apelin is an endogenous prepropeptide that regulates cardiac homeostasis and various physiological processes. Intravenous injection has been shown to improve cardiac contractility in patients with heart failure. However, its short half-life prevents studying its impact on left ventricular remodeling in the long term. Here, we aim to study whether microparticle-mediated slow release of apelin improves heart function and left ventricular remodeling in mice with myocardial infarction (MI). A cardiac patch was fabricated by embedding apelin-containing microparticles in a fibrin gel scaffold. MI was induced via permanent ligation of the left anterior descending coronary artery in adult C57BL/6J mice followed by epicardial patch placement immediately after (acute MI) or 28 days (chronic MI) post-MI. Four groups were included in this study, namely sham, MI, MI plus empty microparticle-embedded patch treatment, and MI plus apelin-containing microparticle-embedded patch treatment. Cardiac function was assessed by transthoracic echocardiography. Cardiomyocyte morphology, apoptosis, and cardiac fibrosis were evaluated by histology. Cardioprotective pathways were determined by RNA sequencing, quantitative polymerase chain reaction, and Western blot. The level of endogenous apelin was largely reduced in the first 7 days after MI induction and it was normalized by day 28. Apelin-13 encapsulated in poly(lactic-co-glycolic acid) microparticles displayed a sustained release pattern for up to 28 days. Treatment with apelin-containing microparticle-embedded patch inhibited cardiac hypertrophy and reduced scar size in both acute and chronic MI models, which is associated with improved cardiac function. Data from cellular and molecular analyses showed that apelin inhibits the activation and proliferation of cardiac fibroblasts by preventing transforming growth factor-β-mediated activation of Smad2/3 (supporessor of mothers against decapentaplegic 2/3) and downstream profibrotic gene expression. Poly(lactic-co-glycolic acid) microparticles prolonged the apelin release time in the mouse hearts. Epicardial delivery of the apelin-containing microparticle-embedded patch protects mice from both acute and chronic MI-induced cardiac dysfunction, inhibits cardiac fibrosis, and improves left ventricular remodeling.

Rapid Forming, Robust Adhesive Fungal-Sourced Chitosan Hydrogels Loaded with Deferoxamine for Sutureless Short-Gap Peripheral Nerve Repair.

Clinically, conventional sutures for repair of short-distance nerve injuries (< 5mm) may contribute to uncontrolled inflammation and scar formation, thus negatively impacting nerve regeneration. To repair transected peripheral nerves with short distances, a rapid-forming, robust adhesive chitosan hydrogel is prepared by synthesizing maleic and dopamine bi-functionalized fungal-sourced chitosan (DM) and subsequently photopolymerizing DM precursor solution. The hydrogel rapidly polymerized under UV light irradiation (≈2 s) and possessed a strong adhesive strength (273.33 ± 55.07kPa), facilitating a fast bonding of nerve stump. Especially, its tailored degradation profile over 28 days supported both early gap bridging and subsequent nerve regeneration. Furthermore, deferoxamine (DFO), a pro-angiogenic drug, is loaded into the hydrogel to reach sustainable release, accelerating axonal growth synergistically. A 3mm long sciatic nerve defects model in rats is used to investigate the efficacy of DM@DFO hydrogel for repairing peripheral nerve defects. After 60 days, the DM@DFO hydrogel significantly outperformed conventional sutures and fibrin glue, improving motor and sensory recovery by reducing inflammation, inhibiting scar formation, and accelerating vascular regeneration within 14 days post-repair. This work highlights the DM@DFO hydrogel as a promising tissue adhesive for effective short-distance peripheral nerve repair.

PH-responsive mupirocin-loaded hybrid nanoparticles in hydrogel and film forming spray against resistant bacterial wound infections

The aim of this work was to fabricate smart Mupirocin loaded Lipid Polymeric Hybrid Nanoparticles (MUP-LPHNs) based hydrogel and Film forming spray (FFS) for targeted release of MUP in response to wound pH. The MUP-LPHNs were optimized through design expert v.12. The optimized MUP-LPHNs had a particle size of 270.7 ± 3.20 nm with zeta potential of 17.05 ± 1.20 mV and entrapment efficiency of 88.0 ± 0.35 %. MUP-LPHNs showed no major chemical interaction, spherical morphology and amorphous nature as confirmed by FTIR, SEM and XRD, respectively. MUP-LPHNs were loaded to MUP-LPHNs based hydrogel (MUP-LPHNs-HG) and MUP-LPHNs based film forming spray (MUP-LPHNs-FFS) with successful characterization. In vitro release data confirmed sustained and pH dependent release from both MUP-LPHNs-HG and MUP-LPHNs-FFS as higher release was observed at pH 7.4. MUP-LPHNs-HG and MUP-LPHNs-FFS showed high efficiency and long-term inhibition of Staphylococcus aureus (SA), Methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa (P. aeruginosa) with 4–6 fold increase in the antibacterial activity compared to MUP solution. MUP-LPHNs-HG and MUP-LPHNs-FFS exhibited both in vitro and in vivo wound pH contingent, sustained drug release. Moreover, the prepared nanocarriers systems flaunted significant therapeutic efficacy against MRSA infected wound model by significant reduction in bacterial load and wound area, increased hydroxy proline level and antioxidant enzymes and reduced proinflammatory cytokines. Similarly, immunohistochemistry, histopathological and trichrome assessment showed significant reduction in level of inflammatory markers, accelerated and enhanced re-epithelization, improved connective tissue remodeling and effectively promote collagen deposition with effective wound regeneration, respectively. It can be concluded that LPHNs could be a potential carrier system for enhancing the therapeutic efficacy of MUP against resistant bacterial wound infections.

Ocotillol Derivatives Mitigate Retinal Ischemia-Reperfusion Injury by Regulating the Keap1/Nrf2/ARE Signaling Pathway.

Retinal ischemia-reperfusion (RIR) injury can lead to various retinal diseases. Oxidative stress is considered an important pathological event in RIR injury. Here, we designed and synthesized 34 ocotillol derivatives, then examined their antioxidant and anti-inflammatory capacities; we found that compounds 7 (C24-R) and 8 (C24-S) were most active. To enhance their water solubility, sustained release, and biocompatibility, compounds 7 and 8 were encapsulated into liposomes for in vivo activity and mechanistic studies. In vivo studies indicated that compounds 7 and 8 protected normal retinal structure and physiological function after RIR injury, reversed damage to retinal ganglion cells, and the S-configuration exhibited significantly stronger activity compared with the R-configuration. Mechanistic studies showed that compound 8 exerted a therapeutic effect on RIR injury by activating the Keap1/Nrf2/ARE signaling pathway; compound 7 did not influence this pathway. We also demonstrated that differential isomerization at the C-24 position influenced protection against RIR injury.

Fabrication of Famotidine Loaded Sepiolite/Pectin Bionanocomposite Hydrogels for Controlled Drug Delivery

AbstractDevelopment of drug delivery systems is an extensively researched area in the biomedical field. In recent years, there has been an increasing interest in fabrication of biocompatible nanofibrous drug delivery systems. The present study describes the fabrication of calcium chloride‐crosslinked bionanocomposite hydrogels based on pectin for the use of gastro‐retentive delivery system. Sepiolite/famotidine/pectin nanocomposite hydrogel was fabricated by using Ionotropic gelation process. The thermal, structural and morphological properties were evaluated via different experimental techniques such as TGA‐DSC, FTIR, and SEM. The prepared hydrogels showed a pH sensitive swelling profile with maximum water absorption at pH 1.2. Analysis of in‐vitro drug release data revealed that the sepiolite/famotidine/pectin nanocomposite hydrogels exhibited a slight initial burst release, followed by a sustained release over a 24 h period. This was observed both in simulated gastric fluid and in phosphate‐buffered saline, suggesting that these hydrogels are well‐suited for prolonged drug delivery. To investigate the drug release kinetics, various models were applied. The release of famotidine was predominantly governed by diffusion, as described by the Korsmeyer‐Peppas model.

P2Y12-targeted modulation of microglial phenotypes: A novel therapeutic strategy for enhanced axonal regeneration post-spinal cord injury

AimsMicroglia activation after spinal cord injury (SCI) is a double-edged sword, modulation of the activated microglia populations toward pro-regenerative phenotypes highlights the potential therapeutic implications. P2Y12, a microglia-specific marker, remains underexplored in its capacity to polarize microglial activation populations in SCI repair. We aimed to explore the effects of modulating P2Y12 on microglia function after spinal cord injury, and further on axonal regeneration and motor recovery after spinal cord injury. Materials and methodsThe study employed both in vitro and in vivo models, using BV2 cells and a mouse model of SCI, respectively. Ticagrelor, a P2Y12 antagonist, was administered via a collagen scaffold to ensure stable and sustained release. Transcriptome sequencing analysis, immunofluorescence staining, and Basso Mouse Scale (BMS) scores were used to assess microglial activation, axonal regeneration, and functional recovery. Key findingsHerein, we observed P2Y12+ microglia localized predominantly at the lesion periphery within 3 days post injury (dpi), manifesting a pro-inflammatory phenotype, but not anti-inflammatory phenotype. In vitro investigations revealed that P2Y12 inhibition of the activated microglia curtailed pro-inflammatory differentiation while augmenting anti-inflammatory differentiation. SignificanceLeveraging this insight, we engineered a collagen scaffold-based delivery system for sustained release of the P2Y12 antagonist, ticagrelor, at the injury site in a mouse complete SCI model. Notably, P2Y12 suppression markedly enhanced axonal regeneration within the injured site and ameliorated lower limb motor functions in SCI mice. Collectively, our findings illuminate P2Y12-targeted microglial modulation as a promising therapeutic approach for SCI.

3D-printed implants loaded with acriflavine for glioblastoma treatment

Drug delivery routes play an essential role in determining the efficacy and safety of medications. This study focused on the development and optimization of 3D-printed reservoir type implants as a combinational therapy drug delivery system for Glioblastoma Multiforme (GBM) post-surgery, possessing also antibacterial properties. In this study, we used a multimodal agent, Acriflavine (ACF) as an alternative drug to treat GBM. To date, ACF is used only as an antiseptic agent, although it has been shown to possess strong anticancer activities. ACF and a low molecular weight PCL were loaded into 3D-printed reservoir-type implants for sustained drug delivery. The study demonstrated that ACF implants exhibited sustained drug release kinetics, with faster release during the initial 30 days, followed by a gradual decrease over 90 days. This controlled release profile enhances the effectiveness of ACF delivery to tumour targets while minimizing side effects associated with systemic administration. In vitro experiments confirmed the inhibitory activity of ACF against GBM cells compared to non-tumour cells. The study also highlighted the bacteriostatic effects of ACF, making the implants potentially useful for post-surgery infection management, particularly against S. aureus, a common bacterial infection associated with brain surgery. The long-term drug-release capabilities of the implants make them attractive candidates for both tumour inhibition and antibacterial treatment. The study suggests that the developed ACF delivery systems have the potential for future clinical studies. Their ability to provide increased drug efficacy without systemic toxicity makes them promising candidates for cancer therapy and post-surgery infection management.