Sustained-release Delivery System Research Articles

Scope and Application of Hot Melt Extrusion in the Development of Controlled and Sustained Release Drug Delivery Systems.

Controlled-release drug delivery systems (CRDDS) are more beneficial than conventional immediate release (IRDDS) for reduced intake, prolonged duration of action, lesser adverse effects, higher bioavailability, etc. The preparation of CRDDS is more complex than IRDDS. The hot melt extrusion (HME) technique is used for developing amorphous solid dispersion of poorly water soluble drugs to improve their dissolution rate and oral bioavailability. HME can be employed to develop CRDDS. Sustained release delivery systems (SRDDS), usually given orally, can also be developed using HME. This technique has the advantages of using no organic solvent, converting crystalline drugs to amorphous, improving bioavailability, etc. However, the heat sensitivity of drugs, miscibility between drug-polymer, and the availability of a few polymers are some of the challenges HME faces in developing CRDDS and SRDDS. The selection of a suitable polymer and the optimization of the process with the help of the QbD principle are two important aspects of the successful application of HME. In this review, strategies to prepare SRDDS and CRDDS using HME are discussed with its applications in research.

Anti-Microbial Drug Metronidazole Promotes Fracture Healing: Enhancement in the Bone Regenerative Efficacy of the Drug by a Biodegradable Sustained-Release In Situ Gel Formulation.

Nitroimidazoles comprise a class of broad-spectrum anti-microbial drugs with efficacy against parasites, mycobacteria, and anaerobic Gram-positive and Gram-negative bacteria. Among these drugs, metronidazole (MTZ) is commonly used with other antibiotics to prevent infection in open fractures. However, the effect of MTZ on bone remains understudied. In this paper, we evaluated six nitroimidazole drugs for their impact on osteoblast differentiation and identified MTZ as having the highest osteogenic effect. MTZ enhanced bone regeneration at the femur osteotomy site in osteopenic ovariectomized (OVX) rats at the human equivalent dose. Moreover, in OVX rats, MTZ significantly improved bone mass and strength and improved microarchitecture compared to the vehicle-treated rats, which was likely achieved by an osteogenic mechanism attributed to the stimulation of the Wnt pathway in osteoblasts. To mitigate the reported neurological and genotoxic effects of MTZ, we designed an injectable sustained-release in situ gel formulation of the drug that improved fracture healing efficacy by 3.5-fold compared to oral administration. This enhanced potency was achieved through a significant increase in the circulating half-life and bioavailability of MTZ. We conclude that MTZ exhibits osteogenic effects, further accentuated by our sustained-release delivery system, which holds promise for enhancing bone regeneration in open fractures.

Hard Gelatin Capsules with Alginate-Hypromellose Microparticles as a Multicompartment Drug Delivery System for Sustained Posaconazole Release.

Microparticles as a multicompartment drug delivery system are beneficial for poorly soluble drugs. Mucoadhesive polymers applied in microparticle technology prolong the contact of the drug with the mucosa surface enhancing drug bioavailability and extending drug activity. Sodium alginate (ALG) and hydroxypropyl methylcellulose (hypromellose, HPMC) are polymers of a natural or semi-synthetic origin, respectively. They are characterized by mucoadhesive properties and are applied in microparticle technology. Spray drying is a technology employed in microparticle preparation, consisting of the atomization of liquid in a stream of gas. In this study, the pharmaceutical properties of spray-dried ALG/HPMC microparticles with posaconazole were compared with the properties of physical mixtures of powders with equal qualitative and quantitative compositions. Posaconazole (POS) as a relatively novel antifungal was utilized as a model poorly water-soluble drug, and hard gelatin capsules were applied as a reservoir for designed formulations. A release study in 0.1 M HCl showed significantly prolonged POS release from microparticles compared to a mixture of powders. Such a relationship was not followed in simulated vaginal fluid (SVF). Microparticles were also characterized by stronger mucoadhesive properties, an increased swelling ratio, and prolonged residence time compared to physical mixtures of powders. The obtained results indicated that the pharmaceutical properties of hard gelatin capsules filled with microparticles were significantly different from hard gelatin capsules with mixtures of powders.

Effect of gum Arabic coating on release behavior of curcumin-loaded kafirin and zein composite nanoparticles

Prolamins extracted from cereal crops have shown promise as delivery vessels for hydrophobic bioactives. Kafirin, the main prolamin in sorghum, is more hydrophobic than its better known relative, zein, which makes kafirin an interesting candidate for encapsulation applications. Our aim was to find effective ways to fabricate kafirin-based nanoparticles with excellent encapsulation and release properties in simulated gastrointestinal fluids. We introduced gum Arabic (GA), a food-grade polysaccharide to stabilize kafirin by collectively forming nanoparticles. We measured encapsulation and release properties of the resulting nanoparticles using curcumin as a model drug, and compared them to zein-based nanoparticles. Electrostatic, hydrogen bonding and hydrophobic interactions drove the formation of curcumin-loaded GA-kafirin and GA-zein nanoparticles. The presence of GA coating improved encapsulation efficiency and pH stability of curcumin-loaded nanoparticles over a wide pH range of 3–8, and markedly slowed down curcumin release in simulated gastrointestinal fluids, especially for kafirin nanoparticles compared to zein-based ones. Regarding the release mechanism, binding forces between kafirin and curcumin played a more significant role in the slow-release rate in gastric fluid compared to the digestibility resistance characteristics of zein. These results indicate that GA-coated kafirin nanoparticles can significantly improve the bioavailability of hydrophobic nutrient molecules, such as curcumin. Our results provide a foundation for their application in sustained-release delivery systems and nutritious drinks, thereby expanding the range of prolamin species for encapsulation applications.

Alginate functionalized chitosan nanoparticles using multilayer co-axial electro-spraying for ovalbumin controlled release via oral delivery

The current oral vaccine delivery presents numerous challenges due to physiological barriers in the gastrointestinal tract including antigen degradation by enzymes and gastric pH conditions. Contributing to overcome these problems, this work developed non-cross-linked chitosan (CHI) nanoparticles, with/without functionalization with alginate (ALG), using multilayer co-axial electro-spraying method, to orally deliver ovalbumin (OVA), a model antigen. The prepared OVA@CHI and OVA@CHI@ALG nanoparticles possessed spherical shape, uniform size and non-agglomeration, high OVA encapsulation efficiency of above 90 %, and core-shell structure with mean diameters of 276.9 ± 70.7 nm (for OVA@CHI) and 304.3 ± 63.9 nm (for OVA@CHI@ALG), determined via SEM images. The particle hydrodynamic diameters, analyzed by the DLS method, were 313.0 ± 72.4 nm for OVA@CHI and 367.6 ± 83.2 nm for OVA@CHI@ALG, in agreement with the SEM results. Additionally, the material functional group interactions and the polyelectrolyte complex formations were confirmed by FTIR spectra and TGA/DSC thermo-grams, indicating the successful formulation. Subsequently, the OVA@CHI@ALG nanoparticles revealed good stability in acidic environment under the presence of digestive enzymes. The OVA release profiles of OVA@CHI@ALG nanoparticles exhibited limited release in simulated gastric fluid (pH 1.2), followed by sustained release in simulated intestinal fluid (pH 6.8) and simulated colonic fluid (pH 7.4) over a 48-h test period. Interestingly, the primary structure of OVA, analyzed by SDS-PAGE analysis, was maintained during the preparation process and after the release test, while the OVA secondary structure, examined by circular dichroism measurement, demonstrated a decrease of α-helix and an increase of β-sheet contents. Finally, the in vitro mucin-binding study indicated a significant adhesive efficiency of 69.21 ± 4.24 % for OVA@CHI and 75.07 ± 2.58 % for OVA@CHI@ALG at pH 7.4. Conclusively, the OVA@CHI@ALG nanoparticles fabricated by tri-axial electro-spraying method could be a promising oral vaccine delivery system for sustained release of OVA.

Exploring oral drug delivery: In vitro release and mathematical modeling of hydrophobic drug (Na-L-thyroxine) and its cyclodextrin inclusion complex in chitosan microparticles

Na-l-Thyroxine (Na-l-Thy) is a frequently prescribed synthetic hormone for hypothyroidism treatment. Despite its efficacy, its hydrophobic nature poses a challenge for achieving optimal bioavailability. To address this, researchers explored various delivery methods, including micro-formulations and nano-formulations, for precise and prolonged release of hydrophobic and hydrophilic drugs. In this study, we developed micro-formulations with cyclodextrin and chitosan. Docking studies identified γ-cyclodextrin as the preferred option for forming a stable complex with Na-l-Thyroxine compared to α, and β-cyclodextrins. Two micro-formulations were prepared compared: Na-l-Thyroxine loaded on chitosan (CS + Na-l-Thy) and Na-l-Thyroxine and γ-cyclodextrin inclusion complex (IC) loaded on chitosan (CS + IC). CS + IC exhibited superior encapsulation efficiency (91.25 %) and loading capacity (18.62 %) compared to CS + Na-l-Thy (encapsulation efficiency: 70.24 %, loading capacity: 21.18 %). Characterization using FTIR, SEM, and TGA validated successful encapsulation of Na-l-Thy in spherical microparticles with high thermal stability. In-vitro release studies at pH 1.2 and 7.4 showed that the CS + IC microparticles displayed gradual, consistent drug release compared to CS + Na-l-Thy -Thy. Both formulations showed faster release at pH 1.2 than at pH 7.4. Reaction kinetics analysis of release studies of CS + Na-l-Thy and CS + IC were best described by Higuchi kinetic model and Korsemeyer-Peppas kinetic model respectively. This study suggests that the CS + IC microparticles are an effective and stable delivery system for sustained release of hydrophobic Na-l-Thy.

Hierarchical porous bio polyurethane film as an implantable delivery system for sustained release of insulin: Synthesis, characterization, and in-vitro evaluation

In this study, a novel star-hyperbranched polyurethane (SR-HPU) with a star-shaped glucose-based PHBV (GS-PHBV) core was synthesized for sustained-release of insulin. The successful synthesis of GS-PHBV, SR-HPU, and preparation of INS-PUF were confirmed by 1HNMR and ATR-IR analysis. Thermogravimetric analysis (TGA), X-Ray diffraction analysis (XRD), and water contact angle (WCA) analysis demonstrated that due to the block copolymerization of GS-PHBV with HDI and PEG, the crystalline patterns of the final films were disrupted, which led to an increase in their hydrophilicity. These results aligned with other findings from in vitro biodegradability and cytocompatibility studies of films as well. As a result, gravimetric measurements of the films in phosphate buffer solution (PBS) (pH 7.4 at 37°) revealed that SR-HPU lost more weight (∼28%) than GS-PHBV (∼4%) after 35 days of degradation, which was also in good agreement with the water contact angles of them (82.9° vs 58.4°). Also, the surface topographical changes of the porous structure before and after degradation were compared by field emission scanning electron microscopy (FESEM)micrographs. XRD and Energy dispersive X-ray (EDX) mapping results revealed that insulin is uniformly present within the highly porous SR-HPU matrix. In vitro cytotoxicity studies of films on (L929) indicated excellent biocompatibility with high cell viability and rapid cell proliferation. Moreover, the findings from the in vitro release studies of INS-PUF showed that a prolonged insulin release pattern had been achieved for 8 weeks and followed the Higuchi model.

Preparation, In Vitro Characterization, and Evaluation of Polymeric pH-Responsive Hydrogels for Controlled Drug Release.

The purpose of the current research is to formulate a smart drug delivery system for solubility enhancement and sustained release of hydrophobic drugs. Drug solubility-related challenges constitute a significant concern for formulation scientists. To address this issue, a recent study focused on developing PEG-g-poly(MAA) copolymeric nanogels to enhance the solubility of olmesartan, a poorly soluble drug. The researchers employed a free radical polymerization technique to formulate these nanogels. Nine formulations were formulated. The newly formulated nanogels underwent comprehensive tests, including physicochemical assessments, dissolution studies, solubility evaluations, toxicity investigations, and stability examinations. Fourier transform infrared (FTIR) investigations confirmed the successful encapsulation of olmesartan within the nanogels, while thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) studies verified their thermal stability. Scanning electron microscopy (SEM) images revealed the presence of pores on the surface of the nanogels, facilitating water penetration and promoting rapid drug release. Moreover, powder X-ray diffraction (PXRD) studies indicated that the prepared nanogels exhibited an amorphous structure. The nanogel carrier system led to a significant enhancement in olmesartan's solubility, achieving a remarkable 12.3-fold increase at pH 1.2 and 13.29-fold rise in phosphate buffer of pH 6.8 (NGP3). Significant swelling was observed at pH 6.8 compared to pH 1.2. Moreover, the formulated nexus is nontoxic and biocompatible and depicts considerable potential for delivery of drugs and protein as well as heat-sensitive active moieties.

Intramuscular injection of palmitic acid-conjugated Exendin-4 loaded multivesicular liposomes for long-acting and improving in-situ stability

ABSTRACT Background Exendin-4 (Ex4) is a promising drug for diabetes mellitus with a half-life of 2.4 h in human bodies. Besides, the Ex4 formulations currently employed in the clinic or under development have problems pertaining to stability. In this study, palmitic acid-modified Ex4 (Pal-Ex4) was prepared and purified to extend the half-life of Ex4. In addition, Pal-Ex4-MVLs were further designed and optimized as a long-acting delivery system for intramuscular injection. Methods Pal-Ex4 was encapsulated within multivesicular liposomes (MVLs) via a two-step double emulsification process. The formulated products were then assessed for their vesicle size, encapsulation efficiency, and in vitro and in vivo. Results Pal-Ex4-MVLs with a notable encapsulation efficiency of 99.18% were successfully prepared. Pal-Ex4-MVLs, administered via a single intramuscular injection in Sprague-Dawley rats, sustained stable plasma concentrations for 168 h, presenting extended half-life (77.28 ± 12.919 h) and enhanced relative bioavailability (664.18%). MVLs protected Ex4 through providing stable retention and slow release. This approach considerably improved the in-situ stability of the drug for intramuscular administration. Conclusions The combination of palmitic acid modification process with MVLs provides dual protection for Ex4 and can be a promising strategy for other hydrophilic protein/polypeptide-loaded sustained-release delivery systems with high drug bioactivity.

Gastric acid-responsive deformable sodium alginate/Bletilla striata polysaccharide in situ gel for the protection and treatment of alcohol-induced peptic ulcers

First-line drugs for peptic ulcer (PU) treatment are typically limited by poor targeting and adverse effects associated with long-term use. Despite recent advancements in novel therapeutic approaches for PU, the development of sustained-release delivery systems tailored to specific pathological characteristics remains challenging. Persistent inflammation, particularly gastric inflammatory microenvironment imbalance, characterizes the PU. In this study, we prepared an in situ gel composed of sodium alginate, deacetylated gellan gum, calcium citrate, and Bletilla striata polysaccharide (BSP) to achieve sustained release of BSP. The BSP in situ gel demonstrated favorable fluidity in vitro and completed self-assembly in vivo in response to the acidic milieu at a pH of 1.5. Furthermore, the shear, extrusion, and deformation properties increased by 26.4 %, 103.7 %, and 46.3 %, respectively, with long-term gastric retention (4 h) and mucosal adaptation. Animal experiments confirmed that the BSP in situ gel could attenuate necrotic injury and inflammatory cell infiltration, maintain mucosal barrier integrity, regulate cytokine imbalance and inflammation-associated hyperapoptosis, thus effectively alleviate the inflammatory microenvironmental imbalance in PU without significant side effects. Overall, our findings demonstrated that the BSP in situ gel is a promising therapeutic strategy for PU and opens avenues for developing self-assembled formulations targeting the pathological features of PUs.

Liquid-like Oral Sustained-Release System Based on Acid-Sensitive in situ Hydrogel for Alleviate Gastrointestinal Side Effects of Indobufen

Commonly, most oral non-steroidal anti-inflammatory drugs (NSAIDs) have known gastric adverse reactions due to their long-term and high dose administration. In this study, a novel liquid sustained-release system based on multiple-unit in situ hydrogel beads was designed to address this issue. The system is composed of sodium alginate (SA), gellan gum (GG), zinc oxide (ZnO), and magnesium oxide (MgO). Furthermore, indobufen was loaded into the system to evaluate its gastric mucosal protection effect. This effect can be attributed to the topical antacid, pepsin inhibition, and sustained drug release properties of the system. It was proven that the stored solid gel system could undergo a “solid to liquid” transition after shaking. Once swallowed, the liquid gel could disperse well in the stomach as hydrogel beads. Then, the “liquid to solid” gelation occurred from the exterior to interior of each multiple-unit gel bead, triggered by the release of Zn2+ and Mg2+ from neutralization reactions. The formed gel demonstrated mild antacid effect that lasted for 3 hours and 66.3% pepsin inhibition in vivo. Moreover, the rats treated with the indobufen gel system showed a drug plasma concentration versus time curve with less fluctuation compared to the rats treated with the marketed preparation (YinDuo®) group. The gel system also exhibited an extended Tmax (6.50 hours) and reduced Cmax (52.87 μg/mL). Additionally, the gastric mucosal protection of the gel system was verified using three types of peptic gastric ulcer models. These findings suggested that this multiple-unit in situ gel could be a potential oral liquid sustained release delivery system for NSAIDs.

Surgical Management of Diabetic Macular Edema

Diabetic macular edema (DME) is the accumulation of fluid in the extracellular space within the macula and is a major cause of visual impairment among patients with diabetes. First-line treatment for DME includes pharmacotherapy with intravitreal anti-vascular endothelial growth factor medications and intravitreal corticosteroids. Alternative therapeutic strategies include laser photocoagulation for non-center involving DME, and surgical options such as pars plana vitrectomy (PPV) with or without internal limiting membrane (ILM) peel in cases with vitreoretinal interface anomalies or DME refractory to pharmacotherapy, and the Port Delivery System (PDS) for sustained release of anti-vascular endothelial growth factor (VEGF) medication. Our aim is to review the existing literature on surgical management of DME including imaging changes in chronic DME and the clinical relevance of surgical intervention. Imaging changes associated with DME and a worse prognosis include disorganization of the retinal layer, disruption of both the external limiting membrane (ELM) and ellipsoid zone, and vitreomacular interface abnormalities. Studies involving pars plana vitrectomy with and without ILM peel show anatomic improvement but may not always be associated with significant change in visual outcomes. Early studies lacked detailed imaging of the retinal layers and PPV was likely performed as a last resort. In addition, the novel PDS is surgically implanted into the pars plana and works as a drug reservoir with controlled release of drug. However, it has been recalled in patients with wet age-related macular degeneration due to issues with dislodgement. Surgical interventions for DME include pars plana vitrectomy with and without ILM peel and new surgical therapies for DME such as the PDS and subretinal gene therapy have the potential to reduce the risk of DME progression.

Biodegradable implants based on photo-cross-linked aliphatic polycarbonates for long-acting contraception

In this study, a new class of biodegradable contraceptive implants was prepared via the UV irradiation molding method, among which, progestin levonorgestrel (LNG) was used as a model drug. Photo-cross-linked aliphatic polycarbonates (APCs), namely, poly (trimethylene carbonate-co-2,2′-dimethyltrimethylene carbonate) [P(TMC-co-DTC)] elastomers, were used as the drug delivery matrix. The results obtained from the degradation experiments carried out in Sprague-Dawley (SD) rats showed that the cross-linked elastomer had the degradation characteristics of the surface erosion degradation mechanism, with no generation of acid degradation products, and excellent form-stability, which met the performance requirements of the matrix for a long-acting sustained-release delivery system. The in vitro cytotoxicity tests and histological and immunohistochemical evaluations showed good biocompatibility and biosafety of the elastomer matrix material and contraceptive implants. Subsequently, the implant formulations were screened by in vitro release experiments, and their release kinetics were explored. Finally, in the evaluation study of the in vivo anti-fertility effect, the implants exhibited excellent dimensional stability and were degraded by a surface erosion mechanism. LNG achieved a stable and sustained release in female SD rats, maintaining a long-acting contraceptive duration of up to 4 months. The contraceptive implants obtained in this study could be used to address the limitations of currently available formulations, which required secondary surgical removal and a single means of regulating drug release kinetics. Therefore, these implants could provide a new option for birth control needs and may be of significance in reducing the incidence of induced abortion and protecting female fertility.

In-vitro simulation of modified-alginate ester as sustained release delivery system for curcumin

Alginate-based hydrogels are highly promising candidates for use as drug delivery systems (DDSs) and as biomedical implants as they are structurally similar to the macromolecular-based components in the body. It can often be delivered into the body via minimally invasive administration. The present study relates to usage of sodium alginate as a sustained release delivery system for curcumin (CUR). We report here the synthesis of Curcumin-Alginate ester (Cur-Alg ester), its characterization and also provide details of in-vitro simulation in different fluids. Present findings have been indicated that the Cur-Alg ester is stable during in-vitro simulation in gastric fluid as well as in intestinal fluid. Modified alginate ester was hydrolyzed in presence of liver enzymes at pH 8.0 and released CUR in consistent amount for 5 h. The results suggested that the modified alginate ester can not only be used for the delivery of CUR only but also acts as prodrug system and release CUR in liver only by the action of liver esterases. It can be used for similar drugs whose ester can be prepared with alginate.

Pomelo peel derived nanocellulose as Pickering stabilizers: Fabrication of Pickering emulsions and their potential as sustained-release delivery systems for lycopene

Two kinds of nanocellulose (cellulose nanofibrils (CNFs) and cellulose nanocrystals (CNCs) were synthesized from pomelo peels via a facile approach of TEMPO oxidation and sulfuric acid treatment respectively. The FTIR results illustrated that hemicelluloses and lignin were completely removed from the pomelo peel cellulose substrate. The obtained CNFs and CNCs possessed a uniform morphology and nanoscale particle size. The stability of CNF-based Pickering emulsions was higher than that of emulsions stabilized with CNCs, due to the formation of gel structure induced by the CNFs’ longer fibrils. Increased oil fractions enhanced the viscoelasticity of CNF-based Pickering emulsions. The in vitro digestion results suggested that increased oil fractions decreased the lipolysis degree, as a result of the larger droplet size and higher viscoelasticity of emulsion. The release of lycopene showed a trend similar to that of FFA release, suggesting that higher oil fractions were beneficial for controlling lycopene release during gastrointestinal digestion.

Combination of FDM 3D Printing and Compressed Tablet for Preparation of Baclofen as Gastro-Floating Drug Delivery System (Conference Paper )#

This study aimed to develop an oral drug delivery system for gastro-retentive sustained drug release of baclofen by using a 3D printed capsular device since baclofen has a short half-life of 2.5 to 4 hours and has a narrow absorption window. Firstly sustained-release tablets of baclofen were formulated through the hot-melt extrusion of various thermoplastic polymers and direct compression of the extrudate, then a capsular device was designed and 3D printed to contain two air pockets to enable floating of the device and has four windows for drug release.
 3D printing of the capsular device was done by an FDM printer using biodegradable PLA filament, and the sustained release tablets were inserted into the device to allow the medicine to be released into the stomach over a longer period. An in vitro buoyance test and an in vitro dissolution test were used to examine the buoyancy and sustained-release features of the formulated gastro-floating system.
 Five sustained release formulas were developed using different thermoplastic polymers in hot-melt extrusion. Produced tablets were assayed for drug content, hardness, and friability while a DSC study was done on the selected formula. F 5 which contains 20% baclofen, 55% Eudragit RS-100, 20% ethylcellulose, and 5% PEG 4000 showed sustained release where the complete dissolution of the drug occurred in 12 hours, and the gastro-floating device remained floating all the time.
 This method has a great potential for developing various floating drug delivery systems with the required release profile.

Electrospun nanofibers using β-cyclodextrin grafted chitosan macromolecules loaded with indomethacin as an innovative drug delivery system

Electrospun nanofibers, as an innovative drug delivery system, provide selective, effective, and safe drug release. The present study aimed to fabricate nanofibers based on β-cyclodextrin grafted chitosan (β-CD-g-CS) macromolecules with incorporated drug via the blend electrospinning technique. The grafting of β-CD onto chitosan (CS) was confirmed by FT-IR, 1H NMR, TGA, XRD, and EDX analysis. Indomethacin was encapsulated in the β-CD-g-CS matrix as blend nanofibers using electrospinning in presence of polyvinyl alcohol (PVA). The SEM images revealed nanofibers with diameters at the nanoscale. The unique features of β-CD-g-CS/PVA as drug delivery system were investigated using indomethacin as a model drug molecule. Controlled release of indomethacin from nanofibers was studied in PBS solution by measuring the absorbance by UV–Vis spectrophotometer. The drug release profile exhibited that the rate of drug release can be tailored by polymer type and changing the drug/polymer ratio. The physicomechanical properties of the developed nanofibers were analyzed by tensile strength and water contact angle. The results demonstrated that β-CD-g-CS revealed enhanced wettability as well as favorable physicomechanical properties. In addition, the growth rate of the L929 cells on the CS and β-CD-g-CS nanofibers was not significantly inhibited and even improved cell proliferation. These findings indicated that β-CD-g-CS nanofibers could be appropriate as a smart drug delivery system for sustained release of indomethacin as an anti-inflammatory medicine in the wound healing and tissue engineering approaches in orthopedic applications.

4-Iodo-6-phenylpyrimidine (4-IPP) suppresses fibroblast-like synoviocyte- mediated inflammation and joint destruction associated with rheumatoid arthritis.

Rheumatoid arthritis (RA) is a systemic immune-mediated inflammatory disease that significantly impacts patients' quality of life. Fibroblast-like synovial cells (FLSs) within the synovial intima exhibit "tumor-like" properties such as increased proliferation, migration, and invasion. Activation of FLSs and secretion of pro-inflammation factors result in pannus formation and cartilage destruction. As an inhibitor of the cytokine, macrophage migration inhibitory factor (MIF), 4-Iodo-6-phenylpyrimidine (4-IPP) has been shown to reduce cell proliferation, migration, invasion, and the secretion of pro-inflammatory mediators in a variety of diseases. However, the usefulness of 4-IPP for RA treatment has not been assessed and was the purpose of this study. In vitro, 4-IPP was demonstrated to inhibit proliferation, migration, and invasion of RA FLSs, as well as the expression of pro-inflammatory cytokines. 4-IPP was also shown to inhibit MIF-induced phosphorylation of ERK, JNK, and p38, as well as reduce expression of COX2 and PGE2. In order to efficiently deliver 4-IPP to anatomical RA sites, we developed lactic-co-glycolic acid (PLGA) nanospheres, which not only protected 4-IPP from degradation but also controlled the release of 4-IPP. 4-IPP/PLGA nanospheres had potent anti-inflammatory activity and a high degree of biosafety. Results showed that local 4-IPP concentration was increased by nanosphere delivery, effectively reducing the inflammatory microenvironment as well as synovial inflammation, joint swelling, and cartilage destruction in a collagen-induced rheumatoid arthritis (CIA) rat model. Therefore, 4-IPP nanospheres are a sustained-release delivery system that may be an effective therapeutic strategy for RA treatment.

Thermosensitive Biodegradable Hydrogels for Local and Controlled Cerebral Delivery of Proteins: MRI-Based Monitoring of In Vitro and In Vivo Protein Release.

Hydrogels have been suggested as novel drug delivery systems for sustained release of therapeutic proteins in various neurological disorders. The main advantage these systems offer is the controlled, prolonged exposure to a therapeutically effective dose of the released drug after a single intracerebral injection. Characterization of controlled release of therapeutics from a hydrogel is generally performed in vitro, as current methods do not allow for in vivo measurements of spatiotemporal distribution and release kinetics of a loaded protein. Importantly, the in vivo environment introduces many additional variables and factors that cannot be effectively simulated under in vitro conditions. To address this, in the present contribution, we developed a noninvasive in vivo magnetic resonance imaging (MRI) method to monitor local protein release from two injected hydrogels of the same chemical composition but different initial water contents. We designed a biodegradable hydrogel formulation composed of low and high concentration thermosensitive polymer and thiolated hyaluronic acid, which is liquid at room temperature and forms a gel due to a combination of physical and chemical cross-linking upon injection at 37 °C. The in vivo protein release kinetics from these gels were assessed by MRI analysis utilizing a model protein labeled with an MR contrast agent, i.e. gadolinium-labeled albumin (74 kDa). As proof of principle, the release kinetics of the hydrogels were first measured with MRI in vitro. Subsequently, the protein loaded hydrogels were administered in male Wistar rat brains and the release in vivo was monitored for 21 days. In vitro, the thermosensitive hydrogels with an initial water content of 81 and 66% released 64 ± 3% and 43 ± 3% of the protein loading, respectively, during the first 6 days at 37 °C. These differences were even more profound in vivo, where the thermosensitive hydrogels released 83 ± 16% and 57 ± 15% of the protein load, respectively, 1 week postinjection. Measurement of volume changes of the gels over time showed that the thermosensitive gel with the higher polymer concentration increased more than 4-fold in size in vivo after 3 weeks, which was substantially different from the in vitro behavior where a volume change of 35% was observed. Our study demonstrates the potential of MRI to noninvasively monitor in vivo intracerebral protein release from a locally administered in situ forming hydrogel, which could aid in the development and optimization of such drug delivery systems for brain disorders.

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.