Alzheimer’s disease (AD), a neurodegenerative disorder exhibiting a gradual decline in cognitive function, is characterized by the presence of neuritic plaques composed of neurofibrillary tangles and ...amyloid-β (Aβ) peptide. Available drugs for AD therapy have small effect sizes and do not alter disease progression. Several studies have been shown that resveratrol is associated with anti-amyloidogenic properties, but therapeutic application of its beneficial effects is limited. Here we compared the neuroprotective effects of free resveratrol treatment with those of resveratrol-loaded lipid-core nanocapsule treatment against intracerebroventricular injection of Aβ1-42 in rats. Animals received a single intracerebroventricular injection of Aβ1-42 (2 nmol), and 1 day after Aβ infusion, they were administered either free resveratrol (RSV) or resveratrol-loaded lipid-core nanocapsules (5 mg/kg, each 12 h, intraperitoneally), for 14 days. Aβ1-42-infused animals showed a significant impairment on learning memory ability, which was paralleled by a significant decrease in hippocampal synaptophysin levels. Furthermore, animals exhibited activated astrocytes and microglial cells, as well as disturbance in c-Jun N-terminal kinase (JNK) and glycogen synthase kinase-3β (GSK-3β) activation, beyond destabilization of β-catenin levels. Our results clearly show that by using lipid-core nanocapsules, resveratrol was able to rescue the deleterious effects of Aβ1-42 while treatment with RSV presented only partial beneficial effects. These findings might be explained by the robust increase of resveratrol concentration in the brain tissue achieved by lipid-core nanocapsules. Our data not only confirm the potential of resveratrol in treating AD but also offer an effective way to improve the efficiency of resveratrol through the use of nanodrug delivery systems.
The hemocompatibility of nanoparticles is of critical importance for their systemic administration as drug delivery systems. Formulations of lipid-core nanocapsules, stabilized with polysorbate ...80-lecithin and uncoated or coated with chitosan (LNC and LNC-CS), were prepared and characterized by laser diffraction (D4,3: 129 and 134nm), dynamic light scattering (119nm and 133nm), nanoparticle tracking (D50: 124 and 139nm) and particle mobility (zeta potential: −15.1mV and +9.3mV) analysis. In vitro hemocompatibility studies were carried out with mixtures of nanocapsule suspensions in human blood at 2% and 10% (v/v). The prothrombin time showed no significant change independently of the nanocapsule surface potential or its concentration in plasma. Regarding the activated partial thromboplastin time, both suspensions at 2% (v/v) in plasma did not influence the clotting time. Even though suspensions at 10% (v/v) in plasma decreased the clotting times (p<0.05), the values were within the normal range. The ability of plasma to activate the coagulation system was maintained after the addition of the formulations. Suspensions at 2% (v/v) in blood showed no significant hemolysis or platelet aggregation. In conclusion, the lipid-core nanocapsules uncoated or coated with chitosan are hemocompatible representing a potential innovative nanotechnological formulation for intravenous administration.
Abstract Multimodal combinations of target agents with radiation and chemotherapy may enhance cancer treatment efficacy; however, despite these treatments, gliomas recur early due to their highly ...proliferative, infiltrative and invasive behaviors. Nanoparticles of biodegradable polymers for anticancer drug delivery have attracted intensive interest in recent years since they may provide a sustained, controlled and targeted delivery. In the present study, we investigated the effect of indomethacin-loaded nanocapsules in an experimental glioma model. The rats treated with indomethacin-loaded nanocapsules demonstrated a significant reduction in tumor size and half of these animals presented just cells with characteristics of a residual tumor, as shown by immunostaining for nestin. Pathological analyses showed that the treated gliomas presented a significant reduction in the mitotic index and other histological characteristics that indicate a less invasive/proliferative tumor. An important finding of the present study is that indomethacin carried by polymeric nanocapsules achieved higher intracerebral drug concentrations than those of indomethacin in solution. Furthermore, indomethacin achieved a greater concentration in the hemisphere where the glioma was implanted, compared with the contralateral healthy hemisphere. Indomethacin-loaded nanocapsule treatment did not cause characteristics of toxicity and increased the survival of animals. Thus, our results show that polymeric nanocapsules are able to increase the intratumoral bioavailability of indomethacin and reduce the growth of implanted gliomas. Data suggest that indomethacin-loaded nanocapsules could offer new and potentially highly effective strategies for the treatment of malignant gliomas.
The development of novel therapeutic strategies to treat gliomas remains critical as a result of the poor prognoses, inef-. ficient therapies and recurrence associated with these tumors. In this ...context, biodegradable nanoparticles are emerging as efficient drug delivery systems for the treatment of difficult-to-treat diseases such as brain tumors. In the current study, we evaluated the antiglioma effect of trans-resveratrol-loaded lipid-core nanocapsules (RSV-LNC) based on in vitro (C6 glioma cell line) and in vivo (brain-implanted C6 cells) models of the disease. In vitro, RSV-LNC decreased the viability of C6 glioma cells to a higher extent than resveratrol in solution. Interestingly, RSV-LNC treatment was not cytotoxic to hippocampal organotypic cultures, a model of healthy neural cells, suggesting selectivity for cancer cells. RSV-LNC induced losses in glioma cell viability through induction of apoptotic cell death, as assessed by Annexin-FITC/PI assay, which was preceded by an early arrest in the S and G1 phases of the cell cycle. In brain-implanted C6 tumors, treatment with RSV-LNC (5 mg/kg/day, i.p.) for 10 days promoted a marked decrease in tumor size and also reduced the incidence of some malignant tumor-associated characteristics, such as intratumoral hemorrhaging, intratumoral edema and pseudopalisading, compared to resveratrol in solution. Taken together, the results presented herein suggest that nanoencapsulation of resveratrol improves its antiglioma activity, thus providing a provocative foundation for testing the clinical usefulness of nanoformulations of this natural compound as a new chemotherapeutic strategy for the treatment of gliomas.
The objective of this work was to study the in vitro skin penetration of a drug model (nimesulide) from semi-solid topical formulations containing nanospheres, nanocapsules or nanoemulsion. ...Nanoprecipitation, interfacial deposition and spontaneous emulsification methods were used to prepare the nanostructured suspension. The hydrodynamic diameters were 252
nm for the nanoemulsion, 277
nm for the nanocapsules and 202
nm for the nanospheres containing nimesulide. The different nanocarrier systems were incorporated in the hydrophilic gels and their ability of delivering the drug into the human skin were investigated using stripping technique and Franz-type diffusion cells. The amount of nimesulide released into the stratum corneum (SC) from the gel containing nanocapsules (GNM-NC) and the gel containing nanospheres (GNM-NS) was similar. On the other hand, for the gel containing nanoemulsion (GNM-NE), the nimesulide was not quantified in SC, but it has been directly permeated for the dermis. The penetration of the nimesulide using the gel containing nanocapsules (GNM-NC) was larger in the deeper skin than using the gel containing nanospheres (GNM-NS) or the one containing nanoemulsion (GNM-NE). The gels containing nanocarriers (GNM-NC, GNM-NS and GNM-NE) were able to release the drug in the viable layer of the skin, comparing to a non-particulated nimesulide-loaded formulation at the same concentration.
Several studies have reported that orally ingested trans-resveratrol is extensively metabolized in the enterocyte before it enters the blood and target organs. Additionally, trans-resveratrol is ...photosensitive, easily oxidized and presents unfavorable pharmacokinetics. Therefore, it is of great interest to stabilize trans-resveratrol in order to preserve its biological activities and to improve its bioavailability in the brain. Here, trans-resveratrol was loaded into lipid-core nanocapsules and analyzed for particle size, polydispersity and zeta potential. The nanocapsule distribution in brain tissue was evaluated by intraperitoneal (i.p.) and gavage routes in healthy rats. The lipid-core nanocapsules had a mean diameter of 241 nm, a polydispersity index of 0.2, and a zeta potential of -15 mV. No physical changes were observed after 1, 2 and 3 months of storage at 25 degrees C. Lipid-core nanocapsules showed high entrapment of trans-resveratrol and displayed a higher trans-resveratrol concentration in the brain, the liver and the kidney after daily i.p. or gavage administration than that observed for the free trans-resveratrol. Because trans-resveratrol is a potent cyclooxygenase-1 inhibitor, gastrointestinal damage was evaluated. The animals that were administered with trans-resveratrol-loaded lipid-core nanocapsules showed significantly less damage when compared to those administered with free trans-resveratrol. In summary, lipid-core nanocapsules exhibited great trans-resveratrol encapsulation efficiency. trans-Resveratrol-loaded lipid-core nanocapsules increased the concentration of trans-resveratrol in the brain tissue. Gastrointestinal safety was improved when compared with free trans-resveratrol. Thus, trans-resveratrol-loaded lipid-core nanocapsules may be used as an alternative potential therapeutic for several diseases including Alzheimer's disease.
Display omitted
•Current therapies to treat cardiovascular diseases have numerous complications.•The pulmonary route is employed for several diseases but not arterial thrombosis.•Antithrombotic ...therapy using microparticles via pulmonary route was revealed.•The prototype showed better antithrombotic activity than acetylsalicylic acid alone.
Several antithrombotic drugs are available to treat cardiovascular diseases due to its high mortality and morbidity worldwide. Despite these, severe adverse effects that can lead to treatment withdrawal have been described, highlighting the importance of new therapies. Thus, this work describes the development of fucoidan microparticles containing acetylsalicylic acid (MP/F4M) for pulmonary delivery and in vitro, ex vivo, and in vivo evaluation. Microparticles were prepared via spray-drying and characterized in vitro (mucoadhesive properties, coagulation time, platelet aggregation, adhesion, and hemolysis) followed by ex vivo platelet aggregation, in vivo arterial thrombosis, and hemorrhagic profile. The formulation physicochemical characterization showed suitable characteristics along with delayed drug release, increased breathable particle fraction, and high washability resistance as well as antiplatelet activity and enhanced platelet adhesion in vitro. In in vivo assays, MP/F4M protected against arterial thrombosis, without changes in the hemorrhagic profile. Finally, no lung changes were observed after prolonged pulmonary administration, whereas isolated ASA led to an inflammatory response. In conclusion, pulmonary administration of fucoidan microparticles with an antiplatelet drug may be an alternative therapy to treat cardiovascular diseases, opening the field for different formulations.
Nanotechnology in pharmaceutics has the potential to improve drug efficacy by influencing drug distribution in tissues. Nanocarriers have been developed as drug delivery systems to be administered by ...different biological routes. To ensure the nanotechnological properties, pre-formulation studies are especially critical in determining the influence of the process parameters on the size and polydispersity of particles. Thus, the objective of this work was to establish the mechanism of self-assembly, by determining the influence of the critical aggregation concentration of the materials in the organic phase on the final average particle size and polydispersity of polymeric lipid-core nanocapsules obtained by interfacial deposition of polymer. Measurements of the surface tension and viscosity of the organic and aqueous phases were correlated with the particle size and the concentration of raw materials. We demonstrated that the lipid-core nanocapsules are formed on the nanoscopic scale as unimodal distributions, if the aggregation state of raw materials in the organic phase tends to infinite dilution. The strategy for controlling the particle size distribution is a valuable tool in producing lipid-core nanocapsule formulations with different loading capacities intended for therapeutics.
Model of the mechanism of the self-assembly of lipid-core nanocapsules.
Aqueous solutions of lipid-core nanocapsules are interesting drug delivery systems for passive drug targeting. In this study, we hypothesized that the drug distribution mechanisms in lipid-core ...nanocapsule formulations could be categorized into six different types. To experimentally determine the type of drug distribution in these formulations, we proposed the use of an algorithm as an innovative strategy. The approach is shown to be a valuable tool to optimize and select formulations intended for drug delivery. The best physico-chemical parameter in terms of predicting the type of distribution was the log
D
value. In conclusion, the use of the algorithm developed in this study represents a simple and rapid approach through which it was possible to experimentally determine the drug distribution in colloidal formulations for eight drug models.
The algorithm described in this work is a simple and rapid approach to experimentally determine the drug distribution in colloidal formulations.
Achieving oral peptide delivery is an elusive challenge. Emulsion-based minispheres of salmon calcitonin (sCT) were synthesized using single multiple pill (SmPill®) technology incorporating the ...permeation enhancers (PEs): sodium taurodeoxycholate (NaTDC), sodium caprate (C10), or coco-glucoside (CG), or the pH acidifier, citric acid (CA). Minispheres were coated with an outer layer of Eudragit® L30 D-55 (designed for jejunal release) or Surelease®/Pectin (designed for colonic release). The process was mild and in vitro biological activity of sCT was retained upon release from minispheres stored up to 4months. In vitro release profiles suggested that sCT was released from minispheres by diffusion through coatings due to swelling of gelatin and the polymeric matrix upon contact with PBS at pH6.8. X-ray analysis confirmed that coated minispheres dissolved at the intended intestinal region of rats following oral gavage. Uncoated minispheres at a dose of ~2000I.U.sCT/kg were administered to rats by intra-jejunal (i.j.) or intra-colonic (i.c.) instillation and caused hypocalcaemia. Notable sCT absolute bioavailability (F) values were: 5.5% from minispheres containing NaTDC (i.j), 17.3% with CG (i.c.) and 18.2% with C10 (i.c.). Coated minispheres administered by oral gavage at threefold higher doses also induced hypocalcaemia. A highly competitive F value of 2.7% was obtained for orally-administered sCT-minispheres containing CG (45μmol/kg) and coated with Eudragit®. In conclusion, the SmPill® technology is a potential dosage form for several peptides when formulated with PEs and coated for regional delivery. PK data from instillations over-estimates oral bioavailability and poorly predicts rank ordering of formulations.
Representative X-ray images of the GI tract of a rat showing the movement of three BaSO4–loaded minispheres coated with Opadry® white and Eudragit®. The three minispheres are seen in the stomach at 30min. Display omitted
PDF
