Biocompatible Solutions: Evaluating the Safety of Repeated Intra-Articular Injections of pMPCylated Liposomes for Knee Osteoarthritis Therapy in Rat Models.

Knee osteoarthritis (OA) poses a significant health care burden globally, necessitating innovative therapeutic approaches. CCoat, a novel poly(2-[methacryloyloxy]ethyl phosphorylcholine) (pMPC)ylated liposome device, protects the cartilage surface of the joint from mechanical wear through an entropy-favored process. Two preclinical studies were performed to explore the safety of CCoat following repeated intra-articular (IA) injections into the knee joint (i.e., femorotibial joint) in Sprague-Dawley rats. The studies involved 2 or 3 IA injections, at an interval of 2 or 3 weeks, and an observation period of 1 or 13 weeks after the last injection. Assessments included clinical, histopathological, and immunofluorescent evaluations. In study 1, no mortality or abnormal clinical signs occurred. At 1 week post last injection, histopathology revealed minimal vacuolated macrophages beneath the synovial membrane, predominantly M2-like, indicating a nonadverse response. Immunofluorescent staining supported M2-like macrophage predominance. Study 2 confirmed these findings with no systemic effects over 13 weeks. Statistical analyses indicated no significant differences in body weight, clinical pathology, or organ weights compared with controls. Results affirming the safety of pMPCylated liposomes following repeated IA injections in rat. This novel lubricant coating approach shows promise in OA therapy, with this safety assessment supporting its potential clinical application.

Immunopharmacological Properties of Methacrylic Acid Polymers as Potential Polymeric Carrier Constituents of Anticancer Drugs.

Cytostatic chemotherapeutics provide a classical means to treat cancer, but conventional treatments have not increased in efficacy in the past years, warranting a search for new approaches to therapy. The aim of the study was, therefore, to obtain methacrylic acid (MAA) (co)polymers and to study their immunopharmacological properties. 4-Cyano-4-[(dodecylsulfanylthiocarbonyl)sulfanyl] pentanoic acid (CDSPA) and 2-cyano-2-propyl dodecyl trithiocarbonate (CPDT) were used as reversible chain transfer agents. Experiments were carried out in Wistar rats. The MTT assay was used to evaluate the cytotoxic effect of the polymeric systems on peritoneal macrophages. An experimental tumor model was obtained by grafting RMK-1 breast cancer cells. Serum cytokine levels of tumor-bearing rats were analyzed. The chain transfer agents employed in classical radical polymerization substantially reduced the molecular weight of the resulting polymers, but a narrow molecular weight distribution was achieved only with CDSPA and high CPDT concentrations. Toxicity was not observed when incubating peritoneal macrophages with polymeric systems. In tumor-bearing rats, the IL-10 concentration was 1.7 times higher and the IL-17 concentration was less than half that of intact rats. Polymeric systems decreased the IL-10 concentration and normalized the IL-17 concentration in tumor-bearing rats. The maximum effect was observed for a MAA homopolymer with a high molecular weight. The anion-active polymers proposed as carrier constituents are promising for further studies and designs of carrier constituents of drug derivatives.

The effect of some acrylic polymers on dissolution of celecoxib solid dispersion formulations.

OBJECTIVE: The purpose of the present study was firstly to identify the effectiveness of Eudragit® polymers (Eudragit® RL, RS, L100-55, L100, S100 and E100) in inhibition of celecoxib precipitation from buffer solutions (pH = 6.8). Furthermore, the influence of Eudragit® polymers on non-sink dissolution behavior of celecoxib from solid dispersions was investigated. METHODS: Solid dispersions were prepared by the rotary evaporation method. In vitro dissolution studies, FT-IR and differential scanning calorimetry were employed to characterize the formulations. RESULTS: The results revealed that Eudragit® E100, L100 and S100 inhibited precipitation of celecoxib efficiently. It is understood that crystallization during the dissolution of solid dispersions could happen through crystallization from solid matrix following contact with the dissolution medium or from the supersaturated solution produced following dissolution. The supersaturated drug concentrations attained from the dissolution of Eudragit®-celecoxib solid dispersions were almost similar, suggesting that crystallization from solid matrix did not occur readily. However, only solid dispersions containing efficient crystallization inhibitor polymers were able to maintain the supersaturated solution up to the end of the dissolution run. CONCLUSION: Results revealed that the principal mechanism of attaining supersaturated solution of celecoxib from solid dispersions was related to crystallization inhibition from solution not from solid matrix.

Real-time imaging of polymersome nanoparticles in zebrafish embryos engrafted with melanoma cancer cells: Localization, toxicity and treatment analysis.

BACKGROUND: The developing zebrafish is an emerging tool in nanomedicine, allowing non-invasive live imaging of the whole animal at higher resolution than is possible in the more commonly used mouse models. In addition, several transgenic fish lines are available endowed with selected cell types expressing fluorescent proteins; this allows nanoparticles to be visualized together with host cells. METHODS: Here, we introduce the zebrafish neural tube as a robust injection site for cancer cells, excellently suited for high resolution imaging. We use light and electron microscopy to evaluate cancer growth and to follow the fate of intravenously injected nanoparticles. FINDINGS: Fluorescently labelled mouse melanoma B16 cells, when injected into this structure proliferated rapidly and stimulated angiogenesis of new vessels. In addition, macrophages, but not neutrophils, selectively accumulated in the tumour region. When injected intravenously, nanoparticles made of Cy5-labelled poly(ethylene glycol)-block-poly(2-(diisopropyl amino) ethyl methacrylate) (PEG-PDPA) selectively accumulated in the neural tube cancer region and were seen in individual cancer cells and tumour associated macrophages. Moreover, when doxorubicin was released from PEG-PDPA, in a pH dependant manner, these nanoparticles could strongly reduce toxicity and improve the treatment outcome compared to the free drug in zebrafish xenotransplanted with mouse melanoma B16 or human derived melanoma cells. INTERPRETATION: The zebrafish has the potential of becoming an important intermediate step, before the mouse model, for testing nanomedicines against patient-derived cancer cells. FUNDING: We received funding from the Norwegian research council and the Norwegian cancer society.

Eudragit L-100 Capsules Aromatize and Quaternerize Chitosan for Insulin Nanoparticle Oral Delivery During Toxic Oxidative Stress in Rat Liver and Kidney.

BACKGROUND: Insulin, like most peptides, is classified as a hydrophilic and macromolecular drug that is considered as a low permeable and unstable compound in the gastrointestinal (GI) tract. The acidic condition of the stomach can degrade insulin molecules. Moreover, the presence of proteolytic activities of some enzymes such as trypsin and chymotrypsin can hydrolyze amide-bonds between various amino-acids in the structures of peptides and proteins. However, due to its simplicity and high patient compliance, oral administration is the most preferred route of systemic drug delivery, and for the development of an oral delivery system, some obstacles in oral administration of peptides and proteins including low permeability and low stability of the proteins in GI should be overcome. OBJECTIVE: In this study, the effects of orally insulin nanoparticles (INPs) prepared from quaternerized N-aryl derivatives of chitosan on the biochemical factors of the liver in diabetic rats were studied. METHODS: INPs composed of methylated (amino benzyl) chitosan were prepared by the PEC method. Lyophilized INPs were filled in pre-clinical capsules, and the capsules were enteric-coated with Eudragit L100. Twenty Male Wistar rats were randomly divided into four groups: group1: normal control rats, group 2: diabetic rats, group 3: diabetic rats received capsules INPs(30 U/kg/day, orally), group 4: the diabetic rats received regular insulin (5 U/kg/day, subcutaneously). At the end of the treatment, serum, liver and kidney tissues were collected. Biochemical parameters in serum were measured using spectrophotometric methods. Also, oxidative stress was measured in plasma, liver and kidney. Histological studies were performed using H and E staining . RESULTS: Biochemical parameters, and liver and kidney injury markers in serum of the diabetic rats that received INPs improved significantly compared with the diabetic group. INPs reduced oxidative toxic stress biomarkers in serum, liver and kidney of the diabetic treated group. Furthermore, a histopathological change was developed in the treated groups. CONCLUSION: Capsulated INPs can prevent diabetic liver and oxidative kidney damages (similar regular insulin). Therefore oral administration of INPs appears to be safe. Lay Summary: Although oral route is the most preferred route of administration, but oral delivery of peptides and proteins is still a challenging issue. Diabetes Mellitus may lead to severe complications, which most of them are life-threatening. In this study, we are testing the toxicity of oral insulin nanoparticles in kidney and liver of rats. For this investigation, we will prepare insulin nanoparticles composed of a quaternized derivative of chitosan. The nanoparticles will be administered orally to rats and the level of oxidative stress in their liver and kidney will be determined. The data will be compared to the subcutaneous injection of insulin.

Expedition of Eudragit® Polymers in the Development of Novel Drug Delivery Systems.

Eudragit® polymer has been widely used in film-coating for enhancing the quality of products over other materials (e.g., shellac or sugar). Eudragit® polymers are obtained synthetically from the esters of acrylic and methacrylic acid. For the last few years, they have shown immense potential in the formulations of conventional, pH-triggered, and novel drug delivery systems for incorporating a vast range of therapeutics including proteins, vitamins, hormones, vaccines, and genes. Different grades of Eudragit® have been used for designing and delivery of therapeutics at a specific site via the oral route, for instance, in stomach-specific delivery, intestinal delivery, colon-specific delivery, mucosal delivery. Further, these polymers have also shown their great aptitude in topical and ophthalmic delivery. Moreover, available literature evidences the promises of distinct Eudragit® polymers for efficient targeting of incorporated drugs to the site of interest. This review summarizes some potential researches that are being conducted by eminent scientists utilizing the distinct grades of Eudragit® polymers for efficient delivery of therapeutics at various sites of interest.

Polypyrrole and polyaniline nanocomposites with high photothermal conversion efficiency.

The simple and scalable synthesis of poly[2-(methacryloyloxy)ethyl phosphorylcholine] (PMPC)-coated conducting polymer (CP) nanocomposites is described. These functional nanocomposites exhibit tunable absorption in the near-infrared region with relatively high photothermal efficiencies. More importantly, their potential for bio-imaging and therapeutic treatment is proven by cellular uptake and cytotoxicity studies.

Ultra pH-sensitive polymeric nanovesicles co-deliver doxorubicin and navitoclax for synergetic therapy of endometrial carcinoma.

Endometrial carcinoma is a kind of epithelial malignant tumor occurring in the endometrium with high incidence (nearly 200 000 people are diagnosed every year). At present, surgery is the main strategy for the treatment of endometrial carcinoma. However, in special cases such as serous, clear cell carcinoma and postoperative recurrences, chemotherapy is still essential and indispensable. The combined chemotherapy schemes of cisplatin, paclitaxel and doxorubicin (DOX) in clinical applications are unfortunately complicated and easily cause severe side effects. In recent years, with the development of nanotechnology, the targeted delivery of multi-chemotherapeutic drugs shows great advantages in reducing side effects and improving anticancer efficacy. Here, an ultra pH-sensitive nanovesicle based on polyethylene glycol-poly(diisopropylamino)ethyl methacrylate (PEG-PDPA) was fabricated. A chemotherapeutic drug (doxorubicin) and an anti-apoptotic Bcl-2 inhibitor (navitoclax) were co-encapsulated in the hydrophilic cavity and hydrophobic membrane of the vesicle, respectively. After accumulating in the tumor tissue via the enhanced permeability and retention (EPR) effect, the nanovesicles could be efficiently diffused in tumor cells by endocytosis and then rapidly release drugs in response to the lysosomal acidic environment, leading to an enhanced tumor-killing effect based on the combination therapy between DOX and the Bcl-2 inhibitor. The drug co-delivery system and microenvironment-triggered drug release may provide an efficient strategy for endometrial carcinoma therapy.

Novel carriers ensuring enhanced anti-cancer activity of Cornus mas (cornelian cherry) bioactive compounds.

Cornusmas' bioactive compounds are powerful antioxidants. In this study, we evaluated the antioxidant activity of the encapsulated bioactive compounds of Cornus mas extract (CME) and its release in semi digestive condition via enteric coated nanocarriers (NCs). The two forms of CME, encapsulated into enteric coated nanocarriers (CME-NCs) and free CME, were studied to determine the effect of encapsulation on the stability of antioxidants. Then, their effect on cell cycle, cell viability and apoptosis of cancer cells were studied. The characterization analysis reported the mean particle size and zeta potential value of NCs equal to 22.7 ± 6.58 nm and -16 ± 5 mV. The results showed that CME-NCs could improve IC50 value 1.33 and 1.47 times more than the free CME after 24 and 48 h of incubation. These findings confirmed that CME-NCs could stop the cells proliferation in G1 phase, and caused apoptosis in cancer cell line HT-29.

Colon-Targeted Therapy of Tacrolimus (FK506) in the Treatment of Experimentally Induced Colitis.

BACKGROUND/AIMS: Inflammatory bowel disease is a chronic or remitting/relapsing intestinal inflammation, which comprises Crohn's disease and ulcerative colitis (UC). Severe UC is a life-threatening condition that requires corticosteroids (CS) as a first-line rescue therapy. Some patients are refractory to CS and may require alternative immunosuppressive therapy. Oral tacrolimus (FK506), an immunosuppressive agent, has been reported to be effective in the management of severe refractory UC, but it can cause serious adverse effects. This work aims to study the effect of tacrolimus delivered by a colon-targeted delivery system (CTDS) in a dextran sulfate sodium (DSS)-induced animal model of colitis. MATERIALS AND METHODS: We developed and evaluated an oral CTDS of tacrolimus (FK506) loaded pH-dependent polymeric microspheres, composed of Eudragit® S100 as a pH-sensitive polymer using the oil-in-water emulsion method. The physicochemical properties and drug release profiles of these microparticles in gastrointestinal tract (GIT) conditions were examined. A DSS-induced colitis rat model was used to evaluate the potential remedial and in vivo distribution of microspheres. RESULTS: The pH-microspheres prevented a burst drug release in acidic pH conditions and showed sustained release at a colonic pH. The in vivo distribution study in the rat GIT demonstrated that pH-microspheres were successfully delivered to the inflamed colon. Moreover, it also demonstrated a significant decrease of disease activity and expression of proinflammatory cytokines, such as tumor necrosis factor α, interleukin-1ß (IL-1ß), and IL-6, and minimized the histological and morphometric changes. CONCLUSION: The results confirmed the efficacy of tacrolimus (FK506) CTDs in the management of DSS-induced colitis.

Raft-forming gastro-retentive formulations based on Centella asiatica extract-solid dispersions for gastric ulcer treatment.

Liquid raft-forming formulations comprising solid dispersions of glycoside-rich Centella asiatica extract and Eudragit® EPO (GR-SD) were developed to achieve prolonged delivery of the glycosides, asiaticoside (AS) and madecassoside (MS) in the stomach and thus increase the effectiveness of gastric ulcer treatment. Solid dispersions of GR extract and Eudragit® EPO (GR-SD, weight ratio 1:0.5) resulted in the highest solubility of AS (41.7 mg/mL) and MS (29.3 mg/mL) and completed dissolution of both glycosides occurred in SGF within 10 min. The optimized raft-forming formulation was composed of alginate (2%), HPMC K-100 (0.5%), GR-SD (1.2%), and calcium carbonate (0.5%) as a calcium source and carbon dioxide producer. The formulation provided sufficient raft strength (> 7.0 g), rapid floating behavior in SGF (~30 s), and sustained release of AS (more than 80%) and MS (85%) over 8 h. GR-SD-based formulations administered once daily to rats for two days at a dose of 10 mg AS/kg reduced the severity of gastric ulcer induced by indomethacin with a greater curative efficacy than those of unformulated GR extract and a standard antiulcer agent: lansoprazole (p < 0.05). These findings demonstrate that GR-SD-based raft-forming systems offer significant promise for improving the treatment of gastric ulcers induced by non-steroidal anti-inflammatory drugs.

Accelerated aging effects on color, microhardness and microstructure of ICON resin infiltration.

OBJECTIVE: Infiltration resins provide an ideal treatment alternative for white spot lesions on teeth. The icon infiltrant has been widely used as a dental material for a few years, but there are some studies on the in vitro accelerated aging process and the change of hardness and microstructure on this material. The innovation of this work is to aim at investigating characteristics associated with this infiltrant resin and comparing the Icon infiltrant with universal Filtek Z350 and flowable Filtek Z350 resins when exposed to artificial accelerated aging. MATERIALS AND METHODS: Materials were prepared as disc-shaped specimens sized to 12 mm × 2.2 mm and were aged through exposure to 150 kJ/m2 in an artificial accelerated aging machine. Two-time points, 24 h after aging and 96 h after aging, were selected for evaluation in the following trials. The morphology was observed using a scanning electron microscopy. The standard CIEL*a*b* color system was employed for color measurements. Microhardness of all specimens was analyzed by a Knoop indenter. Chemical components were examined by Fourier transform infrared spectroscopy. RESULTS: Compared with universal Z350 and flowable Z350, the ICON infiltrant resin presented a uniform, slightly scratched surface before and after accelerated aging. The 24 h artificial accelerated aging of the three investigated materials resulted in acceptable color alterations, a ΔE* range of 2.52±0.63 for universal Z350, 2.43±0.59 for flowable Z350 and 3.31±0.32 for ICON. After 96 h aging, significant color changes were noted for universal Z350 (7.51±0.63) and ICON (4.70±0.69). The ICON infiltrant displayed reduced microhardness when compared to universal Z350 and flowable Z350. The absorption peaks of the chemical bonds were significantly altered after the accelerated aging process. CONCLUSIONS: Composed in a triethylene glycol dimethacrylate (TEGDMA) monomer-based network, the color stability and microhardness of the infiltrant resin provided suitable material for treating white spot lesions (WSLs), yet presented susceptibility under accelerated aging. Thus, osmotic resin therapy has strict limitations to be most effective.

Synthesis, Characterization and Safety Profiling of Eudragit-Based pHResponsive Hydrogels: A Promising Platform for Colonic Delivery of Losartan Potassium.

OBJECTIVE: The aim of the present study was to design an efficient delivery system with an anticipated swelling and drug release properties for a prolonged drug release as well as to target colon for various hydrophilic drugs. METHOD: For this purpose, the pH-responsive hydrogel comprising a combination of Eudragit and acrylic acid was formed. The hydrogels were characterized for spectral (FTIR), thermal (TGA/DSC), structural (XRD), and morphological (SEM) investigations. Oral tolerability was assessed in rabbits for biocompatibility and oral use of the prepared hydrogels. RESULTS: The results showed that an increased incorporation of Eudragit and cross-linking agent retorted the swelling, drug loading, and drug release properties at both acid (pH 1.2) and basic pH (pH 6.8 and 7.4) , while acrylic acid presented the inverse results. The oral tolerability and toxicity studies depicted that the developed hydrogels were safe up to 3800 mg/kg body weight and caused no hematological or histopathological changes when compared with the control group. CONCLUSION: Therefore, the newly developed formulations presented adequate swelling, drug loading, release behavior, and biocompatibility properties and thus can be used as a promising tool for the colonic delivery of various hydrophilic drugs.

Development of pH-responsive organic-inorganic hybrid nanocomposites as an effective oral delivery system of protein drugs.

This research aimed to develop a pH-responsive organic-inorganic hybrid nanocomposite as an effective oral delivery system for protein drugs. Three different nanocomposites were prepared by using bovine serum albumin (BSA) as a model protein. A nanocomplex of BSA with 3-aminopropyl functionalized magnesium phyllosilicate (AC-BSA) was obtained via the spontaneous co-assembly and then sequentially coated with glycol-chitosan (GAC-BSA) and the pH sensitive polymer, Eudragit®L100-55 (EGAC-BSA). These organic-inorganic hybrid nanocomposites exhibited high entrapment efficiency (86-99%) and their structural characteristics were confirmed by using energy dispersive X-ray spectroscopy, Fourier transform infrared spectroscopy, and circular dichroism analysis, indicating that the secondary structure of BSA was well retained in the nanocomposites. At pH 1.2, AC-BSA achieved rapid drug release of about 80% within 2 h, while GAC-BSA and EGAC-BSA exhibited slow drug release of 30% and 15%, respectively, indicating that the surface-coated nanocomposites were more stable in the gastric condition. Furthermore, the conformational stability of BSA entrapped in EGAC-BSA was well retained in the presence of proteolytic enzymes, suggesting that EGAC-BSA should be effective in protecting the protein against gastrointestinal harsh environment. Compared to free BSA, all of tested nanocomposites demonstrated 2.1-3.8-fold higher cellular uptake in Caco-2 cells. Furthermore, energy-dependent endocytosis and paracellular pathway contributed to the cellular transport of nanoparticles. After oral administration in rats, EGAC-BSA significantly enhanced the intestinal permeation of BSA compared to free BSA. In conclusion, EGAC-BSA appears to be promising as an effective oral delivery system for proteins with enhanced intestinal absorption.

Budesonide-Loaded Eudragit S 100 Nanocapsules for the Treatment of Acetic Acid-Induced Colitis in Animal Model.

Nanoparticles for colon-drug delivery were designed and evaluated to solve many discrepancy issues as insufficient drug amount at diseased regions, high adverse effects of released drugs, and unintentionally premature drug release to noninflamed gastrointestinal regions. Herein, the prepared budesonide-loaded Eudragit S 100/Capryol 90 nanocapsules for the treatment of inflammatory bowel disease. Nanocapsules were prepared efficiently by nanoprecipitation technique and composed mainly of the pH-sensitive Eudragit S 100 polymeric coat with a semisynthetic Capryol 90 oily core. Full 31 × 21 factorial design was applied to obtain optimized nanocapsules. Optimal nanocapsules showed mean particle size of 171 nm with lower polydispersity index indicating the production of monodispersed system and negative zeta-potential of - 37.6 mV. Optimized nanocapsules showed high encapsulation efficiency of 83.4% with lower initial rapid release of 10% for first 2 h and higher rapid cumulative release of 72% after 6 h. The therapeutic activity of the prepared budesonide-loaded nanocapsules was evaluated using a rat colitis model. Disease activity score, macroscopical examination, blood glucose level, and histopathological assessment showed marked improvements over that free drug suspension. Obtained results demonstrate that the budesonide-loaded Eudragit S 100 nanocapsules are an effective colon-targeting nanosystem for the treatment of inflammatory bowel disease. Capryol 90 was found to be a successful, and even preferred, alternative to benzyl benzoate, which is commonly employed as the oil core of such nanocapsules.

Revisiting cell-particle association in vitro: A quantitative method to compare particle performance.

Nanoengineering has the potential to revolutionize medicine by designing drug delivery systems that are both efficacious and highly selective. Determination of the affinity between cell lines and nanoparticles is thus of central importance, both to enable comparison of particles and to facilitate prediction of in vivo response. Attempts to compare particle performance can be dominated by experimental artifacts (including settling effects) or variability in experimental protocol. Instead, qualitative methods are generally used, limiting the reusability of many studies. Herein, we introduce a mathematical model-based approach to quantify the affinity between a cell-particle pairing, independent of the aforementioned confounding artifacts. The analysis presented can serve as a quantitative metric of the stealth, fouling, and targeting performance of nanoengineered particles in vitro. We validate this approach using a newly created in vitro dataset, consisting of seven different disulfide-stabilized poly(methacrylic acid) particles ranging from ~100 to 1000 nm in diameter that were incubated with three different cell lines (HeLa, THP-1, and RAW 264.7). We further expanded this dataset through the inclusion of previously published data and use it to determine which of five mathematical models best describe cell-particle association. We subsequently use this model to perform a quantitative comparison of cell-particle association for cell-particle pairings in our dataset. This analysis reveals a more complex cell-particle association relationship than a simplistic interpretation of the data, which erroneously assigns high affinity for all cell lines examined to large particles. Finally, we provide an online tool (http://bionano.xyz/estimator), which allows other researchers to easily apply this modeling approach to their experimental results.

Swellable polymeric particles for the local delivery of budesonide in oral mucositis.

Topical drug delivery in the oral mucosa has its set of challenges due to the unique anatomical and physiological features of the oral cavity. As such, the outcomes of local pharmacological treatments in oral disorders can fail due to unsuccessfully drug delivery. Oral mucositis, a severe inflammatory and ulcerative side effect of oncological treatments, is one of such diseases. Although the damaged tissue is within reach, no approved topical drug treatment is available. Several strategies based on its physiopathology have been implemented and clinically used. Even so, results tend to lack or be insufficient to improve patient's quality of life. The use of corticosteroids has been employed in such strategies due to their strong anti-inflammatory action. Typically, these are administrated in simple liquid formulations, where the drug is dispersed or solubilized, lacking the ability to maintain local concentration. In this work, we propose the development of a biocompatible delivery system with boosted abilities of retention and control release of budesonide, a corticosteroid with an elevated ratio of topical anti-inflammatory to systemic action. Through spray-drying, polymeric particles of Chitosan and Eudragit® E PO were produced and characterized for the vectorization of this drug.

Transcriptome analysis of signaling pathways of human peritoneal mesothelial cells in response to different osmotic agents in a peritoneal dialysis solution.

BACKGROUND: Glucose is a primary osmotic agent in peritoneal dialysis (PD) solutions, but its long-term use causes structural alteration of the peritoneal membrane (PM). Hyperbranched polyglycerol (HPG) is a promising alternative to glucose. This study was designed to compare the cellular responses of human peritoneal mesothelial cells (HPMCs) to these two different osmotic agents in a hypertonic solution using transcriptome analysis. METHODS: Cultured HPMCs were repeatedly exposed to HPG-based or Physioneal 40 (PYS, glucose 2.27%) hypertonic solutions. Transcriptome datasets were produced using Agilent SurePrint G3 Human GE 8 × 60 microarray. Cellular signaling pathways were examined by Ingenuity Pathway Analysis (IPA). Protein expression was examined by flow cytometry analysis and Western blotting. RESULTS: The HPG-containing solution was better tolerated compared with PYS, with less cell death and disruption of cell transcriptome. The levels of cell death in HPG- or PYS- exposed cells were positively correlated with the number of affected transcripts (HPG: 128 at day 3, 0 at day 7; PYS: 1799 at day 3, 212 at day 7). In addition to more affected "biosynthesis" and "cellular stress and death" pathways by PYS, both HPG and PYS commonly affected "sulfate biosynthesis", "unfolded protein response", "apoptosis signaling" and "NRF2-mediated oxidative stress response" pathways at day 3. PYS significantly up-regulated HLA-DMB and MMP12 in a time-dependent manner, and stimulated T cell adhesion to HPMCs. CONCLUSION: The lower cytotoxicity of hypertonic HPG solution is in agreement with its transient and minimal impact on the pathways for the "biosynthesis of cell constituents" and the "cellular stress and death". The significant up-regulation of HLA-DMB and MMP12 by PYS may be part of its initiation of immune response in the PM.

Antioxidant activity of quercetin in Eudragit-coated liposomes for intestinal delivery.

Quercetin, a natural polyphenol with strong antioxidant activity, was loaded in Eudragit-coated liposomes conceived for intestinal delivery. Eudragit was used to form a protective shell on the surface of liposomes to resist gastric environment and allow the delivery of quercetin to the intestine. The physico-chemical properties of the liposomes were assessed by light scattering and cryogenic transmission electron microscopy. Small, spherical, uni- and bilamellar liposomes were produced, with the presence of multilamellar structures in Eudragit-coated liposomes. The Eudragit coating increased the physical stability of the vesicular system in fluids mimicking the gastrointestinal environment. Further, the incorporation of quercetin in the vesicular system did not affect its intrinsic antioxidant activity, as DPPH radical was almost completely inhibited, and the vesicles were also capable of ensuring optimal protection against oxidative stress in human intestinal cells by reducing reactive oxygen species (ROS) production. The proposed approach based on quercetin vesicular formulations may be of value in the treatment of pathological conditions associated with intestinal oxidative stress.

Non-covalent hitchhiking on endogenous carriers as a protraction mechanism for antiviral macromolecular prodrugs.

Albumin is a highly successful tool of drug delivery providing drastically extended body and blood residence time for the associated cargo, but it only traffics single drug copies at a time. In turn, macromolecular prodrugs (MP) are advantaged in carrying a high drug payload but offering only a modest extension of residence time to the conjugated drugs. In this work, we engineer MP to contain terminal groups that bind to albumin via non-covalent association and reveal that this facile measure affords a significant protraction for the associated polymers. This methodology is applied to MP of acyclovir, a successful drug against herpes simplex virus infection but with poor pharmacokinetics. Resulting albumin-affine MP were efficacious agents against herpes simplex virus type 2 (HSV-2) both in vitro and in vivo. In the latter case, sub-cutaneous administration of MP resulted in local (vaginal) antiviral effects and a systemic protection. Presented benefits of non-covalent association with albumin are readily transferrable to a wide variety of MP in development for drug delivery as anticancer, anti-inflammatory, and anti-viral measures.