Role of hydroxypropyl-β-cyclodextrin on freeze-dried and gamma-irradiated PLGA and PLGA–PEG diblock copolymer nanospheres for ophthalmic flurbiprofen delivery

Poly(D,L-lactide-co-glycolide) and poly(D,L-lactide-co-glycolide) with poly(ethylene glycol) nanospheres (NSs) incorporating flurbiprofen (FB) were freeze-dried with several cryoprotective agents and sterilized by γ-irradiation. Only when 5.0% (w/v) hydroxypropyl-β-cyclodextrin (HPβCD) was used, a complete resuspension by manual shaking and almost identical particle size of the NSs was obtained after freeze-drying. In vitro drug release and ex vivo corneal permeation of NSs with and without HPβCD were evaluated. The presence of HPβCD resulted in a reduction of burst effect, providing a more sustained release of the drug. A significant decrease in the FB transcorneal permeation of NSs containing HPβCD was obtained, related to the slower diffusion of FB observed in the in vitro results. The uptake mechanism of the NSs was examined by confocal microscopy, suggesting that NSs penetrate corneal epithelium through a transcellular pathway. Ocular tolerance was assessed in vitro and in vivo by the Eytex™ and Draize test, respectively. Long-term stability studies revealed that γ-irradiated NSs stored as freeze-dried powders maintained their initial characteristics. Stability studies of the resuspended NSs after 3 months of storage in the aqueous form showed that NSs were stable at 4°C, while formulations stored at 25°C and 40°C increased their initial particle size

Influence of freeze-drying and γ-irradiation in preclinical studies of flurbiprofen polymeric nanoparticles for ocular delivery using d-(+)-trehalose and polyethylene glycol.

This study investigated the suspension of poly(ε-caprolactone) nanoparticles as an ocular delivery system for flurbiprofen (FB-PεCL-NPs) in order to overcome the associated problems, such as stability, sterility, tolerance, and efficacy, with two different FB-PεCL-NP formulations. The formulations were stabilized with poloxamer 188 (1.66% and 3.5%) and submitted individually for freeze-drying and γ-irradiation with polyethylene glycol 3350 (PEG3350) and d-(+)-trehalose (TRE). Both formulations satisfied criteria according to all physicochemical parameters required for ocular pharmaceuticals. The FB-PεCL-NP formulations showed non-Newtonian behavior and sustained drug release. Ex vivo permeation analysis using isolated ocular pig tissues suggested that the presence of PEG3350 results in a reduction of FB transcorneal permeation. Moreover, TRE improved the penetration of FB across the cornea, especially after γ-irradiation. In addition, both formulations did not show a significant affinity in increasing FB transscleral permeation. Both formulations were classified as nonirritating, safe products for ophthalmic administration according to hen's egg test-chorioallantoic membrane and Draize eye test. Furthermore, an in vivo anti-inflammatory efficacy test showed that irradiated FB-PεCL-NPs prepared with PEG3350 (IR-NPsPEG) have longer anti-inflammatory effects than those presented with irradiated FB-PεCL-NPs prepared with TRE (IR-NPsTRE). IR-NPsPEG showed a suitable physical stability after an aqueous reconstitution over .30 days. This study concludes that both formulations meet the Goldman's criteria and demonstrate how irradiated nanoparticles, with innovative permeation characteristics, could be used as a feasible alternative to a flurbiprofen solution for ocular application in clinical trials

Comparative study of ex vivo transmucosal permeation of Pioglitazone nanoparticles for the treatment of Alzheimer's disease

Pioglitazone has been reported in the literature to have a substantial role in the improvement of overall cognition in a mouse model. With this in mind, the aim of this study was to determine the most efficacious route for the administration of Pioglitazone nanoparticles (PGZ-NPs) in order to promote drug delivery to the brain for the treatment of Alzheimer's disease. PGZ-loaded NPs were developed by the solvent displacement method. Parameters such as mean size, polydispersity index, zeta potential, encapsulation efficacy, rheological behavior, and short-term stability were evaluated. Ex vivo permeation studies were then carried out using buccal, sublingual, nasal, and intestinal mucosa. PGZ-NPs with a size around of 160 nm showed high permeability in all mucosae. However, the permeation and prediction parameters revealed that lag-time and vehicle/tissue partition coefficient of nasal mucosa were significantly lower than other studied mucosae, while the diffusion coefficient and theoretical steady-state plasma concentration of the drug were higher, providing biopharmaceutical results that reveal more favorable PGZ permeation through the nasal mucosa. The results suggest that nasal mucosa represents an attractive and non-invasive pathway for PGZ-NPs administration to the brain since the drug permeation was demonstrated to be more favorable in this tissue. View Full-Text Keywords: nanoparticles; pioglitazone; PLGA-PEG; transmucosal permeations; Alzheimer's diseas

Penetration of polymeric nanoparticles loaded with an HIV-1 inhibitor peptide derived from GB virus C in a vaginal mucosa model

Despite the great effort to decrease the HIV infectivity rate, current antiretroviral therapy has several weaknesses; poor bioavailability, development of drug resistance and poor ability to access tissues. However, molecules such as peptides have emerged as a new expectative to HIV eradication. The vaginal mucosa is the main spreading point of HIV. There are natural barriers such as the vaginal fluid which protects the vaginal epithelium from any foreign agents reaching it. This work has developed and characterized Nanoparticles (NPs) coated with glycol chitosan (GC), loaded with an HIV-1 inhibitor peptide (E2). In vitro release and ex vivo studies were carried out using the vaginal mucosa of swine and the peptide was determined by HPLC MS/MS validated method. Moreover, the peptide was labeled with 5(6)-carboxyfluoresceine and entrapped into the NPs to carried out in vivo studies and to evaluate the NPs penetration and toxicity in the vaginal mucosa of the swine. The mean size of the NPs, ξ and the loading percentage were fundamental features for to reach the vaginal tissue and to release the peptide within intercellular space. The obtained results suggesting that the fusion inhibitor peptides loaded into the NPs coated with GC might be a new way to fight the HIV-1, due to the formulation might reach the human epithelial mucosa and release peptide without any side effects

Design, Characterization, and Biopharmaceutical Behavior of Nanoparticles Loaded with an HIV‑1 Fusion Inhibitor Peptide

New therapeutic alternatives to fight against the spread of HIV-1 are based on peptides designed to inhibit the early steps of HIV-1 fusion in target cells. However, drawbacks, such as bioavailability, short half-life, rapid clearance, and poor ability to cross the physiological barriers, make such peptides unattractive for the pharmaceutical industry. Here we developed, optimized, and characterized polymeric nanoparticles (NPs) coated with glycol chitosan to incorporate and release an HIV-1 fusion inhibitor peptide (E1) inside the vaginal mucosa. The NPs were prepared by a modified double emulsion method, and optimization was carried out by a factorial design. In vitro, ex vivo, and in vivo studies were carried out to evaluate the optimized formulation. The results indicate that the physicochemical features of these NPs enable them to incorporate and release HIV fusion inhibitor peptides to the vaginal mucosa before the fusion step takes place. KEYWORDS: GB virus C, HIV-1, fusion inhibitor peptide of HIV-1, polymeric nanoparticles, factorial design, permeation studie

Optimization, biopharmaceutical profile and therapeutic efficacy of pioglitazone-loaded PLGA-PEG nanospheres as a novel strategy for ocular inflammatory disorders.

PURPOSE: The main goal of this study was to encapsulate Pioglitazone (PGZ), in biodegradable polymeric nanoparticles as a new strategy for the treatment of ocular inflammatory processes. METHODS: To improve their biopharmaceutical profile for the treatment of ocular inflammatory disorders, nanospheres (NSs) of PGZ were formulated by factorial design with poly (lactic-co-glycolic acid) polyethylene glycol (PLGA-PEG). Interactions drug-polymer have been carried out by spectroscopic (X-ray spectroscopy, FTIR) and thermal methods (DSC). The PGZ-NSs were tested for their in vitro release profile, cytotoxicity, and ocular tolerance (HET-CAM® test); ex vivo corneal permeation, and in vivo inflammatory prevention and bioavailability. RESULTS: The optimized system showed a negative surface charge of -13.9 mV, an average particle size (Zav) of around 160 nm, a polydispersity index (PI) below 0.1, and a high encapsulation efficiency (EE) of around 92%. According to the DSC results, the drug was incorporated into the NSs polymeric matrix. The drug release was sustained for up to 14 h. PGZ-NSs up to 10 μg/ml exhibited no retinoblastoma cell toxicity. The ex vivo corneal and scleral permeation profiles of PGZ-NSs showed that retention and permeation through the sclera were higher than through the cornea. Ocular tolerance in vitro and in vivo demonstrated the non-irritant character of the formulation. CONCLUSION: The in vivo anti-inflammatory efficacy of developed PGZ-NSs indicates this colloidal system could constitute a new approach to prevent ocular inflammation. KEYWORDS: PLGA-PEG; drug delivery; nanospheres; ocular anti-inflammatory efficacy; pioglitazon

State of the art on toxicological mechanisms of metal and metal oxide nanoparticles and strategies to reduce toxicological risks

Metal nanoparticles have been extensively investigated for different types of pharmaceutical applications. However, their use has raised some concerns about their toxicity involving the increase of reactive oxygen species causing cellular apoptosis. Therefore, in this review we summarize the most relevant toxicity mechanisms of gold, silver, copper and copper oxide nanoparticles as well as production methods of metal nanoparticles. Parameters involved in their toxicity such as size, surface charge and concentration are also highlighted. Moreover, a critical revision of the literature about the strategies used to reduce the toxicity of this type of nanoparticles is carried out throughout the review. Additionally, surface modifications using different coating strategies, nanoparticles targeting and morphology modifications are deeply explained.This work was funded by the Portuguese Science and Technology Foundation (FCT) from the Ministry of Science and Technology (MCTES), European Social Fund (FSE) of EU, through the project UIDB/04469/2020 (CEB strategic fund), co-funded by European Funds (PRODER/COMPETE) and FEDER, under the Partnership Agreement PT2020.info:eu-repo/semantics/publishedVersio

Surface functionalization of PLGA nanoparticles to increase transport across the BBB for Alzheimers disease

Alzheimers disease (AD) is a chronic neurodegenerative disorder that accounts for about 60% of all diagnosed cases of dementia worldwide. Although there are currently several drugs marketed for its treatment, none are capable of slowing down or stopping the progression of AD. The role of the blood-brain barrier (BBB) plays a key role in the design of a successful treatment for this neurodegenerative disease. Nanosized particles have been proposed as suitable drug delivery systems to overcome BBB with the purpose of increasing bioavailability of drugs in the brain. Biodegradable poly (lactic-co-glycolic acid) nanoparticles (PLGA-NPs) have been particularly regarded as promising drug delivery systems as they can be surface-tailored with functionalized molecules for site-specific targeting. In this review, a thorough discussion about the most recent functionalization strategies based on PLGA-NPs for AD and their mechanisms of action is provided, together with a description of AD pathogenesis and the role of the BBB in brain targeting.A.C. [Amanda Cano] acknowledges the support of the Spanish Ministry of Science, Innovation and Universities under the grant Juan de la Cierva (FJC2018-036012-I). Authors acknowledge the support of the Spanish Ministry of Economy and Competitiveness under the project SAF2017-84283-R; Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED, CB06/05/0024) and Portuguese Science and Technology Foundation (FCT) for the strategic fund (UIDB/04469/2020).info:eu-repo/semantics/publishedVersio

Nanoparticles in Endodontics Disinfection: State of the Art

Endodontic-related diseases constitute the fourth most expensive pathologies in industrialized countries. Specifically, endodontics is the part of dentistry focused on treating disorders of the dental pulp and its consequences. In order to treat these problems, especially endodontic infections, dental barriers and complex root canal anatomy should be overcome. This constitutes an unmet medical need since the rate of successful disinfection with the currently marketed drugs is around 85%. Therefore, nanoparticles constitute a suitable alternative in order to deliver active compounds effectively to the target site, increasing their therapeutic efficacy. Therefore, in the present review, an overview of dental anatomy and the barriers that should be overcome for effective disinfection will be summarized. In addition, the versatility of nanoparticles for drug delivery and their specific uses in dentistry are comprehensively discussed. Finally, the latest findings, potential applications and state of the art nanoparticles with special emphasis on biodegradable nanoparticles used for endodontic disinfection are also reviewed. Keywords: PLGA; dentistry; endodontics; metal nanoparticles; nanoparticles

Biodegradable nanoparticles for the treatment of epilepsy: from current advances to future challenges

Epilepsy is the second most prevalent neurological disease worldwide. It is mainly characterized by an electrical abnormal activity in different brain regions. The massive entrance of Ca2+ into neurons is the main neurotoxic process that lead to cell death and finally to neurodegeneration. Although there are a huge number of antiseizure medications, there are many patients who do not respond to the treatments and present refractory epilepsy. In this context, nanomedicine constitutes a promising alternative to enhance the central nervous system bioavailability of antiseizure medications. The encapsulation of different chemical compounds at once in a variety of controlled drug delivery systems gives rise to an enhanced drug effectiveness mainly due to their targeting and penetration into the deepest brain region and the protection of the drug chemical structure. Thus, in this review we will explore the recent advances in the development of drugs associated with polymeric and lipid based nanocarriers as novel tools for the management of epilepsy disorders.Amanda Cano acknowledges the support of the Spanish Ministry of Science, Innovation and Universities under the grant Juan de la Cierva (FJC2018-036012-I). Authors acknowledge the support of the Spanish Ministry of Economy and Ccompetitiveness under project SAF2017-84283-R; Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED, CB06/05/0024) and Portuguese Science and Technology Foundation (FCT) for the strategic fund (UIDB/04469/2020).info:eu-repo/semantics/publishedVersio