Bromo-substituted indirubins for inhibition of protein kinase-mediated signalling involved in inflammatory mediator release in human monocytes.

Targeting protein kinases that regulate signalling pathways in inflammation is an effective pharmacological approach to alleviate uncontrolled inflammatory diseases. In this context, the natural product indirubin and its 6-bromo-substituted analogue 6-bromoindirubin-3 -glycerol-oxime ether (6BIGOE; 1) were identified as potent inhibitors of glycogen synthase kinase-3ß (GSK-3ß). These inhibitors suppress the release of pro-inflammatory cytokines and prostaglandins (PG) from human monocytes. However, indirubin derivatives target several protein kinases such as cyclin-dependent kinases (CDKs) which has been a major concern for their application in inflammation therapy. Here, we report on a library of 13 5-bromo-substituted indirubin derivatives that have been designed to improve potency and target selectivity. Side-by-side comparison of reference compound 1 (6BIGOE) with 5-bromo derivatives revealed its isomer 2 (5BIGOE), as the most potent derivative able to supress pro-inflammatory cytokine and PG release in lipopolysaccharide-stimulated human monocytes. Analysis of protein kinase inhibition in intact monocytes, supported by our in silico findings, proposed higher selectivity of 1 for GSK-3ß inhibition with lesser potency against CDKs 8 and 9. In contrast, 2 supressed the activity of these CDKs with higher effectiveness than GSK-3ß, representing additional targets of indirubins within the inflammatory response. Encapsulation of 1 and 2 into polymer-based nanoparticles (NP) improved their pharmacological potential. In conclusion, the 5- and 6-brominated indirubins 1 and 2 as dual GSK-3ß and CDK8/9 inhibitors represent a novel concept for intervention with inflammatory disorders.

Analytical techniques for the characterization of nanoparticles for mRNA delivery.

Nanotechnology-assisted RNA delivery has gotten a tremendous boost over the last decade and made a significant impact in the development of life-changing vaccines and therapeutics. With increasing numbers of emerging lipid- and polymer-based RNA nanoparticles progressing towards the clinic, it has become apparent that the safety and efficacy of these medications depend on the comprehensive understanding of their critical quality attributes (CQAs). However, despite the rapid advancements in the field, the identification and reliable quantification of CQAs remain a significant challenge. To support these efforts, this review aims to summarize the present knowledge on CQAs based on the regulatory guidelines and to provide insights into the available analytical characterization techniques for RNA-loaded nanoparticles. In this context, routine and emerging analytical techniques are categorized and discussed, focusing on the operation principle, strengths, and potential limitations. Furthermore, the importance of complementary and orthogonal techniques for the measurement of CQAs is discussed in order to ensure the quality and consistency of analytical methods used, and address potential technique-based differences.

Poly-ε-caprolactone based nanoparticles for delivery of genistein in melanoma treatment

We developed poly-ε-caprolactone (PCL)-based nanoparticles containing D-α-tocopherol polyethylene glycol-1000 succinate (TPGS) or Poloxamer 407 as stabilizers to efficiently encapsulate genistein (GN). Two formulations, referred to as PNTPGS and PNPol, were prepared using nanoprecipitation. They were characterized by size and PDI distribution, zeta potential, nanoparticle tracking analysis (NTA), GN association (AE%), infrared spectroscopy (FT-IR), and differential scanning calorimetry (DSC). PNTPGS-GN exhibited a particle size of 141.2 nm, a PDI of 0.189, a zeta potential of -32.9 mV, and an AE% of 77.95%. PNPol-GN had a size of 146.3 nm, a better PDI than PNTPGS-GN (0.150), a less negative zeta potential (-21.0 mV), and an AE% of 68.73%. Thermal and spectrometric analyses indicated that no new compounds were formed, and there was no incompatibility detected in the formulations. Cellular studies revealed that Poloxamer 407 conferred less toxicity to PCL nanoparticles. However, the percentage of uptake decreased compared to the use of TPGS, which exhibited almost 80% cellular uptake. This study contributes to the investigation of stabilizers capable of conferring stability to PCL nanoparticles efficiently encapsulating GN. Thus, the PCL nanoparticle proposed here is an innovative nanomedicine for melanoma therapy and represents a strong candidate for specific pre-clinical and in vivo studie

Lipid polymer hybrid nanoparticles: a custom-tailored next-generation approach for cancer therapeutics.

Lipid-based polymeric nanoparticles are the highly popular carrier systems for cancer drug therapy. But presently, detailed investigations have revealed their flaws as drug delivery carriers. Lipid polymer hybrid nanoparticles (LPHNPs) are advanced core-shell nanoconstructs with a polymeric core region enclosed by a lipidic layer, presumed to be derived from both liposomes and polymeric nanounits. This unique concept is of utmost importance as a combinable drug delivery platform in oncology due to its dual structured character. To add advantage and restrict one's limitation by other, LPHNPs have been designed so to gain number of advantages such as stability, high loading of cargo, increased biocompatibility, rate-limiting controlled release, and elevated drug half-lives as well as therapeutic effectiveness while minimizing their drawbacks. The outer shell, in particular, can be functionalized in a variety of ways with stimuli-responsive moieties and ligands to provide intelligent holding and for active targeting of antineoplastic medicines, transport of genes, and theragnostic. This review comprehensively provides insight into recent substantial advancements in developing strategies for treating various cancer using LPHNPs. The bioactivity assessment factors have also been highlighted with a discussion of LPHNPs future clinical prospects.

An overview of topical lipid-based and polymer-based nanocarriers for treatment of psoriasis.

Psoriasis is a consistently recurring, inflammatory skin disease, affecting about 2-5 % of the world population. Different types of psoriasis can be observed such as guttate psoriasis, pustular psoriasis, psoriatic arthritis, scalp psoriasis, flexural psoriasis etc. Several therapeutic approaches are available for the treatment of psoriasis. However, none of them are entirely safe and effective to treat the disease without compromising patient compliance. The traditional treatment plan is associated with harmful side effects such asimmune system suppression and damage of essential organs at high doses, which poses a challenge to treat psoriasis. Novel drug delivery systems are being developed to replace traditional therapy in order to address these shortcomings. Currently, nanoformulations have gained widespread application for treatment of psoriasis. Researchers have developed different types of lipid-based nanoparticles like liposomes, niosomes, ethosomes, transethosomes, nanostructured lipid carriers and solid lipid nanoparticles. These innovative formulations provide advantages in terms of reduction in dose, dosing frequency, dose-dependency with enhanced efficacy, improved encapsulation efficiency, controlled release, increased surface area, high bioavailability and greater stratum corneum permeability. This review highlights detailed and comparative discussion of lipid-based and polymer-based nanoparticles for psoriasis along with the pathophysiology and other treatments of psoriasis.

Neurogenic Hypertension, the Blood-Brain Barrier, and the Potential Role of Targeted Nanotherapeutics.

Hypertension is a major health concern globally. Elevated blood pressure, initiated and maintained by the brain, is defined as neurogenic hypertension (NH), which accounts for nearly half of all hypertension cases. A significant increase in angiotensin II-mediated sympathetic nervous system activity within the brain is known to be the key driving force behind NH. Blood pressure control in NH has been demonstrated through intracerebrovascular injection of agents that reduce the sympathetic influence on cardiac functions. However, traditional antihypertensive agents lack effective brain permeation, making NH management extremely challenging. Therefore, developing strategies that allow brain-targeted delivery of antihypertensives at the therapeutic level is crucial. Targeting nanotherapeutics have become popular in delivering therapeutics to hard-to-reach regions of the body, including the brain. Despite the frequent use of nanotherapeutics in other pathological conditions such as cancer, their use in hypertension has received very little attention. This review discusses the underlying pathophysiology and current management strategies for NH, as well as the potential role of targeted therapeutics in improving current treatment strategies.

An update of nano-based drug delivery systems for cannabinoids: Biopharmaceutical aspects & therapeutic applications.

Nanotechnology has been widely used to improve stability, efficacy, release control and biopharmaceutical aspects of natural and synthetic cannabinoids. In this review, the main types of cannabinoid-based nanoparticles (NPs) reported so far are addressed, taking into account the advantages and disadvantages of each system. Formulation, preclinical and clinical studies performed with colloidal carriers were individually analyzed. Lipid-based nanocarriers have been recognized for their high biocompatibility and ability to improve both solubility and bioavailability. Δ9-tetrahydrocannabinol-loaded lipid systems designed to treat glaucoma, for example, showed superior in vivo efficacy in comparison to market formulations. The analyzed studies have shown that product performance can be modulated by varying particle size and composition. In the case of self-nano-emulsifying drug delivery systems, the reduced particle size shortens the time to reach high plasma concentrations while the incorporation of metabolism inhibitors extends the plasma circulation time. The use of long alkyl chain lipids in NP formulations, in turn, is strategized to achieve intestinal lymphatic absorption. Polymer NPs have been prioritized when a sustained or site-specific cannabinoid release is desirable (e.g., CNS-affecting diseases/cancer). The functionalization of the surface of polymer NPs makes their action even more selective whereas surface charge modulation is highlighted to provide mucoadhesion. The present study identified promising systems for targeted applications, making the process of optimizing new formulations more effective and faster. Although NPs have shown a promising role in the treatment of several difficult-to-treat diseases, more translational studies should be performed to confirm the benefits reported here.

Polymer-Based Nanosystems-A Versatile Delivery Approach.

Polymer-based nanoparticles of tailored size, morphology, and surface properties have attracted increasing attention as carriers for drugs, biomolecules, and genes. By protecting the payload from degradation and maintaining sustained and controlled release of the drug, polymeric nanoparticles can reduce drug clearance, increase their cargo's stability and solubility, prolong its half-life, and ensure optimal concentration at the target site. The inherent immunomodulatory properties of specific polymer nanoparticles, coupled with their drug encapsulation ability, have raised particular interest in vaccine delivery. This paper aims to review current and emerging drug delivery applications of both branched and linear, natural, and synthetic polymer nanostructures, focusing on their role in vaccine development.

Recent innovations of nanotechnology in water treatment: A comprehensive review.

Environmental pollution from organic and inorganic pollutants poses a threat to the ecosystem. Pollutant's prevalence and persistence have increased significantly in recent years. In order to enhance the quality of naturally accessible water to a level suitable for human consumption, a number of techniques have been employed. In this context, the use of cutting-edge nanotechnology to classical process engineering paves the way for technical encroachments in advanced water and wastewater technology. Nanotechnology has the potential to ameliorate the quality, availability, and viability of water supplies in the long run by facilitating reuse, recycling and remediation of water. The promising role of nanotechnology in wastewater remediation is highlighted in this paper, which also covers current advancements in nanotechnology-mediated remediation systems. Moreover, nano-based materials such as nano-adsorbents, photocatalysts, nano-metals and nanomembranes are discussed in this review of recent breakthroughs in nanotechnologies for water contaminant remediation.

In Vitro Evaluation of a Nanoparticle-Based mRNA Delivery System for Cells in the Joint.

Biodegradable and bioresponsive polymer-based nanoparticles (NPs) can be used for oligonucleotide delivery, making them a promising candidate for mRNA-based therapeutics. In this study, we evaluated and optimized the efficiency of a cationic, hyperbranched poly(amidoamine)s-based nanoparticle system to deliver tdTomato mRNA to primary human bone marrow stromal cells (hBMSC), human synovial derived stem cells (hSDSC), bovine chondrocytes (bCH), and rat tendon derived stem/progenitor cells (rTDSPC). Transfection efficiencies varied among the cell types tested (bCH 28.4% ± 22.87, rTDSPC 18.13% ± 12.07, hBMSC 18.23% ± 14.80, hSDSC 26.63% ± 8.81) and while an increase of NPs with a constant amount of mRNA generally improved the transfection efficiency, an increase of the mRNA loading ratio (2:50, 4:50, or 6:50 w/w mRNA:NPs) had no impact. However, metabolic activity of bCHs and rTDSPCs was significantly reduced when using higher amounts of NPs, indicating a dose-dependent cytotoxic response. Finally, we demonstrate the feasibility of transfecting extracellular matrix-rich 3D cell culture constructs using the nanoparticle system, making it a promising transfection strategy for musculoskeletal tissues that exhibit a complex, dense extracellular matrix.

Advancements in Polymer and Lipid-based Nanotherapeutics for Cancer Drug Targeting.

Cancer is a global disease. It is the second leading cause of death worldwide, according to the health report. Approximately 70% of deaths from cancer occurs in low- and middle-income countries. According to the WHO, in 2015 8.8 million deaths were reported due to cancer worldwide. The conventional system of medicine was used since a long for the management of the disease, but it comes with the drawback of low safety, less efficacy and non-targeting of cancer cells. Nanotherapeutics has become the most exploited drug targeting system based on the safety and efficacy this system provides over the conventional system. This review summarizes an advanced design consideration in anticancer therapy, recent advancements in the nanocarrier-based advanced drug targeting, challenges and limitations related to nanoparticles-based therapy in cancer and its future perspective. The review also lists the on-going clinical trials in the last five years on nano-based therapy for different types of cancer. The data for this article was obtained by an extensive literature review of related published scientific contents from the WHO's website, PubMed, Scopus, Scielo, clinicaltrials.gov and other relevant scientific archiving services. The safety and efficacy that nanoparticles provide, and the current research strongly support their application in cancer drug targeting. However, their presence in the market is still limited. Nanotherapeutics in cancer drug targeting needs extensive research in association with pharmaceutical industries. Nano-targeting based therapies are the future of pharmaceutical designing for the diagnosis, management and prevention of different forms of cancer.

Energy Transfer Systems for In Vivo Tracking.

With recent advances, fluorescent imaging has gained momentum as an important tool for in vivo imaging. FRET systems consist of molecules that absorb in the near-infrared region which are efficient candidates for in vivo imaging, basic research, and clinical applications. Nontoxic, photostable fluorophores, such as fluorescent proteins and dyes, can successfully be used to visualize spatial and temporal dynamics of living cells. Selected cells to be injected are first tagged with the FRET-based biosensor and then injected to the living animal. Then, these foreign cells in the host body can be visualized under fluorescence microscope via excitation of the fluorophores at the correct wavelength.

Zwitterionic Polymer-Based Nanoparticles Encapsulated with Linalool for Regulating Central Nervous System.

Aromatherapy is widely used in the treatment of diseases of the central nervous system, such as depression and anxiety. However, the rapid and uncontrolled release of aroma weakens the effects of aromatherapy. In this study, zwitterionic polymer-based nanoparticles encapsulated with linalool were prepared to improve the regulation of the central nervous system. First, the nanoparticles were modified with positive charges to adhere to the surface of silk via electrostatic interactions between the cationic nanoparticles and anionic silk. Besides, the fragrance was sustainably and controllably released from the nanoparticles. The effects of polymerization degree, polymer structure, and zeta potential on encapsulation efficiency, adhesion efficiency, and release profiles of linalool were then explored. The results showed that the linalool-encapsulated nanoparticles had the best performances of encapsulation, adhesion and release of fragrance when the polymerization degrees of hydrophilic block and hydrophobic block were 20 and 5, respectively. In addition, open field tests evaluated the regulation of nanoparticles on the central nervous system at the behavioral level. Measurements of dopamine, acetylcholine, and γ-aminobutyric acid expressions explored the mechanism of moderating effects on the central nervous system at the molecular level.

Lipid-polymer hybrid nanoparticles as a next-generation drug delivery platform: state of the art, emerging technologies, and perspectives.

Lipid-polymer hybrid nanoparticles (LPHNPs) are next-generation core-shell nanostructures, conceptually derived from both liposome and polymeric nanoparticles (NPs), where a polymer core remains enveloped by a lipid layer. Although they have garnered significant interest, they remain not yet widely exploited or ubiquitous. Recently, a fundamental transformation has occurred in the preparation of LPHNPs, characterized by a transition from a two-step to a one-step strategy, involving synchronous self-assembly of polymers and lipids. Owing to its two-in-one structure, this approach is of particular interest as a combinatorial drug delivery platform in oncology. In particular, the outer surface can be decorated in multifarious ways for active targeting of anticancer therapy, delivery of DNA or RNA materials, and use as a diagnostic imaging agent. This review will provide an update on recent key advancements in design, synthesis, and bioactivity evaluation as well as discussion of future clinical possibilities of LPHNPs.

Nanodelivery systems for overcoming limited transportation of therapeutic molecules through the blood-brain barrier.

Due to the impermeable structure and barrier function of the blood-brain barrier (BBB), the delivery of therapeutic molecules into the CNS is extremely limited. Nanodelivery systems are regarded as the most effective and versatile carriers for the CNS, as they can transport cargo molecules across the BBB via various mechanisms. This review emphasizes the multi-functionalization strategies of nanodelivery systems and combinatorial approaches for the delivery of therapeutic drugs and genes into the CNS. The characteristics and functions of the BBB and underlying mechanisms of molecular translocation across the BBB are also described.

New Combination/Application of Polymer-Based Nanoparticles for Biomedical Engineering.

Polymer-based nanoparticles (PNPs) are attractive in part due to their ultra-small size, versatility and target specificity. Therefore, PNPs have been increasingly used in a variety of biomedical applications including diagnoses and therapeutic treatment. In this chapter, we focus on the recent studies (within 5 years) with some new ideas/agent's application in biomedical field and roughly divide applications of PNPs into four categories: (1) Delivery, (2) In vivo imaging, (3) Therapies, and (4) Other applications. First, we introduce how PNPs can enhance the treatment and delivery efficiency of therapeutic agent. Second, how PNPs can be used to help in vivo imaging system for disease tracking and monitor. Then, we reveal some novel PNPs which is able to function as an agent in photodynamic, photothermal, sonodynamic and neuron capture therapy. Furthermore, we also mention some interesting applications of PNPs for biomedical field in individual form or cluster employment, such as immunoswitch particles, surface fabrication. Finally, the challenges and future development of PNPs are also discussed. In delivery section, we focus on how polymer "can be used" as vehicles in delivery application. But, in the section of imaging and therapies, we carried on how polymer as an "adjuvant" for functional enhancement. The biodegradable property of PNPs is the feature that they can be controllable for itself degradation and drug release as a chief actor. Besides, in imaging and therapies application, PNPs can be the support role for helping contrast agent or photo/sonosensitizer to enlarge their imaging or therapeutic effect.

Nanoparticles as Delivery Vehicles for the Treatment of Retinal Degenerative Diseases.

Over the last few years, huge progress has been made in the understanding of molecular mechanisms underlying the pathogenesis of retinal degenerative diseases. Such knowledge has led to the development of gene therapy approaches to treat these devastating disorders. Non-viral gene delivery has been recognized as a prospective treatment for retinal degenerative diseases. In this review, we will summarize the constituent characteristics and recent applications of three representative nanoparticles (NPs) in ocular therapy.

Polymer nanoparticles containing essential oils: new options for mosquito control.

Mosquitoes (Diptera: Culicidae) are vectors of important parasites and pathogens causing death, poverty and social disability worldwide. The overuse of synthetic insecticides to control mosquito vectors lead to resistance, adverse environmental effects and high operational costs. Therefore, the development of eco-friendly control tools is an important public health challenge. In this study, two different essential oils (EO) (geranium, Geranium maculatum, and bergamot, Citrus bergamia) loaded polymeric nanoparticle (PN) were elaborated using polyethylene glycol (PEG) and chitosan (Qx) as the polymeric matrix/coating. In addition, the mosquito larvicidal acute and residual activity of the PN was evaluated on Culex pipiens pipiens. The physicochemical characterization of PN revealed that PEG-PN had sizes <255 nm and encapsulation efficiency between 68 and 77%; Qx-PN showed sizes <535 nm and encapsulation efficiency between 22 and 38%. From the toxicological test, it was observed that Qx-PN produced higher acute and residual activity than PEG-PN. Overall, this study highlights that polymer nanoparticles containing essential oil are a promising source of eco-friendly mosquito larvicidal products.

Nanoparticles as a Carrier System for Drug Delivery Across Blood Brain Barrier.

Brain, the centre of the nervous system and an integral part the body, is protected by two anatomical and physiological barriers- Blood-Brain Barrier (BBB) and Blood-Cerebrospinal Fluid Barrier (BCSFB). Blood-Brain Barrier is a very complex and highly organized multicellular structure that shields the brain from harmful substances and invading organisms from the bloodstream and thus offering protection against various brain diseases and injuries. However, it also impede the effective delivery of drug to the brain, thus, preventing treatment of numerous neurological disorders. Even though various traditional approaches such as Intra-Cerebro-Ventricular (ICV) injection, use of implants, disruption of BBB and use of prodrugs have achieved some success in overcoming these barriers, researchers are continuously working for promising alternatives for improved brain drug delivery. Recent breakthroughs in the field of nanotechnology provide an appropriate solution to problems associated with these delivery approaches and thus can be effectively used to treat a wide variety of brain diseases. Thus, nanotechnology promises to bring a great future to the individuals with various brain disorders. This review provides a brief overview of various brain drug delivery approaches along with limitations. In addition, the significance of nanoparticles as drug carrier systems for effective brain specific drug delivery has been highlighted. To show the complexity of the problems to be overcome for improved brain drug delivery, a concise intercellular classification of the BBB along with general transport routes across it is also included.

Evaluation of sublethal effects of polymer-based essential oils nanoformulation on the german cockroach.

The German cockroach, Blattella germanica (L.), is a serious household and public health pest worldwide. The aim of the present study was to evaluate the sublethal activity of polymer-based essential oils (EOs) nanoparticles (NPs) on adults of B. germanica. The LC50 and LC25 for contact toxicity were determined. To evaluate the repellency of EOs and NPs at LC25, a software was specially created in order to track multiple insects on just-recorded videos, and generate statistics using the obtained information. The effects of EOs and NPs at LC25 and LC50 on the nutritional physiology were also evaluated. The results showed that NPs exerted sublethal effects on the German cockroach, since these products enhance the repellent effects of the EOs and negatively affected the nutritional indices and the feeding deterrence index.