Preparation of External Stimulus-Free Gelatin-Catechol Hydrogels with Injectability and Tunable Temperature Responsiveness.

Gelatin is one of the most versatile biopolymers in various biomedical applications. A gelatin derivative gelatin-catechol (Gel-C) was developed in this study to further optimize its chemical and physical properties such as thermal reversibility and injectability. We found that Gel-C remains in a solution state at room temperature, and the temperature-dependent gelation capability of gelatin is well preserved in Gel-C. Its gel-forming temperature decreased to about 10 °C (about 30 °C for gelatin), and a series of gelatin derivatives with different gel-forming temperatures (10-30 °C) were formed by mixing gelatin and Gel-C in different ratios. Additionally, irreversible Gel-C hydrogels could be made without the addition of external stimuli by combining the physical cross-linking of gelatin and the chemical cross-linking of catechol. At the same time, properties of Gel-C hydrogels such as thermal reversibility and injectability could be manipulated by controlling the temperature and pH of the precursor solution. By simulating the formation of an irreversible Gel-C hydrogel in vivo, an in situ gelling system was fabricated by lowering the local temperature of the hydrogel with cold shock, thus realizing targeted and localized molecular delivery with prolonged retention time. This simple system integrated with the temperature responsiveness of gelatin and chemical cross-linking of catechol groups thus provides a promising platform to fabricate an in situ gelling system for drug delivery.

Metabolism is not a Major Contributor to the Toxicity of Piperaquine, a Long-acting Antimalarial Agent in Artemisinin-based Combination Therapy.

BACKGROUND: Hepatocellular damage has been reported for the antimalarial piperaquine (PQ) in the clinic after cumulative doses. OBJECTIVES: The role of metabolism in PQ toxicity was evaluated, and the mechanism mediating PQ hepatotoxicity was investigated. METHODS: The toxicity of PQ and its major metabolite (PQ N-oxide; M1) in mice was evaluated in terms of serum biochemical parameters. The role of metabolism in PQ toxicity was investigated in mice pretreated with an inhibitor of CYP450 (ABT) and/or FMO enzyme (MMI). The dose-dependent pharmacokinetics of PQ and M1 were studied in mice. Histopathological examination was performed to reveal the mechanism mediating PQ hepatotoxicity. RESULTS: Serum biochemical levels (ALT and BUN) increased significantly (P < 0.05) in mice after three-day oral doses of PQ (> 200 mg/kg/day), indicating hepatotoxicity and nephrotoxicity of PQ at a high dose. Weaker toxicity was observed for M1. Pretreatment with ABT and/or MMI did not increase PQ toxicity. PQ and M1 showed linear pharmacokinetics in mice after a single oral dose, and multiple oral doses led to their cumulative exposures. Histopathological examination showed that a high dose of PQ (> 200 mg/kg/day for three days) could induce hepatocyte apoptosis. The mRNA levels of targets in NF-κB and p53 pathways could be up-regulated by 2-30-fold in mice by PQ or M1. CONCLUSION: PQ metabolism led to detoxification of PQ, but there was a low possibility of altered toxicity induced by metabolism inhibition. The hepatotoxicity of PQ and its N-oxidation metabolite was partly mediated by NF-κB inflammatory pathway and p53 apoptosis pathway.

Injectable Micelle-Incorporated Hydrogels for the Localized Chemo-Immunotherapy of Breast Tumors.

Although immune checkpoint blockade (ICB) holds potential for the treatment of various tumors, a considerable proportion of patients show a limited response to ICB therapy due to the low immunogenicity of a variety of tumors. It has been shown that some chemotherapeutics can turn low-immunogenic tumors into immunogenic phenotypes by inducing a cascade of immune responses. In this paper, we synthesized an injectable micelle-incorporated hydrogel, which was able to sequentially release the chemotherapeutic gemcitabine (GEM) and the hydrophobic indoleamine 2, 3-dioxygenase inhibitor, d-1-methyltryptophan (d-1MT) at tumor sites. The hydrogel was formed via the thiol-ene click reaction between the thiolated chondroitin sulfate and the micelle formed by amphiphilic methacrylated Pluronic F127, in which hydrophobic d-1MT was encapsulated in the core of the F127 micelles and the hydrophilic GEM was dispersed in the hydrogel network. The successive release of chemotherapeutics and immune checkpoint inhibitors at tumor tissues will first promote the infiltration of cytotoxic T lymphocytes and subsequently induce a robust antitumor immune response, ultimately exerting a synergetic therapeutic efficacy. In a 4T1 tumor-bearing mice model, our results showed that the combination of chemotherapy and immunotherapy through the micelle-incorporated hydrogel triggered an effective antitumor immune response and inhibited tumor metastasis to the lung. Our results highlight the potential of the injectable micelle-incorporated hydrogel for the localized chemo-immunotherapy in the treatment of breast tumors.

Triple-Configurational Magnetic Robot for Targeted Drug Delivery and Sustained Release.

Active targeted therapy for bowel cancer using untethered microrobots has attracted extensive attention. However, traditional microrobots face challenges, such as issues of mobility, biocompatibility, drug loading, sustained-release capabilities, and targeting accuracy. Here, we propose an untethered triple-configurational magnetic robot (TCMR) that is composed of three geometrically nested parts: actuation and guarding, anchoring and seeding, and drug release part. A targeting magnetic driving system actuates the TCMR along the predetermined trajectory to the target position. The pH-sensitive actuation and guarding part formed by electrodeposition is degraded in the intestinal environment and separates from the two other parts. A majority of magnetic nanoparticles encapsulated in this part are retrieved. The anchoring and seeding part anchors the lesion area and seeds the drug release part in the gaps of intestinal villi by hydrolysis. Ultimately, the drug release part containing the therapeutic completes the sustained release to prolong the duration of the therapeutic agent. Cytotoxicity and therapeutic tests reveal that TCMRs are biocompatible and suitable for targeted therapy and have good therapeutic performance. The newly designed TCMR will provide new ideas for targeted therapy, thus expanding the application scope of robotics technology in the biomedical field.

Evaluation of natural gum-based cryogels for soft tissue engineering.

In this study, three natural biomaterials, Locust bean gum (LBG), Xanthan gum (XG), and Mastic gum (MG), were combined to form cryogel scaffolds. Thermal and chemical characterizations revealed the successful blend formation from LBG-XG (LX) and LBG-XG-MG (LXM) polymers. All blends resulted in macro-porous scaffolds with interconnected pore structures under the size of 400 µm. The swollen cryogels had similar mechanical properties compared with other polysaccharide-based cryogels. The mean tensile and compressive modulus values of the wet cryogels were in the range of 3.5-11.6 kPa and 82-398 kPa, respectively. The sustained release of the small molecule Kartogenin from varying concentrations and ratios of cryogels was in between 32 and 66% through 21 days of incubation. Physical, mechanical, and chemical properties make LX and LXM polysaccharide-based cryogels promising candidates for cartilage and other soft tissue engineering, and drug delivery applications.

Efficient Design to Monitor the Site-specific Sustained Release of a Non-Emissive Anticancer Drug.

A pH-responsive smart nanocarrier with significant components was synthesized by conjugating the non-emissive anticancer drug methyl orange and polyethylene glycol derived folate moiety to the backbone of polynorbornene. Complete synthesis procedure and characterization methods of three monomers included in the work: norbornene-derived Chlorambucil (Monomer 1), norbornene grafted with polyethylene glycol, and folic acid (Monomer 2) and norbornene attached methyl orange (Monomer 3) connected to the norbornene backbone through ester linkage were clearly discussed. Finally, the random copolymer CHO PEG FOL METH was synthesized by ring-opening metathesis polymerization (ROMP) using Grubbs' second-generation catalyst. Advanced polymer chromatography (APC) was used to find the final polymer's molecular weight and polydispersity index (PDI). Dynamic light scattering, scanning electron microscopy (SEM), and transmission electron microscopy (TEM) were utilized to explore the prodrug's size and morphology. Release experiments of the anticancer drug, Chlorambucil and the coloring agent, methyl orange, were performed at different pH and time. Cell viability assay was carried out for determining the rate of survived cells, followed by the treatment of our final polymer named CHO PEG FOL METH.

Antimicrobial nanofibrous mats with controllable drug release produced from hydrophobized hyaluronan.

Due to their large active surface, high loading efficiency, and tunable dissolution profiles, nanofibrous mats are often cited as promising drug carriers or antimicrobial membranes. Hyaluronic acid has outstanding biocompatibility, but it is hydrophilic. Nanofibrous structures made from hyaluronan dissolve immediately, making them unsuitable for controlled drug release and longer applications. We aimed to prepare a hyaluronan-based antimicrobial nanofibrous material, which would retain its integrity in aqueous environments. Self-supporting nanofibrous mats containing octenidine dihydrochloride or triclosan were produced by electrospinning from hydrophobized hyaluronan modified with a symmetric lauric acid anhydride. The nanofibrous mats required no cross-linking to be stable in PBS for 7 days. The encapsulation efficiency of antiseptics was nearly 100%. Minimal release of octenidine was observed, while up to 30% of triclosan was gradually released in 72 h. The nanofibrous materials exhibited antimicrobial activity, the fibroblast viability was directly dependent on the antiseptic content and its release.

Multi-Encapsulation Combination of O/W/O Emulsions with Polyurea Microcapsules for Controlled Release and Safe Application of Dimethyl Disulfide.

Dimethyl disulfide (DMDS), a promising alternative fumigant, has been highly desirable for excellent management of soil pests and diseases. However, high volatility and moderate toxicity of this sulfide limit its application. To address these issues, a novel controlled release formulation of DMDS was proposed employing multiple emulsions and polyurea microcapsules (DMDS@MEs-MCs). The successful combination of the two technologies was revealed by confocal laser scanning microscopy, scanning electron microscopy, thermogravimetric analysis, and Fourier transform infrared. According to the multiple encapsulation structure, the encapsulation efficiency decreased by only 3.13% after thermal storage, compared with a 15.21% decrease of microcapsules made with only a monolayer film. DMDS@MEs-MCs could effectively control the release of active ingredient, which increased applicator and environmental safety during application. Moreover, it could be facilely used by spraying and drip irrigation instead of a special fumigation device. The innovative formulation exhibited better control efficacy on soil pathogens (Fusarium spp. and Phytophthora spp.) and root-knot nematodes (Meloidogyne spp.) than DMDS technical concentration (DMDS TC). In addition, it did not inhibit seed germination after 10 days when the plastic film was removed from the fumigated soil. This method appears to be of broad interest for the development of safe and handy fumigant application.

Construction of a Mesoporous Polydopamine@GO/Cellulose Nanofibril Composite Hydrogel with an Encapsulation Structure for Controllable Drug Release and Toxicity Shielding.

The development of intelligent and multifunctional hydrogels having photothermal properties, good mechanical properties, sustained drug release abilities with low burst release, antibacterial properties, and biocompatibility is highly desirable in the biomaterial field. Herein, mesoporous polydopamine (MPDA) nanoparticles wrapped with graphene oxide (GO) were physically cross-linked in cellulose nanofibril (CNF) hydrogel to obtain a novel MPDA@GO/CNF composite hydrogel for controllable drug release. MPDA nanoparticles exhibited a high drug loading ratio (up to 35 wt %) for tetracycline hydrochloride (TH). GO was used to encapsulate MPDA nanoparticles for extending the drug release time and reinforcing the physical strength of the obtained hydrogel. The mechanical strength of the as-fabricated MPDA@GO/CNF composite hydrogel was five times greater compared to that of the pure CNF hydrogel. Drug release experiments demonstrated that burst release behavior was significantly reduced by adding MPDA@GO. The drug release time of the MPDA@GO/CNF composite hydrogel was 3 times and 7.2 times longer than that of the polydopamine/CNF hydrogel and pure CNF hydrogel, respectively. The sustained and controlled drug release behaviors of the composite hydrogel were highly dependent on the proportion of MPDA and GO. Moreover, the rate of drug release could be accelerated by near-infrared (NIR) light irradiation and pH value change. The drug release kinetics of the as-prepared composite hydrogel was well described by the Korsmeyer-Peppas model, and the drug release mechanism of TH from the composite hydrogel was anomalous transport. Importantly, this carefully designed MPDA@GO/CNF composite hydrogel showed good biocompatibility through an in vitro cytotoxicity test. In particular, the toxicity of GO was well shielded by the CNF hydrogel. Therefore, this novel MPDA@GO/CNF composite hydrogel with an encapsulation structure for controllable drug release and toxicity shielding of GO could be used as a very promising controlled drug delivery carrier, which may have potential applications for chemical and physical therapies.

Development of Sustained Release Oseltamivir Phosphate Dry Powder Inhaler: In-Vitro Characterization and In-Vivo Toxicological Studies.

BACKGROUND: Oseltamivir Phosphate (OP) is an ethyl ester prodrug prescribed for the treatment of influenza virus infection. Current marketed formulations of OP have been observed to be supplemented with an adverse effect during post-marketing surveillance. These prerequisites are sufficed by developing a sustained release Dry Powder for Inhalation (DPI). OBJECTIVE: The objective of the present study was to develop OP-DPI by an innovative formulation approach comprising of Immediate (IR) and Sustained (SR) Release portions. METHODS: DPI formulation comprising IR and SR portions were prepared by spray drying technique using Hydroxy Propyl Methyl Cellulose (HPMC) as the rate-controlling polymer for SR portion. The spray-dried product was further characterized for various pharmaco-technical, in-vitro and in-vivo parameters. RESULTS: OP-DPI showed a burst release of 49% within 15 min further sustaining the drug release up to 9 hrs. The in-vitro aerodynamic performance of OP-DPI showed maximum deposition at stage 3 and Fine Particle Dose (FPD) of 1.08 mg indicating deposition in the upper respiratory tract. Solid-state characterization by DSC and XRD indicated the partial amorphization of OP due to spray drying. In-vivo toxicological examination revealed no sign of inflammation, indicating the safety of the developed formulation. Accelerated stability study as per ICH guidelines displayed no significant change in the solid-state characterization and drug-related performance of OP-DPI. CONCLUSION: Prepared novel and scalable OP-DPI may have the potential to overcome the problems associated with existing marketed dosage forms of OP. Further, localized drug delivery of the antiviral drug through the pulmonary route might be clinically beneficial in controlling the viral proliferation.

Squalenyl Hydrogen Sulfate Nanoparticles for Simultaneous Delivery of Tobramycin and an Alkylquinolone Quorum Sensing Inhibitor Enable the Eradication of P.†aeruginosa Biofilm Infections.

Elimination of pulmonary Pseudomonas aeruginosa (PA) infections is challenging to accomplish with antibiotic therapies, mainly due to resistance mechanisms. Quorum sensing inhibitors (QSIs) interfering with biofilm formation can thus complement antibiotics. For simultaneous and improved delivery of both active agents to the infection sites, self-assembling nanoparticles of a newly synthesized squalenyl hydrogen sulfate (SqNPs) were prepared. These nanocarriers allowed for remarkably high loading capacities of hydrophilic antibiotic tobramycin (Tob) and a novel lipophilic QSI at 30 % and circa 10 %, respectively. The drug-loaded SqNPs showed improved biofilm penetration and enhanced efficacy in relevant biological barriers (mucin/human tracheal mucus, biofilm), leading to complete eradication of PA biofilms at circa 16-fold lower Tob concentration than Tob alone. This study offers a viable therapy optimization and invigorates the research and development of QSIs for clinical use.

Exploring the potential of tianeptine matrix tablets: Synthesis, physico-chemical characterization and acute toxicity studies.

The main objective of the present study was to explore the potential of matrix tablets as extended release dosage form of tianeptine, using HMPC K100 as a polymer. HPMC K100 extended the release of the drug from formulation due to the gel-like structure. Direct compression method was adopted to compress the tablets using different concentrations of polymer. Tablets were evaluated for pre-compression and post-compression parameters. Drug release study showed that tablet extends the release of drug with the increasing concentration of polymer. Drug, polymers and tablets were analyzed and/or characterized for compatibility, degradation, thermal stability, amorphous or crystalline nature via FTIR, DSC, TGA, XRD studies. SEM study predicted that tablets had a uniform structure. HPMC K100 based tablets were similar to that of the reference product. Acute toxicity study conducted on Swiss albino mice showed that matrix tablets were safe and non-toxic, as no changes in physical activity and functions of organs were observed. Biochemical and histopathological study revealed lack of any kind of abnormality in liver and renal function. Moreover, necrotic changes were absent at organ level.

Acrylamide grafted neem (Azadirachta indica) gum polymer: Screening and exploration as a drug release retardant for tablet formulation.

The study was initiated with the intent to synthesize acrylamide grafted neem gum polymer (AAm-g-NG), and screen its drug release retardation ability both in vitro and in vivo. Different batches (NGP-1 to NGP-9) of tablet formulation were prepared by varying polymer concentration using propranolol HCl and compared with HPMC K100 M and marketed SR tablets. FTIR study proved the grafting phenomenon and showed no incompatibility between AAm-g-NG and propranolol HCl. AAm-g-NG showed significant swelling and water retention capacity than NG. AAm-g-NG was found to be biodegradable and exhibited no toxicity to Artemia salina. After 12 h, NGP-6 showed non-significant (p > 0.05; f2= ∼ 90) percent drug release (80.52 ±â€¯3.41%) compare to marketed formulation (79.65 ±â€¯4.08%). Significant swelling of the matrix caused slower diffusion of the drug. NGP-6 and marketed formulation in rabbits showed the non-significant difference between Cmax and Tmax, hence NGP-6 meets the requirement of sustained-release tablets.

Amino-decorated mesoporous silica nanoparticles for controlled sofosbuvir delivery.

The present study describes synthesis of amino-decorated mesoporous silica nanoparticles (MSNs) for sustained delivery and enhanced bioavailability of sofosbuvir. Sofosbuvir is active against hepatitis C virus and pharmaceutically classified as class III drug according to biopharmaceutics classification system (BCS). MSNs were synthesized using modified sol-gel method and the surface was decorated with amino functionalization. Drug loaded MSNs were also grafted with polyvinyl alcohol in order to compare it with the amino-decorated MSNs for sustained drug release. The prepared MSNs were extensively characterized and the optimized formulation was toxicologically and pharmacokinetically evaluated. The functionalized MSNs of 196 nm size entrapped 29.13% sofosbuvir in the pores, which was also confirmed by the decrease in surface area, pore volume and pore size. The drug-loaded amino-decorated MSNs revealed an improved thermal stability as confirmed by thermal analysis. Amino-decorated MSNs exhibited Fickian diffusion controlled sofosbuvir release as compared with non-functionalized and PVA grafted MSNs. Amino-decorated MSNs were deemed safe to use in Sprague-Dawley rats after 14-days exposure as confirmed by the toxicological studies. More interestingly, we achieved a 2-fold higher bioavailability of sofosbuvir in Sprague-Dawley rats in comparison with sofosbuvir alone, and the Tmax was delayed 3-times indicating a sustained release of sofosbuvir.

Local and controlled release of tamoxifen from multi (layer-by-layer) alginate/chitosan complex systems.

Herein, multilayer polysaccharide films were proposed and characterized as biomaterials for the local and controlled release of an antitumoral drug. To that aim, multilayer films of alginate (Alg) and chitosan (Chi) were built up through spray assisted layer-by-layer (LbL) technique employing an automatic equipment. A specific drug against breast cancer, tamoxifen (TMX), was incorporated in different intermediate positions of the multilayer Alg/Chi films. Our findings highlight that Alg/Chi multilayer films can be employed for sustained and local TMX delivery and their therapeutic effect can be modulated and optimized by the number of bilayers deposited over the loaded tamoxifen, the quantity of tamoxifen loaded in several intermediate positions and the total area of the film.

A novel injectable in situ forming gel based on carboxymethyl hexanoyl chitosan/hyaluronic acid polymer blending for sustained release of berberine.

An in situ forming gel based on simply blending carboxymethyl hexanoyl chitosan (CHC) with low molecular weight hyaluronic acid (LMW HA) was developed, without needing cross-linking, photopolymerization or thermal treatments. The CHC/LMW HA blends formed nanoparticles and then rapidly transformed into supermolecular hydrogels under stirring. The gel formation mechanism was examined by Förster resonance energy transfer (FRET). The gels were injectable, cytocompatible and biodegradable, and showed shape-persistent behavior and adhesive property. Berberine, an anti-apoptotic and anti-arthritis naturally occurring compound, was encapsulated within the CHC/LMW HA gels. The gels demonstrated a pH-responsive characteristic which were able to release berberine in a sustained manner at pH 6.0 (simulating inflamed arthritic articular cartilage) and the degradation rates were accelerated at pH 7.4 (simulating healed normal tissue). The berberine-loaded gels effectively protected chondrocytes against sodium nitroprusside-induced apoptosis. The gels may be potentially useful as an injectable system for intra-articular drug delivery and cartilage tissue engineering.

The Use of an Efficient Microfluidic Mixing System for Generating Stabilized Polymeric Nanoparticles for Controlled Drug Release.

Microfluidics is a promising system for efficiently optimizing the experimental conditions for preparing nanomedicines, such as self-assembled nanoparticles. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles are promising drug carriers allowing sustained drug release. Here, we encapsulated the model drug curcumin, which has many pharmacological activities, into PLGA nanoparticles and investigated the effects of experimental conditions on the resulting PLGA nanoparticles using a microfluidics system with a staggered herringbone structure that can stir solutions through chaotic advection. The total flow rate and flow rate ratio of the solutions in the microfluidics system affected the diameters, polydispersity index, and encapsulation efficiency of the resulting PLGA nanoparticles and produced small, homogenous PLGA nanoparticles. The incorporation of polyethylene glycol (PEG)-PLGA into the PLGA nanoparticles reduced the particle size and improved the encapsulation efficiency. Initial burst release from the PLGA nanoparticles was prevented by the incorporation of PEG2000-PLGA. Curcumin-loaded PEGylated PLGA nanoparticles showed cytotoxicity similar to that of other formulations. This microfluidics system allows high throughput and is scalable for the efficient preparation of PLGA nanoparticles and PEGylated PLGA nanoparticles. Our results will be useful for developing novel PLGA-based polymer nanoparticles by using the microfluidics.

Glutathione-sensitive hollow mesoporous silica nanoparticles for controlled drug delivery.

Tunable glutathione (GSH)-sensitive hollow mesoporous silica nanoparticles (HMSiO2 NPs) were developed using a structural difference-based selective etching strategy. These organosilica hollow nanoparticles contained disulfide linkages (S-S) in the outer shell which were degraded by GSH. The particles were compared with their nonGSH-sensitive tetraethyl orthosilicate (TEOS) HMSiO2 counterparts in terms of their synthesis method, characterization, doxorubicin (DOX) release profile, and in vitro cytotoxicity in MCF-7 breast cancer cells. Transmission electron microscopy (TEM) of the particles indicated that the fabricated HMSiO2 NPs had an average diameter of 130 ±â€¯5 nm. Thermogravimetric analysis (TGA) revealed that GSH-sensitive particles had approximately 5.3% more weight loss than TEOS HMSiO2 NPs. Zeta potential of these redox-responsive particles was -23 ±â€¯1 mV at pH 6 in deionized (DI) water. Nitrogen adsorption-desorption isotherm revealed that the surface area of the hollow mesoporous nanoreservoirs was roughly 446 ±â€¯6 m2 g-1 and the average diameter of the pores was 2.3 ±â€¯0.5 nm. TEM images suggest that the nanoparticles started to lose mass integrity from Day 1. The particles showed a high loading capacity for DOX (8.9 ±â€¯0.5%) as a model drug, due to the large voids existing in the hollow structures. Approximately 58% of the incorporated DOX released within 14 days in phosphate buffered saline (PBS) at pH 6 and in the presence of 10 mM of GSH, mimicking intracellular tumor microenvironment while release from TEOS HMSiO2 NPs was only c.a. 18%. The uptake of these hollow nanospheres by MCF-7 cells and RAW 264.7 macrophages was evaluated using TEM and confocal microscopy. The nanospheres were shown to accumulate in the endolysosomal compartments after incubation for 24 h with the maximum uptake of c.a. 2.1 ±â€¯0.3% and 5.2 ±â€¯0.4%, respectively. Cytotoxicity of the nanospheres was investigated using CCK-8 assay. Results indicate that intact hollow particles (both GSH-sensitive and TEOS HMSiO2 NPs) were nontoxic to MCF-7 cells after incubation for 24 h within the concentration range of 0-1000 µg ml-1. DOX-loaded GSH-sensitive nanospheres containing 6 µg ml-1 of DOX killed c.a. 51% of MCF-7 cells after 24 h while TEOS HMSiO2 NPs killed c.a. 20% with the difference being statistically significant. Finally, cytotoxicity data in RAW 264.7 macrophages and NIH 3 T3 fibroblasts shows that intact GSH-sensitive HMSiO2 NPs did not show any toxic effects on these cells with the concentrations equal or <125 µg ml-1.

Experimental optimization of Lornoxicam liposomes for sustained topical delivery.

The purpose of the present investigation is to formulate liposomes of Lornoxicam for topical delivery using Central Composite Design, to provide a sustained release of the drug and thereby extend its elimination half-life. Liposomes were prepared by thin film hydration method with pH induced vesiculation. The liposomes were assessed for their particle size, charge, morphology and drug entrapment and characterized using TGA-DSC and FTIR analysis, to assess the interaction between the drug and excipients. The in vitro release study was performed using modified USP dissolution apparatus-I using three different dissolution media and the ex vivo release study was performed using goat skin. The cytotoxicity of Lornoxicam liposomes were studied on NIH 3T3 cells by MTT assay. The optimized formulation with particle size ranging from 100-200nm provided sustained release for 8h. The characterization studies proved very less interactions between the drug and the excipients. The ex vivo studies showed flux value of 23.29µg/cm2/h and Kp 0.011645cm/h. The cytotoxicity study showed increase in toxicity with increase in concentration more than 0.5µg/mL. The in vivo skin toxicity studies and histopathology analysis showed absence of toxic lesions, which confirmed the suitability of the formulation for topical application. Lornoxicam liposomes with good skin permeation and sustained release of drug were finally optimized by the experimental design.

Liposomal Cytarabine Induces Less Neurocognitive Dysfunction Than Intrathecal Methotrexate in an Animal Model.

Liposomal cytarabine is currently being tested clinically as an alternative to intrathecal (IT) methotrexate (MTX) for preventing relapse within the central nervous system among patients with acute lymphoblastic leukemia. To compare the toxicity and cognitive deficits caused by IT MTX versus liposomal cytarabine, juvenile Long Evans rats were treated with IT injections of MTX 1 mg/kg×4 doses over 8 days, or liposomal cytarabine 0.8 mg once. Mean concentrations of free cytarabine in cerebrospinal fluid remained above the cytotoxic threshold of 0.4 µM for 2 weeks after dosing. Animals treated with liposomal cytarabine exhibited normal recognition and spatial memory 4 weeks after injection. In contrast, exposure to IT MTX led to impaired cognitive function. In addition, mean hematocrit on day 11 was significantly lower in the MTX-treated animals (30.8%; 95% confidence interval, 27.0%-34.7%; n=6) compared with that in the liposomal cytarabine-treated animals (39.5%; 95% confidence interval, 38.4%-40.6%; n=6; P<0.0001). Our data suggest that liposomal cytarabine induces fewer neurocognitive deficits and less acute hematologic toxicity compared with IT MTX. Liposomal cytarabine may therefore have therapeutic advantages over IT MTX, if it is equally effective in preventing relapse.