Larvicidal properties of terpenoid-based nanoemulsions against the dengue vector Aedes aegypti L. and their potential toxicity against non-target organism.

The development of insecticide resistance in mosquitoes of public health importance has encouraged extensive research into innovative vector control methods. Terpenes are the largest among Plants Secondary Metabolites and have been increasingly studied for their potential as insecticidal control agents. Although promising, terpenes are insoluble in water, and they show low residual life which limits their application for vector control. In this study, we developed and evaluated the performances of terpenoid-based nanoemulsions (TNEs) containing myrcene and p-cymene against the dengue vector Aedes aegypti and investigated their potential toxicity against non-target organisms. Our results showed that myrcene and p-cymene showed moderate larvicidal activity against mosquito larvae compared to temephos an organophosphate widely used for mosquito control. However, we showed similar efficacy of TNEs against both susceptible and highly insecticide-resistant mosquitoes from French Guyana, hence suggesting an absence of cross-resistance with conventional insecticides. We also showed that TNEs remained effective for up to 45 days in laboratory conditions. The exposure of zebrafish to TNEs triggered behavioral changes in the fish at high doses but they did not alter the normal functioning of zebrafish organs, suggesting a good tolerability of non-target organisms to these molecules. Overall, this study provides new insights into the insecticidal properties and toxicity of terpenes and terpenoid-based formulations and confirms that TNE may offer interesting prospects for mosquito control as part of integrated vector management.

Delivery Strategies of Probiotics from Nano- and Microparticles: Trends in the Treatment of Inflammatory Bowel Disease-An Overview.

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder, most known as ulcerative colitis (UC) and Crohn's disease (CD), that affects the gastrointestinal tract (GIT), causing considerable symptoms to millions of people around the world. Conventional therapeutic strategies have limitations and side effects, prompting the exploration of innovative approaches. Probiotics, known for their potential to restore gut homeostasis, have emerged as promising candidates for IBD management. Probiotics have been shown to minimize disease symptoms, particularly in patients affected by UC, opening important opportunities to better treat this disease. However, they exhibit limitations in terms of stability and targeted delivery. As several studies demonstrate, the encapsulation of the probiotics, as well as the synthetic drug, into micro- and nanoparticles of organic materials offers great potential to solve this problem. They resist the harsh conditions of the upper GIT portions and, thus, protect the probiotic and drug inside, allowing for the delivery of adequate amounts directly into the colon. An overview of UC and CD, the benefits of the use of probiotics, and the potential of micro- and nanoencapsulation technologies to improve IBD treatment are presented. This review sheds light on the remarkable potential of nano- and microparticles loaded with probiotics as a novel and efficient strategy for managing IBD. Nonetheless, further investigations and clinical trials are warranted to validate their long-term safety and efficacy, paving the way for a new era in IBD therapeutics.

Nanocarrier functionalization strategies for targeted drug delivery in skin cancer therapy: current progress and upcoming challenges.

INTRODUCTION: Skin cancer is the most common form of cancer worldwide, with increasing incidence rates in recent years. Although conventional chemotherapy and radiation therapy have been used for its treatment, these therapies have several limitations such as lack of selectivity and significant side effects. Targeted nanocarriers have emerged as a promising approach for the treatment of skin cancer. AREAS COVERED: This review article provides an overview of targeted nanocarriers for skin cancer treatment. It covers the various types of targeted nanocarriers, including liposomes, polymeric nanoparticles, dendrimers, and inorganic nanoparticles. EXPERT OPINION: There are still several challenges that need to be addressed before the clinical translation of targeted nanoparticles, such as optimization of their properties, development of reliable and robust characterization methods, and evaluation of their safety and efficacy in clinical trials. Another key aspect for the advancement of these studies is the need to improve regulatory aspects related to the toxicity and regulation of nanomedicines targeting skin cancer. Overall, targeted nanocarriers hold great potential for the development of safe and effective treatments for skin cancer, which can contribute to a better prognosis and overall patients' life quality.

A receptor-mediated landscape of druggable and targeted nanomaterials for gliomas.

Gliomas are the most common type of brain cancer, and among them, glioblastoma multiforme (GBM) is the most prevalent (about 60% of cases) and the most aggressive type of primary brain tumor. The treatment of GBM is a major challenge due to the pathophysiological characteristics of the disease, such as the presence of the blood-brain barrier (BBB), which prevents and regulates the passage of substances from the bloodstream to the brain parenchyma, making many of the chemotherapeutics currently available not able to reach the brain in therapeutic concentrations, accumulating in non-target organs, and causing considerable adverse effects for the patient. In this scenario, nanocarriers emerge as tools capable of improving the brain bioavailability of chemotherapeutics, in addition to improving their biodistribution and enhancing their uptake in GBM cells. This is possible due to its nanometric size and surface modification strategies, which can actively target nanocarriers to elements overexpressed by GBM cells (such as transmembrane receptors) related to aggressive development, drug resistance, and poor prognosis. In this review, an overview of the most frequently overexpressed receptors in GBM cells and possible approaches to chemotherapeutic delivery and active targeting using nanocarriers will be presented.

Design of rapamycin and resveratrol coloaded liposomal formulation for breast cancer therapy.

Aims: The development of rapamycin (RAP) and resveratrol (RSV) coloaded liposomes (RAP-RSV-LIP) for breast cancer therapy. Materials & methods: Liposomes were prepared using a high-pressure homogenization technique and evaluated according to their physicochemical characteristics, cellular uptake and cytotoxicity against tumoral and normal cells. Results & conclusion: The RAP-RSV-LIP showed negative surface charge, size around 100 nm, low polydispersity and high encapsulation efficiency for RAP and RSV (58.87 and 63.22%, respectively). RAP-RSV-LIP showed great stability over 60 days and a prolonged drug-release profile. In vitro studies indicated that RAP-RSV-LIP were internalized in an estrogen receptor-positive human breast cancer cell line (MCF-7, 34.2%) and improved cytotoxicity when compared with free drugs. Therefore RAP-RSV-LIP showed great antitumoral potential against breast cancer cells.

Development, characterization and in vitro cytotoxicity of kaempferol-loaded nanostructured lipid carriers in glioblastoma multiforme cells.

Glioblastoma multiforme is the most common and most aggressive human brain cancer. GBM treatment is still a challenge because many drugs are not able to cross the blood-brain barrier, in addition to the increasing resistance to currently available chemotherapy. New therapeutic alternatives are emerging, and, in this context, we highlight kaempferol, a flavonoid with remarkable anti-tumor activity but with limited bioavailability due to its strong lipophilic property. A promising tool to improve the biopharmaceutical properties of molecules such as kaempferol is the use of drug-delivery nanosystems, such as nanostructured lipid carriers (NLC), which can facilitate the dispersion and delivery of highly lipophilic molecules. The present work aimed at the development and characterization of kaempferol-loaded NLC (K-NLC) and the evaluation of its biological properties using in vitro models. The K-NLC showed an average size of 120 nm, zeta potential of - 21 mV, and polydispersity index of 0.099. The K-NLC presented high kaempferol encapsulation efficiency (93%), a drug loading of 3.58%, and a sustained kaempferol release profile for up to 48 h. In addition to presenting a 7-fold increase in kaempferol cytotoxicity, its encapsulation in NLC promoted a cellular uptake of 75%, which corroborates with increased cytotoxicity in U-87MG cells, as observed. Together, these data reinforce the promising antineoplastic properties of kaempferol in addition to the key role of NLC as a platform for the efficient delivery of lipophilic drugs to neoplastic cells, which improved their uptake and therapeutic efficacy in glioblastoma multiforme cells.

New Technological Approaches for Dental Caries Treatment: From Liquid Crystalline Systems to Nanocarriers.

Dental caries is the most common oral disease, with high prevalence rates in adolescents and low-income and lower-middle-income countries. This disease originates from acid production by bacteria, leading to demineralization of the dental enamel and the formation of cavities. The treatment of caries remains a global challenge and the development of effective drug delivery systems is a potential strategy. In this context, different drug delivery systems have been investigated to remove oral biofilms and remineralize dental enamel. For a successful application of these systems, it is necessary that they remain adhered to the surfaces of the teeth to allow enough time for the removal of biofilms and enamel remineralization, thus, the use of mucoadhesive systems is highly encouraged. Among the systems used for this purpose, liquid crystalline systems, polymer-based nanoparticles, lipid-based nanoparticles, and inorganic nanoparticles have demonstrated great potential for preventing and treating dental caries through their own antimicrobial and remineralization properties or through delivering drugs. Therefore, the present review addresses the main drug delivery systems investigated in the treatment and prevention of dental caries.

Polymeric Systems for Colon-specific Mesalazine Delivery in the Intestinal Bowel Diseases Management.

The anti-inflammatory 5-aminosalicylic acid (5-ASA) is the main therapeutic option used to prevent and treat inflammatory bowel diseases. The upper intestinal tract performs rapid and almost complete absorption of this drug when administered orally, making local therapeutic levels of the molecule in the inflamed colonic mucosa difficult to achieve. Micro and nanoparticle systems are promising for 5-ASA incorporation because the reduced dimensions of these structures can improve the drug's pharmacodynamics and contribute to more efficient and localized therapy. Together, the association of these systems with polymers will allow the release of 5-ASA through specific targeting mechanisms to the colon, as demonstrated in the mesalazine modified-release dosage form. This review will summarize and discuss the challenges for the oral administration of 5-ASA and the different colon-specific delivery strategies using polymers.

In Vitro Skin Co-Delivery and Antibacterial Properties of Chitosan-Based Microparticles Containing Ascorbic Acid and Nicotinamide.

Vitamins are widely found in nature, for example, in plants and fruits. Ascorbic acid and nicotinamide are examples of these compounds that have potent antioxidant properties, besides stimulating collagen production and depigmenting properties that protect the skin from premature aging. To overcome the skin barrier and reduce the instability of antioxidant compounds, alternative systems have been developed to facilitate the delivery of antioxidants, making them efficiently available to the tissue for an extended time without causing damage or toxicity. The objective of this study was to obtain chitosan biodegradable microparticles containing ascorbic acid and nicotinamide for topical delivery. The microparticles were obtained by spray drying and characterized chemically by means of scanning electron microscopy, infrared spectroscopy, X-ray diffraction, and differential exploratory calorimetry. The drugs were successfully encapsulated and the microparticles showed positive zeta potential. In vitro release assays showed a sustained release profile. The evaluation of ex vivo skin permeation and retention demonstrated low permeation and adequate retention of the compounds in the epidermis/dermis, suggesting the efficient delivery from the obtained microparticles. Antibacterial assays have shown that microparticles can inhibit the growth of microorganisms in a time- and dose-dependent manner, corroborating their use in cosmetic products for application on the skin.

[10]-Gingerol-Loaded Nanoemulsion and its Biological Effects on Triple-Negative Breast Cancer Cells.

The apoptotic, cytotoxic, and cytostatic activities for [10]-gingerol in triple-negative breast cancer cells (TNBCs) were already reported. However, despite these important antitumor activities, the compound has the disadvantage to have a hydrophobic characteristic, hindering in vivo administration. To surpass this issue, in this study we have created a [10]-gingerol-loaded nanoemulsion (10GNE) in order to increase the stability and solubility of the compound. The nanoemulsion was characterized and tested for its cytotoxic, cytostatic, and apoptotic effects on a panel of murine and human TNBC cell lines, as well as non-tumor cells, and compared with a [10]-gingerol-free nanoemulsion (NE) and with [10]-gingerol itself. Except for the murine 4T1.13 cell line, the IC50 of the free 10G molecule, after 72 h of incubation, was higher in all cell lines tested, both murine and human, demonstrating therefore the efficacy of the 10GNE regarding cytotoxicity. In murine tumor cells, 60 µM 10GNE was able to arrest cell cycle at sub-G0 phase and induce apoptosis, leading to 48% and 78% of total cell death in 4T1.13 and 4T1Br4 murine tumor cells, respectively. This represents an improvement compared to 10G-free molecule that only induced 74% of total apoptosis at 100 µM in 4T1Br4 cells. Taken together, our results show that nanoformulation preserved the [10]-gingerol cytotoxic and cytostatic properties and improved its apoptotic function on murine TNBC cell lines. These data open new perspectives to a more suitable drug-delivery approach for [10]-gingerol for TNBC treatment that should be further demonstrated using in vivo assays.

Highlights in poloxamer-based drug delivery systems as strategy at local application for vaginal infections.

Infectious diseases related to the vagina include diseases caused by the imbalance of the vaginal flora and by sexually transmitted infections. Some of these present themselves as a public health problem due to the lack of efficient treatment that leads to their complete cure, and others due to the growing resistance to drugs used in therapy. In this sense, new treatment strategies are desirable, with vaginal administration rout being a great choice since can bypass first-pass metabolism and decrease drug interactions and adverse effects. However, it is worth highlighting limitations related to patient's discomfort at application time. Thereby, the use of poloxamer-based drug delivery systems is desirable due its stimuli-sensitive characteristic. Therefore, the present review reports a brief overview of poloxamer properties, biological behavior and advances in poloxamer applications in controlled drug release systems for infectious diseases related to the vagina treatment and prevention.

Nanosystem functionalization strategies for prostate cancer treatment: a review.

Prostate cancer (PC) has a high morbidity and mortality rate worldwide, and the current clinical guidelines can vary depending on the stage of the disease. Drug delivery nanosystems (DDNs) can improve biopharmaceutical properties of encapsulated anti-cancer drugs by modulating their release kinetics, improving physicochemical stability and reducing toxicity. DDN can also enhance the ability of specific targeting through surface modification by coupling ligands (antibodies, nucleic acids, peptides, aptamer, proteins), thus favouring the cell internalisation process by endocytosis. The purposes of this review are to describe the limitations in the treatment of PC, explore different functionalization such as polymeric, lipid and inorganic nanosystems aimed at the treatment of PC, and demonstrate the improvement of this modification for an active target, as alternative and promising candidates for new therapies.

Chitosan-based systems aimed at local application for vaginal infections.

Vaginal administration is a promising route for the local treatment of infectious vaginal diseases since it can bypass the first-pass metabolism, drug interactions, and adverse effects. However, the commercial products currently available for topical vulvovaginal treatment have low acceptability and do not adequately explore this route. Mucoadhesive systems can optimize the efficacy of drugs administered by this route to increase the retention time of the drug in the vaginal environment. Several polymers are used to develop mucoadhesive systems, among them chitosan, a natural polymer that is highly biocompatible and technologically versatile. Thus, the present review aimed to analyze the studies that used chitosan to develop mucoadhesive systems for the treatment of local vaginal infections. These studies demonstrated that chitosan as a component of mucoadhesive drug delivery systems (DDS) is a promising device for the treatment of vaginal infectious diseases, due to the intrinsic antimicrobial activity of this biopolymer and because it does not interfere with the effectiveness of the drugs used for the treatment.

Nanotechnology as a tool for detection and treatment of arbovirus infections.

Arboviruses are medically important viruses that cause high rates of infection all over the world. In addition, the severity of the symptoms and the inadequate diagnostic methods represent a challenge far beyond eradicating the vector. The lack of specific treatments for arbovirus infections reflects the imminent need for new research for safe and efficient medicines to treat these infections. Nanotechnology is an innovative approach currently used as a platform for developing new treatments, thus improving the biopharmaceutical properties of drugs. It can also be applied to the development of diagnostic devices, improving their detection capacity. The purpose of this paper is to review recent research on the use of nanotechnology for developing new treatments and detection devices for arbovirus infections. Interestingly, it was found that only a few studies report on the use of nanotechnology to treat arbovirus infections and that most of these reports focus on the fabrication of diagnostic tools. Also, some papers report on the use of nanotechnology for the development of vaccines, which in association with mosquito eradication programs could effectively reduce the high rates of infections by these viruses.

Gene Therapy Based on Lipid Nanoparticles as Non-viral Vectors for Glioma Treatment.

Gliomas are primary brain tumors originating from glial cells, representing 30% of all Central Nervous System (CNS) neoplasia. Among them, the astrocytoma grade IV (glioblastoma multiforme) is the most common, presenting an invasive and aggressive profile, with an estimated life expectancy of about 15 months after diagnosis even after treatment with radiation, surgical resection, and chemotherapy. This poor prognosis is related to the presence of the blood-brain barrier (BBB) and multidrug resistance mechanisms that prevent the uptake and retention of chemotherapeutics inside the brain. Gene therapy has been a promising strategy to overcome these treatment limitations since it has the ability to modify the defective genetic information in tumor cells, being able to induce cellular apoptosis and silence the genes responsible for multidrug resistance. Lipidbased nanoparticles, non-viral vectors, have been investigated to deliver genes across the BBB to reach the glioma cell target. Besides, their low immunogenicity, easy production, ability to incorporate ligands to specific target cells, and capacity to carry higher size genes have made the gene therapy based on non-viral vectors a promising glioma treatment. In this context, this review addresses the most common non-viral vectors based on lipid-based nanoparticles used for glioma gene therapy, such as liposomes, solid lipid nanoparticles, nanostructured lipid carriers, and nanoemulsions.

Drug Delivery Nanosystems in Glioblastoma Multiforme Treatment: Current State of the Art.

Glioblastoma multiforme (GBM) is the most common primary malignant Central Nervous System cancer, responsible for about 4% of all deaths associated with neoplasia, characterized as one of the fatal human cancers. Tumor resection does not possess curative character, thereby radio and/or chemotherapy are often necessary for the treatment of GBM. However, drugs used in GBM chemotherapy present some limitations, such as side effects associated with non-specific drug biodistribution as well as limited bioavailability, which limits their clinical use. To attenuate the systemic toxicity and overcome the poor bioavailability, a very attractive approach is drug encapsulation in drug delivery nanosystems. The main focus of this review is to explore the actual cancer global problem, enunciate barriers to overcome in the pharmacological treatment of GBM, as well as the most updated drug delivery nanosystems for GBM treatment and how they influence biopharmaceutical properties of anti-GBM drugs. The discussion will approach lipid-based and polymeric nanosystems, as well as inorganic nanoparticles, regarding their technical aspects as well as biological effects in GBM treatment. Furthermore, the current state of the art, challenges to overcome and future perspectives in GBM treatment will be discussed.

Nanosystems against candidiasis: a review of studies performed over the last two decades.

The crescent number of cases of candidiasis and the increase in the number of infections developed by non-albicans species and by multi-resistant strains has taken the attention of the scientific community, which has been searching for new therapeutic alternatives. Among the alternatives found the use of nanosystems for delivery of drugs already commercialized and new biomolecules have grown, in order to increase stability, solubility, optimize efficiency and reduce adverse effects. In view of the growing number of studies involving technological alternatives for the treatment of candidiasis, the present review came with the intention of gathering studies from the last two decades that used nanotechnology for the treatment of candidiasis, as well as analysing them critically and pointing out the future perspectives for their application with this purpose. Different studies were considered for the development of this review, addressing nanosystems such as metallic nanoparticles, mesoporous silica nanoparticles, polymeric nanoparticles, liposomes, nanoemulsion, microemulsion, solid lipid nanoparticle, nanostructured lipid carrier, lipidic nanocapsules and liquid crystals; and different clinical presentations of candidiasis. As a general overview, nanotechnology has proven to be an important ally for the treatment against the diversity of candidiasis found in the clinic, whether in increasing the effectiveness of commercialized drugs and reducing their adverse effects, as well as allowing exploring more effectively properties therapeutics of new biomolecules.

Botanical insecticide-based nanosystems for the control of Aedes (Stegomyia) aegypti larvae.

Aedes (Stegomyia) aegypti is a cosmopolitan species that transmits arbovirus of medical importance as dengue, Zika, and chikungunya. The main strategy employed for the control of this mosquito is the use of larvicidal agents. However, the overuse of synthetic chemical larvicides has led to an increase in resistant insects, making management difficult. Therefore, the use of botanical insecticide-based nanosystems as an alternative to the use of synthetic agents for the control of Ae. aegypti has gained more considerable attention in the last years, mainly due to the advantages of nanostructured delivery systems, such as (a) controlled release; (b) greater surface area; (c) improvement of biological activity; (d) protection of natural bioactive agents from the environment and thus achieving stability; and (e) lipophilic drugs are easier dispersed even in aqueous vehicles. This review summarizes the current knowledge about botanical insecticide-based nanosystems as larvicidal against Ae. aegypti larvae. The majority of papers used metallic nanoparticles (NPs) as larvicidal agents, mainly silver nanoparticles (AgNPs), showing potential for their use as an alternative, followed by nanoemulsions containing vegetable oils, most essential oils, nanosystems that allow the dispersion of this high hydrophobic product in water, the environment of larval development. The final section describes scientific findings about the mode of action of these NPs, showing the gap about this subject in literature.

Advances and challenges in nanocarriers and nanomedicines for veterinary application.

To ensure success in the development and manufacturing of nanomedicines requires forces of an interdisciplinary team that combines medicine, engineering, chemistry, biology, material and pharmaceutical areas. Numerous researches in nanotechnology applied to human health are available in the literature. Althought, the lack of nanotechnology-based pharmaceuticals products for use exclusively in veterinary pharmacotherapy creates a potential area for the development of innovative products, as these animal health studies are still scarce when compared to studies in human pharmacotherapy. Nano-dosage forms can ensure safer and more effective pharmacotherapy for animals and can more be safer for the consumers of livestock products, once they can offer higher selectivity and smaller toxicity associated with lower doses of the drugs. In addition, the development and production of nanomedicines may consolidate the presence of pharmaceutical laboratories in the global market and can generate greater profit in a competitive business environment. To contribute to this scenario, this article provides a review of the main nanocarriers used in nanomedicines for veterinary use, with emphasis on liposomes, nanoemulsions, micelles, lipid nanoparticles, polymeric nanoparticles, mesoporous silica nanoparticles, metallic nanoparticles and dendrimers, and the state of the art of application of these nanocarriers in drug delivery systems to animal use. Finnaly, the major challenges involved in research, scale-up studies, large-scale manufacture, analytical methods for quality assessment, and regulatory aspects of nanomedicines were discussed.

Nanosuspension of quercetin: preparation, characterization and effects against Aedes aegypti larvae

Abstract Aedes aegypti (Diptera: Culicidae) is the main vector of some neglected diseases, including dengue. It is very important to develop formulations that increase effectiveness of vector control with low toxicity. Quercetin is a plant-derived flavonoid that modulates the development of some insects. The low water solubility of quercetin impairs the development of water-dispersible commercial products. To circumvent this problem, the preparation of nanoformulations is considered promising. Thus, this study aimed to evaluate the effect of bulk and quercetin nanosuspension against A. aegypti larvae and also to investigate their ecotoxicity. Quercetin nanosuspension was produced by a solvent displacement method followed by solvent evaporation and was maintained in two different temperatures (4 and 25 ºC). Its size distribution and zeta potential were monitored along 30 days. The influence of quercetin nanosuspension and bulk-quercetin was investigated at various concentrations against A. aegypti and the green algae Chlorella vulgaris. The quercetin nanosuspension presented higher stability at 4 ºC and negative zeta potential values. Quercetin nanosuspension and bulk-quercetin adversely affected the larvae development, especially at the highest concentrations. Larvae mortality was between 44% and 100% (48 h) for quercetin nanosuspension at 100 and 500 ppm, respectively. The bulk-quercetin induced around 50% mortality regardless the concentration used at this same time-period. Absence of emerging mosquitoes from water was observed on the survival larvae of all the treated groups. Quercetin nanosuspension was less toxic than bulk-quercetin against C. vulgaris, especially at higher concentrations. These data indicate that quercetin nanosuspension may represent a potential larvicide for A. aegypti control, once they induced larvae death and inhibited the survival ones to emerge from water. In addition, it did not demonstrated ecotoxicity against a non-target organism, highlighting its better properties, when compared to the bulk-quercetin.