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Tadpole-Like Anisotropic Polymer/Lipid Janus Nanoparticles for Nose-to-Brain Drug Delivery: Importance of Geometry, Elasticity on Mucus-Penetration Ability
In the development of nasal‐to‐brain (N2B) drug delivery systems, the key challenge lies in penetrating the mucus, crossing the nasal epithelial barrier, and achieving broad distribution within the central nervous system (CNS) while ensuring biosafety. Non‐biomimetic delivery systems raise concerns regarding metabolism, while biomimetic systems, though safer, still face premature drug release into nasal tissues and limited distribution. Moreover, the N2B transport mechanisms of most existing drug delivery systems remain inadequately understood. This study proposed an efficient nasal‐to‐brain delivery system based on tetrahedral framework nucleic acids (tFNAs). These nanostructures, ≈10 nm in size, possess densely negative‐charged surfaces that help evade protein capture in mucus, facilitate rapid penetration of the mucus layer, and travel along the olfactory and trigeminal nerve axons to achieve widespread distribution in the CNS. The transport pathway is clearly elucidated. Additionally, tFNAs are used to deliver peptide via intranasal administration to treat sepsis‐associated encephalopathy (SAE). Results showed that tFNA‐NAP can regulate microglial activity, reduce neuronal damage, and improve behavioral outcomes. Moreover, both short‐ and long‐term safety experiments revealed no adverse effects. In summary, the development of the tFNA‐based N2B delivery system fills a gap in this field, offering a non‐invasive treatment approach for CNS diseases.
One of the most important issues in the design and preparation of drug delivery systems in the recent years is versatility which includes providing synergistic therapeutic effects and sustainability. This study uses a redox‐active ferrocenyl surfactant (FcN⁺(CH2CH3)3(CH2)10CH3, Fc(C11) where Fc is ferrocene) and pH responsive Zeolitic Imidazolate Framework‐8 (ZIF‐8) structures to form multifunctional assemblies (Fc(C11)‐AOT/Rhb@ZIF‐8/PDA) that can be used in several application including the drug delivery. The vesicles prepared using AOT‐FC(C11) constitute the core of the structure. Since the location of the ferrocene group in the molecule structure, which is next to head group, the surface of the vesicles is decorated with the ferrocene group which can act as a Fenton reaction catalyst. The polydopamine (PDA) covered ZIF‐8 are used to decorate the surface of the vesicles, creating a truly remarkable structure. The porous structure of ZIF‐8 as well as the core of the vesicles can accommodate drug molecules. With the added NIR‐responsive character upon PDA coating, this assembled structure can be used for phototermal therapy applications. The properties of this designed multifunctional and multi‐responsive system are studied at different pH and under NIR‐laser irradiation and show that it has potential to display a triple chemodynamic/ photothermal/ chemotherapeutic effect.
Microrobots are of significant interest due to their smart transport capabilities, especially for precisely targeted delivery in dynamic environments (blood, cell membranes, tumor interstitial matrixes, blood–brain barrier, mucosa, and other body fluids). To perform a more complex micromanipulation in biological applications, it is highly desirable for microrobots to be stimulated with multiple stimuli rather than a single stimulus. Herein, the biodegradable and biocompatible smart micromotors with a Janus architecture consisting of PrecirolATO 5 and polycaprolactone compartments inspired by the anisotropic geometry of tadpoles and sperms are newly designed. These bioinspired micromotors combine the advantageous properties of polypyrrole nanoparticles (NPs), a high near-infrared light-absorbing agent with high photothermal conversion efficiency, and magnetic NPs, which respond to the magnetic field and exhibit multistimulus-responsive behavior. By combining both fields, we achieved an “on/off” propulsion mechanism that can enable us to overcome complex tasks and limitations in liquid environments and overcome the limitations encountered by single actuation applications. Moreover, the magnetic particles offer other functions such as removing organic pollutants via the Fenton reaction. Janus-structured motors provide a broad perspective not only for biosensing, optical detection, and on-chip separation applications but also for environmental water treatment due to the catalytic activities of multistimulus-responsive micromotors.
The aim of the present study is to develop Doxorubicin–Erlotinib nanoparticles (Dox–Erlo NPs) and folate-armored Dox–Erlo-NP conjugates for targeting glioma cancer. Glioma is one of the most common progressive cancerous growths originating from brain glial cells. However, the blood–brain barrier (BBB) is only semi-permeable and is highly selective as to which compounds are let through; designing compounds that overcome this constraint is therefore a major challenge in the development of pharmaceutical agents. We demonstrate that the NP conjugates studied in this paper may ameliorate the BBB penetration and enrich the drug concentration in the target bypassing the BBB. NPs were prepared using a biopolymer with a double-emulsion solvent evaporation technique and functionalized with folic acid for site-specific targeting. Dox–Erlo NPs and Dox–Erlo-NP conjugates were extensively characterized in vitro for various parameters. Dox–Erlo NPs and Dox–Erlo-NP conjugates incurred a z-average of 95.35 ± 10.25 nm and 110.12 ± 9.2 nm, respectively. The zeta potentials of the Dox–Erlo NPs and Dox–Erlo-NP conjugates were observed at −18.1 mV and −25.1 mV, respectively. A TEM image has shown that the NPs were well-dispersed, uniform, de-aggregated, and consistent. A hemolytic assay confirmed hemocompatibility with the developed formulation and that it can be safely administered. Dox–Erlo-NP conjugates significantly reduced the number of viable cells to 24.66 ± 2.08% and 32.33 ± 2.51% in U87 and C6 cells, respectively, and IC50 values of 3.064 µM and 3.350 µM in U87 and C6 cells were reported after 24 h, respectively. A biodistribution study revealed that a significant concentration of Dox and Erlo were estimated in the brain relative to drug suspension. Dox–Erlo-NP conjugates were also stable for three months. The findings suggest that the developed Dox–Erlo-NP conjugates may be a promising agent for administration in glioma therapy.
The administration of drugs to the central nervous system (CNS) is primarily controlled by the blood-brain barrier (BBB), a structure that prevents the passage of foreign compounds from the blood to the brain's extracellular fluid. Although currently available treatments for brain diseases that affect millions of people globally are partially effective, they are associated with severe side effects of systemic drug distribution. On the other hand, the ability of certain drugs to permeate through the BBB is impeded by their physicochemical properties, achieving sub-therapeutic concentrations in their target tissues. In this sense, the intranasal route with its unique anatomical features provides a promising passage for the delivery of drugs to the brain. Nanoparticle-based systems, in particular, have demonstrated an outstanding capacity to overcome the challenges presented by the intranasal route and produce drug accumulation in the brain while avoiding systemic distribution. This review covers recent developments in the use of polymer, lipid, and inorganic nanoparticles, as well as drug nanocrystals, to deliver drugs to the brain via intranasal administration. A general discussion including favourable aspects and limitations of this approach is also provided.
Neurodegenerative diseases are progressive conditions that affect the neurons of the central nervous system (CNS) and result in their damage and death. Neurodevelopmental disorders include intellectual disability, autism spectrum disorder, and attention-deficit/hyperactivity disorder and stem from the disruption of essential neurodevelopmental processes. The treatment of neurodegenerative and neurodevelopmental conditions, together affecting ∼120 million people worldwide, is challenged by the blood–brain barrier (BBB) and the blood–cerebrospinal fluid barrier that prevent the crossing of drugs from the systemic circulation into the CNS. The nose-to-brain pathway that bypasses the BBB and increases the brain bioavailability of intranasally administered drugs is promising to improve the treatment of CNS conditions. This pathway is more efficient for nanoparticles than for solutions, hence, the research on intranasal nano-drug delivery systems has grown exponentially over the last decade. Polymeric nanoparticles have become key players in the field owing to the high design and synthetic flexibility. This review describes the challenges faced for the treatment of neurodegenerative and neurodevelopmental conditions, the molecular and cellular features of the nasal mucosa and the contribution of intranasal nano-drug delivery to overcome them. Then, a comprehensive overview of polymeric nanocarriers investigated to increase drug bioavailability in the brain is introduced.
Neurodegenerative disorders (NDs) have become a serious health problem worldwide due to the rapid increase in the number of people that are affected and the constantly aging population. Among all NDs, Alzheimer's and Parkinson's disease are the most common, and many efforts have been made in the development of effective and reliable therapeutic strategies. The in-tranasal route of drug administration offers numerous advantages, such as bypassing the blood-brain barrier and providing a direct entrance to the brain through the olfactory and trigeminal neu-rons. The present review summarizes the available information on recent advances in micro-and nanoscale nose-to-brain drug-delivery systems as a novel strategy for the treatment of Alzheimer's and Parkinson's disease. Specifically, polymer-and lipid-base micro-and nanoparticles have been studied as a feasible approach to increase the brain bioavailability of certain drugs. Furthermore, nanocomposites are discussed as a suitable formulation for administration into the nasal cavity.
The unavailability of clean drinking water is one of the significant health issues in modern times. Industrial dyes are one of the dominant chemicals that make water unfit for drinking. Among these dyes, methylene blue (MB) is toxic, carcinogenic, and non-biodegradable and can cause a severe threat to human health and environmental safety. It is usually released in natural water sources, which becomes a health threat to human beings and living organisms. Hence, there is a need to develop an environmentally friendly, efficient technology for removing MB from wastewater. Photodegradation is an advanced oxidation process widely used for MB removal. It has the advantages of complete mineralization of dye into simple and nontoxic species with the potential to decrease the processing cost. This review provides a tutorial basis for the readers working in the dye degradation research area. We not only covered the basic principles of the process but also provided a wide range of previously published work on advanced photocatalytic systems (single-component and multi-component photocatalysts). Our study has focused on critical parameters that can affect the photodegradation rate of MB, such as photocatalyst type and loading, irradiation reaction time, pH of reaction media, initial concentration of dye, radical scavengers and oxidising agents. The photodegradation mechanism, reaction pathways, intermediate products, and final products of MB are also summarized. An overview of the future perspectives to utilize MB at an industrial scale is also provided. This paper identifies strategies for the development of effective MB photodegradation systems.
Based on the phase separation phenomenon in micro-droplets, polymer-lipid Janus particles were prepared on a microfluidic flow focusing chip. Phase separation of droplets was caused by solvent volatilization and Janus morphology was formed under the action of interfacial tension. Because phase change from solid to liquid of the lipid hemisphere could be triggered by physiological temperature, the lipid hemisphere could be used for rapid release of drugs. While the polymer we selected was pH sensitive that the polymer hemisphere could degrade under acidic conditions, making it possible to release drugs in a specific pH environment, such as tumor tissues. Janus particles with different structures were obtained by changing the experimental conditions. To widen the application range of the particles, fatty alcohol and fatty acid-based phase change materials were also employed to prepare the particles, such as 1-tetradecanol, 1-hexadecanol and lauric acid. The melting points of these substances are higher than the physiological temperature, which can be applied in fever triggered drug release or in thermotherapy. The introduction of poly (lactic-co-glycolic acid) enabled the formation of multicompartment particles with three distinct materials. With different degradation properties of each compartment, the particles generated in this work may find applications in programmed and sequential drug release triggered by multiple stimuli.
Nanoparticles are promising mediators to enable nasal systemic and brain delivery of active compounds. However, the possibility of reaching therapeutically relevant levels of exogenous molecules in the body is strongly reliant on the ability of the nanoparticles to overcome biological barriers. In this work, three paradigmatic nanoformulations vehiculating the poorly soluble model drug simvastatin were addressed: (i) hybrid lecithin/chitosan nanoparticles (LCNs), (ii) polymeric poly-ε-caprolactone nanocapsules stabilized with the nonionic surfactant polysorbate 80 (PCL_P80), and (iii) polymeric poly-ε-caprolactone nanocapsules stabilized with a polysaccharide-based surfactant, i.e., sodium caproyl hyaluronate (PCL_SCH). The three nanosystems were investigated for their physicochemical and structural properties and for their impact on the biopharmaceutical aspects critical for nasal and nose-to-brain delivery: biocompatibility, drug release, mucoadhesion, and permeation across the nasal mucosa. All three nanoformulations were highly reproducible, with small particle size (∼200 nm), narrow size distribution (polydispersity index (PI) < 0.2), and high drug encapsulation efficiency (>97%). Nanoparticle composition, surface charge, and internal structure (multilayered, core–shell or raspberry-like, as assessed by small-angle neutron scattering, SANS) were demonstrated to have an impact on both the drug-release profile and, strikingly, its behavior at the biological interface. The interaction with the mucus layer and the kinetics and extent of transport of the drug across the excised animal nasal epithelium were modulated by nanoparticle structure and surface. In fact, all of the produced nanoparticles improved simvastatin transport across the epithelial barrier of the nasal cavity as compared to a traditional formulation. Interestingly, however, the permeation enhancement was achieved via two distinct pathways: (a) enhanced mucoadhesion for hybrid LCN accompanied by fast mucosal permeation of the model drug, or (b) mucopenetration and an improved uptake and potential transport of whole PCL_P80 and PCL_SCH nanocapsules with delayed boost of permeation across the nasal mucosa. The correlation between nanoparticle structure and its biopharmaceutical properties appears to be a pivotal point for the development of novel platforms suitable for systemic and brain delivery of pharmaceutical compounds via intranasal administration.
Oral administration of the drugs is considered as one of the most convenient and comfortable routes. However, an effective oral delivery of insulin still remains a challenging and elusive goal, due to bioavailability problem. The aim of our work is to develop a pH sensitive polymeric system for the oral delivery of insulin based on a poly (ϵ‐caprolactone) (PCL) core and shells of chitosan (CS) and alginate (ALG). The particles were prepared based on the double emulsion (water/oil/water) solvent evaporation method. The effect of blending Pluronic127 (F127) into the hydrophobic PCL matrix to improve its water permeability by increasing specific surface area. ALG have been chosen to provide the needed pH‐sensitivity to the system. However, to coat the PCL surface with this anionic ALG layer a cationic CS layer has been added. The influence of each of the CS and ALG layers on the nanoparticle's physiochemical properties as well as on the encapsulation efficiency and the drug release behavior of the nanoparticles was investigated. The results showed that CS and ALG shells increased the stability of the nanoparticles. The in vitro release studies using two different pH environments (1.2 and 6.8) to simulate the physiological conditions in the gastrointestinal tract (GIT) showed that, the particles have pH‐responsive release patterns. The kinetics studies showed that, the insulin release from all the particles formulations obey the Korsmeyer‐ Peppas kinetic model.
Reactive oxygen species (ROS) play an important role in various physiological processes of living organisms. However, their increased concentration is usually considered as a threat for our health. Plants, invertebrates, and vertebrates including humans have various enzymatic and non-enzymatic defence systems against reactive oxygen species. Unfortunately, both bad condition of surrounding environment and unhealthy lifestyle can interfere with an activity of enzymes responsible for a regulation of ROS levels. Therefore, it is important to look for alternative ROS scavengers, which could be administrated to chosen tissues to prevent pathological processes such as distortion of DNA or RNA structures and oxidation of proteins and lipids. One of the most recently proposed solutions is the application of nanozymes, which could mimic the activity of essential enzymes and prevent excessive activity of ROS. In this work, nanoparticles of Au, Pt, Pd, Ru and Rh were synthesized and studied in this regard. Peroxidase-, catalase- and superoxide dismutase-like activity of obtained nanoparticles were tested and compared using different methods. The influence of bovine and human albumins on catalase- and peroxidase-like activity was examined. Moreover, in the case of catalase-like activity, an influence of pH and temperature was examined and compared. Determination of superoxide dismutase-like activity using the methods described for the examination of the activity of native enzyme was not fully successful. Moreover, cytotoxicity of chosen nanoparticles was studied on both regular and tumor cells.
A valid option to bypass the obstacle represented by the blood–brain barrier (BBB) in brain delivery is the use of the unconventional intranasal route of administration. The treatment of depressive diseases, resulting from the depletion of a neurotransmitter in the inter-synaptic space, such as serotonin, is indirectly treated using molecules that can permeate the BBB unlike the latter. In the present article, a set of nanovectors were produced using a mucoadhesive biopolymer, i.e. alginate (Alg). Optimizing the reaction, polymeric nanoparticles having diameter of 30–70 nm were produced, and water stable multi-walled carbon nanotubes functionalized (MWCNT-COOH)/Alg complexes were obtained. These nanovectors were loaded with serotonin, evaluating drug loading/release. By means of Raman microscopy, the cellular internalization of the (MWCNT-COOH)/Alg complex was demonstrated. A complete biocompatibility on neuronal cells was proved for the whole set of nanovectors. Finally, a method of self-administration was tested, which involves the use of a household apparatus, such as an aerosol machine, observing a fine particulate, able to deliver the nanovectors through the nose.
Engineered nanomaterials (ENMs) are used in food additives, food packages, and therapeutic purposes owing to their useful properties, Therefore, human beings are orally exposed to exogenous nanomaterials frequently, which means the intestine is one of the primary targets of nanomaterials. Consequently, it is of great importance to understand the interaction between nanomaterials and the intestine. When nanomaterials enter into gut lumen, they inevitably interact with various components and thereby display different effects on the intestine based on their locations; these are known as location‐oriented effects (LOE). The intestinal LOE confer a new biological‐effect profile for nanomaterials, which is dependent on the involvement of the following biological processes: nano–mucus interaction, nano–intestinal epithelial cells (IECs) interaction, nano–immune interaction, and nano–microbiota interaction. A deep understanding of NM‐induced LOE will facilitate the design of safer NMs and the development of more efficient nanomedicine for intestine‐related diseases. Herein, recent progress in this field is reviewed in order to better understand the LOE of nanomaterials. The distant effects of nanomaterials coupling with microbiota are also highlighted. Investigation of the interaction of nanomaterials with the intestine will stimulate other new research areas beyond intestinal nanotoxicity.
Direct nose-to-brain delivery has been raised as a non-invasive powerful strategy to deliver drugs to the brain bypassing the blood-brain barrier (BBB). This study aimed at preparing and characterizing an innovative composite formulation, associating the liposome and hydrogel approaches, suitable for intranasal administration. Thermosensitive gel formulations were obtained based on a mixture of two hydrophilic polymers (Poloxamer 407, P407 and Poloxamer 188, P188) for a controlled delivery through nasal route via liposomes of an active pharmaceutical ingredient (API) of potential interest for Alzheimer’s disease. The osmolarity and the gelation temperature (T° sol-gel) of formulations, defined in a ternary diagram, were investigated by rheometry and visual determination. Regarding the issue of assays, a mixture composed of P407/P188 (15/1%, w/w) was selected for intranasal administration in terms of T° sol-gel and for the compatibility with the olfactory mucosal (280 ± 20 mOsmol, pH 6). Liposomes of API were prepared by the thin film hydration method. Mucoadhesion studies were performed by using mucin disc, and they showed the good natural mucoadhesive characteristics of in situ gel formulations, which increased when liposomes were added. The study demonstrated successful pharmacotechnical development of a promising API-loaded liposomes in a thermosensitive hydrogel intended for nasal Alzheimer’s disease treatment.
Bicompartmental Janus particles have many advantages in drug delivery, including co-delivery of two compounds with varying solubilities, differential release kinetics, and two surfaces available for targeting ligands. We present a novel strategy using the double emulsion method for the coencapsulation and staggered release of a hydrophobic and hydrophilic drug from anisotropic PLGA/PCL Janus particles, as well as a UV detection method to measure the release of two different compounds from Janus particles. Curcumin and quercetin were chosen as the model hydrophobic compounds for drug loading studies, while acetaminophen (APAP) and naproxen were chosen as the model hydrophilic–hydrophobic drug pair for encapsulation methods and drug loading. Also, a similar double emulsion method was also applied for PLGA/Preicrol® Janus particles containing Doxorubicin and Curcumin. Hydrophobic drugs were encapsulated by the single O/W emulsion technique. Hydrophilic compounds required special modifications due to their poor oil solubility and tendency to escape to the outer aqueous phase during the emulsification and solvent evaporation steps. In total, three different strategies for incorporating hydrophilic drugs were employed: (1) O/W emulsion with partially water miscible solvent, (2) O/W emulsion with co-solvent (i.e. acetone, methanol, ethanol), or (3) W/O/W double emulsion. The encapsulation efficiencies and drug loading percentages were measured using UV/Vis spectroscopy and compared for the different synthesis methods. It was found that the double emulsion method resulted in the highest encapsulation efficiency and drug loading of the hydrophilic drug.
The treatment of central nervous system (CNS) disorders always remains a challenge for the researchers. The presence of various physiological barriers, primarily the blood–brain barrier (BBB) limits the accessibility of the brain and hinders the efficacy of various drug therapies. Hence, drug targeting to the brain, particularly to the diseased cells by circumventing the physiological barriers is essential to develop a promising therapy for the treatment of brain disorders. Presently, the investigations emphasize the role of different nanocarrier systems or surface modified target specific novel carrier system to improve the efficiency and reduce the side effects of the brain therapeutics. Such approaches supposed to circumvent the BBB or have the ability to cross the barrier function and thus increases the drug concentration in the brain. Although the efficacy of novel carrier system depends upon various physiological factors like active efflux transport, protein corona of the brain, stability, and toxicity of the nanocarrier, physicochemical properties, patient-related factors and many more. Hence, to develop a promising carrier system, it is essential to understand the physiology of the brain and BBB and also the other associated factors. Along with this, some alternative route like direct nose-to-brain drug delivery can also offer a better means to access the brain without exposure of the BBB. In this review, we have discussed the role of various physiological barriers including the BBB and blood-cerebrospinal fluid barrier (BCSFB) on the drug therapy and the mechanism of drug transport across the BBB. Further, we discussed different novel strategies for brain targeting of drug including, polymeric nanoparticles, lipidic nanoparticles, inorganic nanoparticles, liposomes, nanogels, nanoemulsions, dendrimers, quantum dots, etc. along with the intranasal drug delivery to the brain. We have also illustrated various factors affecting the drug targeting efficiency of the developed novel carrier system.
Polylactic acid (PLA), a biodegradable and biocompatible polymer produced from renewable resources, has been widely used as a nanoparticulate platform for antigen and drug delivery. Despite generally regarded as safe, its immunotoxicological profile, when used as a polymeric nanoparticle (NP), is not well-documented. Thus, this study intends to address this gap, by evaluating the toxicity of two different sized PLA NPs (PLAA NPs and PLAB NPs), produced by two nanoprecipitation methods and extensively characterized regarding their physicochemical properties in in vitro experimental conditions. After production, PLAA NPs mean diameter (187.9 ± 36.9 nm) was superior to PLAB NPs (109.1 ± 10.4 nm). Interestingly, when in RPMI medium, both presented similar mean size (around 100 nm) and neutral zeta potential, possibly explaining the similarity between their cytotoxicity profile in PBMCs. On the other hand, in DMEM medium, PLAA NPs presented smaller mean diameter (75.3 ± 9.8 nm) when compared to PLAB NPs (161.9 ± 8.2 nm), which may explain its higher toxicity in RAW 264.7. Likewise, PLAA NPs induced a higher dose-dependent ROS production. Irrespective of size differences, none of the PLA NPs presented an inflammatory potential (NO production) or a hemolytic activity in human blood. The results herein presented suggest the hypothesis, to be tested in the future, that PLA NPs presenting a smaller sized population possess increased cytotoxicity. Furthermore, this study emphasizes the importance of interpreting results based on adequate physicochemical characterization of nanoformulations in biological medium. As observed, small differences in size triggered by the dispersion in cell culture medium can have repercussions on toxicity, and if not correctly evaluated can lead to misinterpretations, and subsequent ambiguous conclusions.
The global prevalence of neurologic disorders is rising, and yet we are still unable to deliver most drug molecules, in therapeutic quantities, to the brain. The blood brain barrier consists of a tight layer of endothelial cells surrounded by astrocyte foot processes, and these anatomic features constitute a significant barrier to drug transport from the blood to the brain. One way to bypass the blood brain barrier and thus treat diseases of the brain is to use the nasal route of administration and deposit drugs at the olfactory region of the nares, from where they travel to the brain via mechanisms that are still not clearly understood, with travel across nerve fibers and travel via a perivascular pathway both being hypothesized. The nose-to-brain route has been demonstrated repeatedly in preclinical models, with both solution and particulate formulations. The nose-to-brain route has also been demonstrated in human studies with solution and particle formulations. The entry of device manufacturers into the arena will enable the benefits of this delivery route to become translated into approved products. The key factors that determine the efficacy of delivery via this route include the following: delivery to the olfactory area of the nares as opposed to the respiratory region, a longer retention time at the nasal mucosal surface, penetration enhancement of the active through the nasal epithelia, and a reduction in drug metabolism in the nasal cavity. Indications where nose-to-brain products are likely to emerge first include the following: neurodegeneration, post-traumatic stress disorder, pain, and glioblastoma.
Routes of drug administration and the corresponding physicochemical characteristics of a given route play significant roles in therapeutic efficacy and short term/long term biological effects. Each delivery method has favorable aspects and limitations, each requiring a specific delivery vehicles design. Among various routes, oral delivery has been recognized as the most attractive method, mainly due to its potential for solid formulations with long shelf life, sustained delivery, ease of administration and intensified immune response. At the same time, a few challenges exist in oral delivery, which have been the main research focus in the field in the past few years. The present work concisely reviews different administration routes as well as the advantages and disadvantages of each method, highlighting why oral delivery is currently the most promising approach. Subsequently, the present work discusses the main obstacles for oral systems and explains the most recent solutions proposed to deal with each issue.
To optimally penetrate biological hydrogels such as mucus and the tumor interstitial matrix, nanoparticles (NPs) require physicochemical properties that would typically preclude cellular uptake, resulting in inefficient drug delivery. Here, we demonstrate that (poly(lactic-co-glycolic acid) (PLGA) core)-(lipid shell) NPs with moderate rigidity display enhanced diffusivity through mucus compared with some synthetic mucus penetration particles (MPPs), achieving a mucosal and tumor penetrating capability superior to that of both their soft and hard counterparts. Orally administered semi-elastic NPs efficiently overcome multiple intestinal barriers, and result in increased bioavailability of doxorubicin (Dox) (up to 8 fold) compared to Dox solution. Molecular dynamics simulations and super-resolution microscopy reveal that the semi-elastic NPs deform into ellipsoids, which enables rotation-facilitated penetration. In contrast, rigid NPs cannot deform, and overly soft NPs are impeded by interactions with the hydrogel network. Modifying particle rigidity may improve the efficacy of NP-based drugs, and can be applicable to other barriers.
Janus particles are emerging as structurally unique drug carriers with the potential to deliver multiple drugs and agents. Although synthesis methods have been extensively explored to fabricate Janus particles, it remains a challenge to generate drug-loaded Janus particles through an economical, high throughput technique. Here, we report the formation of the first drug-loaded, micro-scale Janus particles prepared using a single-step emulsion solvent evaporation approach. Our results revealed that both the net charge of drug molecules (i.e. glibenclamide, tolbutamine, rapamycin and lidocaine) and polymer weight ratio (i.e. poly(lactic-co-glycolic) and polycaprolactone) were critical in determining the formation of Janus particles. The formation of drug-loaded Janus particles was proven to be thermodynamically-driven in accordance to the classical equilibrium spreading coefficient theory, which is strongly governed by interfacial tensions. Specifically, comparable interfacial tensions between the two interacting polymers with the water phase were identified to be key criteria to achieve the Janus particles hemispheric structure. Such interfacial tensions were amenable, and were found to be highly dependent on the interfacial charge density attributed to both drug and polymer ratio. Hereby, this study provides a mechanistic insight into the fabrication of drug-loaded Janus particles and paves an important path towards large-scale production of Janus particles using a simplified, single-step emulsion solvent evaporation strategy.
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.
Alginate/chitosan nanoparticles were synthesized by ionotropic method using natural honey as the stabilizing agent. The nanoparticles were characterized and the potential of these nanoparticles for the controlled oral delivery of antitubercular drug rifampicin was evaluated in terms of entrapment efficiency, swelling behaviour and in vitro release of the drug. Carboxyl content and in vitro cytotoxicity of the nanoparticles were also evaluated. The swelling and in vitro drug release indicates that the system undergoes pH-dependent swelling and release of drug. Drug release was very low in acidic pH and a maximum of only 20 % of the drug was released in 5 h. A sustained release of drug was observed at pH 7.4 and complete release was obtained in 8 h. Kinetics of the drug release was analyzed by fitting the experimental data into Korsmeyer-Peppas equation and show that the mechanism involved in the release was non-Fickian, controlled by a combined mechanism of diffusion and polymer relaxation. This study shows that the obtained nanoparticles can be a potential carrier for the pH controlled oral delivery of rifampicin.
Present review highlights the potential of nasal mucosa as an administration route for targeting the centralnervous system, the brain. Targeted drug delivery seeks to concentrate the medication in the tissues ofinterest while reducing the relative concentration of medication in the remaining tissues. Thus improvingefficacy of the drug and reducing side effects. The nasal mucosa when compared to other mucousmembranes is easily accessible and provides a practical entrance portal for small and large molecules.Intranasal administration offers rapid onset of action, no first-pass effect, no gastrointestinal degradationor lung toxicity and non-invasiveness application and also improves bioavailability. It is thought thatolfactory route of drug transport, by pass the blood-brain barrier and allows the direct transport of drugfrom the nose to the brain. This review provides an overview of strategies to improve the drug delivery tobrain via nasal mucosa and recent advances in this field.
The research aimed to formulate the nanostructured lipid carriers (NLCs) and coated with chitosan (CH) for brain targeting through the intranasal route. NLCs were prepared by homogenization and sonication technique and optimized by three factors-three levels Box-Behnken design (BBD). The composition of DPZ-loaded CH-NLCs was established by using a mixture of Compritol & Capryol 90 as lipid, poloxamer 188 as a surfactant, and chitosan (CH) as a coating agent. The effect of formulation factors was evaluated on particle size, entrapment efficiency, and polydispersity index (PDI). Finally, ex-vivo permeation, in-situ perfusion as well as in-vivo study was conducted on albino Wister rats for the detection of pharmacokinetic and neuropharmacokinetic parameters like drug targeting efficiency (% DTE), nose to brain drug transport percentage (DTP), etc of the optimized formulation. Optimized formulation (DPZ-CH-NLCs-OPT2) exhibited an acceptable particle size (192.5 ± 7.3 nm) with 89.85 ± 2.17% entrapment efficiency, 0.298 ± 0.021 PDI, and 38.9 mV zeta potential and particles were spherical shape as shown by TEM. DSC thermogram displayed that the drug existed in amorphous form within the NLCs matrix. Permeability coefficient (Papp) of DPZ-CH-NLCs-OPT2 formulation (10.14 ± 1.73 × 10⁻³ cm h⁻¹) was two folds than DPZ-Sol (4.55 ± 1.18 × 10⁻³ cm h⁻¹). The nasal absorption rate constant for DPZ-CH-NLCs-OPT2 (1.4 × 10⁻³ h⁻¹) was found to be significantly higher than DPZ-Sol (0.5 × 10⁻³ h⁻¹). The bioavailability of DPZ-CH-NLCs was 2.02 fold than that of DPZ-Sol administered intranasally and 2.41 fold than DPZ-CH-NLCs administered via the intravenous route. Efficient brain targeting and targeting potential was observed as showed by DTE (321.21%) and DTP (74.55%) after intranasal administration of DPZ-CH-NLCs as compared to DPZ-Sol (DTE 158.52% and DTP 36.92%). From the findings, it could be concluded that DPZ-CH-NLCs might be an effective strategy for the brain targeting of DPZ through the intranasal route for the treatment of Alzheimer's disease.
Background:
Cranial nerve-related diseases such as brain tumors, Alzheimer's disease, and epilepsy are serious diseases that continue to threaten human. Brain-related diseases are increasing worldwide, including in the United States and Korea, and these increases are closely related to the exposure to harmful substances and excessive stress caused by rapid industrialization and environmental pollution. Drug delivery to the brain is very important for the effective prevention and treatment of brain-related diseases. However, due to the presence of the blood-brain barrier and the extensive first-pass metabolism effect, the general routes of administration such as oral and intravenous routes have limitations in drug delivery to the brain. Therefore, as an alternative, the nasal-brain drug delivery route is attracting attention as a route for effective drug delivery to the brain.
Areas covered:
This review includes physiological factors, advantages, limitations, current application status, especially in clinical applications, and the necessary factors for consideration in formulation development related to nasal-brain drug delivery.
Expert opinion:
The nasal-brain drug delivery route has the advantage of enhancing drug delivery to the brain locally, mainly through the olfactory route rather than the systemic circulation. The nasal-brain lymphatic system has recently attracted attention, and it has been implied that the delivery of anticancer drugs to the brain nervous system is possible effectively. However, there are limitations such as low drug permeability, as well as nasal mucosa and the mucociliary system, as obstacles in nasal-brain drug delivery. Therefore, to overcome the limitations of nasal-brain drug delivery, the use of nanocarriers and mucoadhesive agents is being attempted. However, very few drugs have been officially approved for clinical application via the nasal-brain drug delivery route. This is probably because the understanding of and related studies on nasal-brain drug delivery are limited. In this review, we tried to explore the major considerations and target factors in drug delivery through the nasal-brain route based on physiological knowledge and formulation research information. This will help to provide a mechanistic understanding of drug delivery through the nasal-brain route and bring us one step closer to developing effective formulations and drugs in consideration of the key factors for nasal-brain drug delivery.
Objective(s): Mitoxantrone (MTX) is one of the most commonly used chemotherapeutic agents for treatment of different cancers. However, prolonged treatment with MTX results in unwanted side effects and drug resistant cancer cells. Combination therapies and exploiting of targeted nanoparticles have the potential of improving the efficiency of drug treatment as well as reducing the side effects. Curcumin (CUR) is a biological molecules with anticancer property. In this study, we investigated whether targeted PLGA (Poly Lactic-co-Glycolic Acid)-CUR nanoparticles (NPs) can reinforce the effect of MTX on breast cancer cells. Materials and Methods: PLGA NPs containing CUR targeted with AS1411 aptamer were prepared by single emulsion evaporation method. Physicochemical properties of NPs were investigated. The cytotoxicity of non-targeted and targeted NPs along with MTX was evaluated on MCF7, 4T1 and L929 cell lines. Results: The results showed that PLGA-CUR NPs were synthetized with an average encapsulation efficiency of 66% with a mean size of 186 }3.2 nm. The drug release of curcumin from these NPs within 72h was about 59% in neutral medium and 90% in acidic medium. Interestingly, the combined treatment with PLGA-CURApt and MTX inhibited the cancer cell's proliferation significantly more than the non-targeted nanoparticles, CUR and MTX-treated group alone. Conclusion: These results suggest that targeted PLGA-CUR nanoparticles may consider as a potential therapeutic contender in improving the efficacy of MTX in Breast cancer therapy. © 2021 Mashhad University of Medical Sciences. All Rights Reserved.
The aim of this study was the preparation of solid lipid nanoparticles (SLN) formed from cetyl palmitate with having targeting molecules for monocarboxylate transporter-1 (MCT-1): β-hydroxybutyric acid and anticancer agents: carmustine (BCNU) and temozolomide (TMZ) for enhanced anti-proliferation against glioblastoma multiforme (GBM). Properties including size, morphology, chemical structure, zeta potential, drug encapsulation efficacy, drug release, biocompatibility, stability were determined, and in vitro studies were done. BCNU and TMZ loaded SLNs had a hydrodynamic size of 227 nm ± 46 a zeta potential of -25 mV ± 4 with biocompatible features. The data showed rapid drug release at first and then continuous release. Nanoparticles could be stored for nine months. BCNU and TMZ loaded SLNs exhibited a remarkable increment in the antitumor activity compared to the free-drugs and induced apoptosis on U87MG cells. In addition, targeted nanoparticles were more uptaken by MCT-1 expressing brain cells. This study indicated that BCNU and TMZ loaded SLNs could act as a useful anticancer system for targeted GBM therapy.
Preparation of stable nanofluids is one of the major issues. Dispersion and retention of the nanoparticles in the base fluid require a lot of efforts and are the crucial steps in nanofluid preparation. There are several mechanisms and theoretical aspects that are claimed to be responsible for nanofluid stability. Dispersion techniques of nanofluids play a major role in determining their stability. Various physical and chemical methods that can be further employed to enhance the stability are reviewed in this chapter. Techniques developed for evaluation and monitoring of stability of nanofluids are also discussed in this chapter.
Rod-shaped nanoparticles have been reported to exhibit improved cellular uptake, intracellular processing and transport through tissues and organs, as compared to spherical nanoparticles. We use C-S-B triblock polypeptides composed of a collagen-like block (C), a silk-like block (S) and an oligolysine domain (B) for one-dimensional co-assembly with siRNA into rod-shaped nanoparticles. Here we investigate these siRNA encapsulating rod-shaped nanoparticles as a gene delivery system. Uptake experiments for C-S-B and C-S-B/siPlk1 particles indicate that these rod-shaped nanoparticles can efficiently deliver siPlk1 into HeLa cells. Moreover, C-S-B/siPlk1 complexes display significant mPlk1 gene knockdown in a dose-dependent manner, causing apoptosis as intended. The lower effectiveness of C-S-B/siPlk1 in inducing cell death as compared to cationic lipid-based formulations is explained by the high lysosome-C-S-B/siPlk1 co-localization ratio, which will need to be addressed in a future redesign of polypeptide sequence. Overall, the non-toxic and unique rod-shaped C-S-B nanoparticles deserve further optimization as a new siRNA delivery system for cancer therapy.
The research work was intended to formulate teriflunomide (TFM) loaded nano lipid-based (TNLC) carbopol�gellan gum in situ gel (TNLCGHG) and to investigate its therapeutic efficacy against glioma, a brain and spine
tumor. Nanoformulation was developed using gellan gum and carbopol 974P as gelling and mucoadhesive
agents, respectively, Glyceryl di-behenate and Glyceryl mono-linoleate blend as lipids, and Gelucire 44/14:
water blend as surfactant system. Globule size, PDI, zeta potential, encapsulation efficiency, mucoadhesive
strength, and nasal permeation were found to be 117.80 nm, 0.56, −21.86 mV, 81.16%, 4.80 g, and 904 μg/cm2
,
respectively. Anticancer efficacy of TFM-loaded nano lipid-based carbopol-gellan gum in situ gel (TNLCGHG)
was determined in human U-87MG glioma cell line. IC50 was found 7.0 μg/mL for TNLCGHG, 4.8 μg/mL for
pure TFM, and 78.5 μg/mL for TNLC, which approve the superiority of surfactant along with gellan gum as perme�ation enhancer. Brain Cmax for technetium (99mTC) labeled intranasal (i.n.) 99mTC-TNLCGHG was found 2-folds
higher than 99mTC-TNLC (i.n.) and 99mTC-TNLC intravenous (i.v.) because the TNLCGHG formulation contains sur�factant with natural gelling polymers, which promisingly improved drug permeability. Finally, this research re�vealed encouraging outcomes and successfully developed intranasal TNLCGHG nanoformulation as a novel tool
for safe delivery of TFM in glioma patients.
Overcoming epithelial barriers to enhance drug absorption is a major challenge for nanoparticle (NP)-based mucosal delivery systems. With adequate physicochemical properties, the transepithelial delivery of NPs may be efficiently enhanced. However, little is known about the role of elasticity on the transport of NPs across the polarized epithelium, especially the processes and mechanisms of endocytosis, intracellular trafficking and exocytosis. In this study, we discovered that zwitterionic hydrogel NPs with varied elasticity displayed considerably different oral insulin absorption on diabetic rats. It was found that NP elasticity strongly shaped the transepithelial behaviors of NPs, and the increase of elasticity boosted the transcytosis by improving both endocytosis and exocytosis. Elasticity also showed a profound effect on the intracellular trafficking routes of NPs, which was closely related to distribution of NPs in exocytosis pathway and their intra-endosome sphere-to-ellipsoid shape transformation. Importantly, NPs with zwitterionic surface experienced more efficient basolateral exocytosis than apical exocytosis, while the elasticity-related exocytosis enhancement appeared to be non-selective. Therefore, tailored elasticity could promote mucosal transcytosis of NPs, which was able to be further improved with biomimetic zwitterionic surface. This study may provide important knowledge for the design of functional nanovehicles to efficiently overcome mucosal epithelial barriers in the future.
Nose-to-brain delivery is an attractive route for direct drug delivery to the central nervous system (CNS), avoiding hepatic first-pass metabolism and solving blood-brain barrier passage issues. Therefore, the aim of the present study was the development of PLGA and PLGA/chitosan (chit) nanoparticles (NPs) with mucoadhesive properties, able to encapsulate ropinirole hydrochloride (RH), an anti-Parkinsonian dopaminergic agonist, and suitable to promote RH delivery across the nasal mucosa.
NPs produced by nanoprecipitation showed spherical shape and a mean average size of 98.8 nm and 468.0 nm (PLGA and PLGA/chit, respectively). RH loaded PLGA/chit NPs showed a complete release of the drug in simulated nasal electrolyte solution (SNES) over the period of 24 h and increased the permeation of RH through sheep nasal mucosa by 3.22-fold in comparison to PLGA NPs. None of RH loaded NPs induced hemolysis in whole blood or the production of reactive oxygen species (ROS) in Raw 264.7 cells. On their turn, PLGA/chit NPs decreased cell viability of Raw 264.7 cells and Peripheral Blood Mononuclear Cells (PBMCs) in a concentration-dependent manner.
These results revealed that, particularly PLGA/chit NPs, could be a valuable carrier for the delivery of RH to the CNS, opening a new path for Parkinson’s disease therapy.
Janus nanoparticles (JNPs) have two faces with differing physical or chemical characteristics which endow them with unique properties. This anisotropy can lead to phenomena like self-assembly or interfacial activity, and JNPs have been under intense scientific scrutiny since the 1990s. Since then, powerful synthetic techniques have been developed which allow for JNPs with near limitless combinations of materials, properties, and morphologies. As such, JNPs have been featured in a number of applications such as drug delivery, catalysis, interfacial engineering, and optics. This perspective discusses the synthesis of these important anisotropic materials. We will focus exclusively on JNPs that involve polymers. In particular, we outline the various classes of JNP synthetic techniques including some historical context, describe recent developments in this area, and weigh the pros and cons of the different methods with an eye on future directions and applications. We hope this perspective will help acclimate those new to the field who want to make and/or use JNPs.
The present study elucidates the development of an accurate, precise and simple simultaneous estimation method for the routine analysis of Betamethasone Valerate (BV) and Tazarotene (TZ). This combination is widely used in the treatment of psoriasis. No method has been reported so far for the simultaneous estimation of BV and TZ in topical dosage forms. The method proposed by this study for the quantification of BV and TZ is the Absorption factor method. The developed method was validated as per the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) guideline. The validated method was found to be linear in a concentration range of 10–38 μg/mL and 4–14 μg/mL for BV and TZ respectively with a regression coefficient >0.990. The method was validated for accuracy and precision which revealed the recovery of >99.80% with RSD <2.0. The method was found to be precise with RSD <2% for inter and intraday. The developed method was employed for quantification of BV and TZ in lipid based nanocarriers formulation and their in-vitro drug release samples. Further, the developed method was successfully applied for the estimation of BV and TZ in the ex-vivo skin matrix. This showed that the method can sensitively determine the drugs in aqueous and biological samples.
Lungs are critical organs that are continuously exposed to exogeneous matter. The presence of the mucus layer helps to protect them via its adhesive structure and filtering mechanisms. Mucus also acts as a strong barrier against the drugs and nanocarriers in drug delivery. In this study, solid lipid nanoparticles (SLNs), at different sizes and surface properties, were prepared and their spreading/penetration ability was tested for their use in pulmonary drug delivery. The biophysical interactions of SLNs have been studied via light scattering (LS) and zeta potential analyses by incubating the SLNs in mucin solution and forming a model mucus layer using a Langmuir-Blodgett (LB) trough. In addition, the penetration performance of the particles was evaluated using Franz diffusion cell and rotating diffusion tubes. It was determined that 36% of SLNs can penetrate through a 1.2 ± 0.2-mm-thick mucus layer. Finally, the spreading behavior of the particles on a mucus-mimicking subphase was characterized and enhanced using a catanionic surfactant mixture. Overall, the current study was the first to investigates both the spreading and penetration performance of SLNs. The developed systems offer a drug delivery system that is able to achieve high penetration rates through a thick mucus layer.
Polymer Janus particles (PJPs) have been extensively investigated due to their intriguing features which cannot be achieved in traditional counterparts. Chiral polymer particles also have constituted a unique research area in polymer science. However, how to construct PJPs derived from chiral polymers, especially chiral helical polymers, still remains as a significant academic challenge. This contribution reports the first success in preparing optically active PJPs constructed by chiral helical substituted polyacetylene via emulsion polymerization combined with solvent evaporation to induce phase separation. In the emulsion polymerization systems, polymethyl methacrylate worked as template and separated from polyacetylene domains in the course of acetylenic monomers’ polymerization and evaporation of solvent, by which optically active PJPs were formed. Major affecting factors were explored to elucidate their effects on the formation and morphology of PJPs. Mushroom- and bowl-like PJPs were obtained. Scanning electron microscopic images ascertain non-spherical morphologies of the obtained PJPs. Circular dichroism and UV-vis absorption spectra demonstrate their optical activity, which is originated in the predominantly one-handed helical polyacetylene chains constructing the PJPs. A formation mechanism was then proposed for understanding this unprecedented type of PJPs.
Different blood groups of ABO system have specific antigen which bestows them with different biochemical properties and hence they can show different hemolytic activity. In this report, hemolytic activity of thiol-functionalized Fe3O4-Au nanoparticles were studied in presence and absence of doxorubicin and the effect of various thiol coatings were correlated towards their hemolysis tendency. The nanoparticles were functionalized with four different amino thiols, cysteamine (CEA), cystamine (CA), cysteine (Cys) and cystine (Cyt) to form Fe3O4-Au CEA, Fe3O4-Au CA, Fe3O4-Au Cys and Fe3O4-Au Cyt nanoparticles which were loaded with anticancer drug, doxorubicin. The functionalization was characterized using ATR-FTIR, HR-TEM, XPS and other spectroscopic methods. Maximum drug encapsulation efficiency of 83% was observed with Fe3O4-Au CA nanoparticles. In-vitro experiments were performed on HeLa cells to check the cellular uptake and cytotoxicity using MTT assay. Hemolytic activity was then analyzed with all the blood groups (positive and negative). The amino acid functionalized, Fe3O4-Au Cys and Fe3O4-Au Cyt nanoparticles, shows lesser hemolysis compared to amino thiol functionalized Fe3O4-Au CEA, and Fe3O4-Au CA nanoparticles. In positive blood groups, the Fe3O4-Au CA nanoparticles shows the highest rate of hemolysis followed by Fe3O4-Au CEA, while the lowest hemolysis rate was observed for Fe3O4-Au Cyt nanoparticles. For negative blood groups, the thiol coated nanoparticles show more abrupt hemolysis rate depending upon the type of antigen.
Mucus is a viscoelastic biological hydrogel that protects the epithelial surface from penetrating by most nanoparticles, which limits the efficiency of oral drug delivery. Pursuing highly efficient, biocompatible and biodegradable oral drug vehicles is of central importance to the development of promising nanomedicine. Here, we prepared five peptosomes (PSs) with various sizes, shapes and rigidities based on self-assembly of amphiphilic α-lactalbumin (α-lac) peptides from partial enzymolysis and cross-linking. The mucus permeation of α-lac PSs and release of curcumin (Cur) encapsulated in these PSs were evaluated. Compared with long nanotube (LNT), big nanosphere (BNS), small nanosphere (SNS) and crosslinked short nanotube (CSNT), we demonstrated that short nanotube (SNT) exhibits excellent permeability in mucus, which enables it to arrive at epithelial cells quickly. Besides, SNT exhibits the highest cellular uptake and transmembrane permeability on Caco-2/HT29-MTX (E12) 3D model. In vivo pharmacokinetic evaluation revealed that the SNT shows the highest curcumin bioavailability, which is 6.85-folds higher than free Cur. Most importantly, Cur-loaded SNT exhibits the optimum therapeutic efficacy for in vivo treatment of DSS-induced ulcerative colitis (UC). In the end, the mechanism of the high permeability of SNT through mucus was explained by coarse-grained molecular dynamics simulations, which indicated that short timescale jiggling and flying across pores of mucus network played key roles. These findings revealed the tubular α-lac PSs could be a promising oral drug delivery system targeted to mucosal for improving absorption and bioavailability of hydrophobic bioactive ingredients.
Glioblastoma (GBM) is one of the most devastating and deadly types of tumor. Among all the present treatment strategies, the utmost prerequisite is prolonged intervention at the malignant site. The blood-brain barrier (BBB) is the bottleneck in the delivery of anti-GBM drugs and invasive treatment comes with many pitfalls. This review will discuss the potential of embedding antitumor drugs into nanocarriers for intranasal delivery. Additionally, it emphasizes the significance of applying quality by design (QbD) methodology from the early development stages to ensure the high quality, safety and efficacy of the developed carrier system.
Nose-to-brain delivery has gained significant interest over the past several decades. This has resulted in numerous strategies described to improve the delivery of drugs to the brain directly through the olfactory epithelium of the nasal cavity. In some cases, intranasal administration may be more effective than other routes of administration in treating central nervous system and related disorders. Here, we briefly review the strategies that have been used to facilitate nose-to-brain delivery as well as approaches to block the delivery of drugs from the nose to the brain. Even though numerous strategies have already been used to increase nose-to-brain delivery, the research for strategies inhibitory of nose-to-brain delivery seems to be scarce.
This work demonstrated a microfluidic preparation process for novel Janus microparticles with individual drug release properties in each compartment. A flow-focusing microfluidic chip was designed to produce oil-in-water droplets from a mixed solution of poly(lactic-co-glycolic acid) and a triglyceride type lipid. Based on solvent evaporation-induced phase separation, droplets evolved and were solidified into Janus particles, each of which had a polymer compartment and a lipid compartment. The ratio of the two compartments in a particle can be discretionarily regulated, and the particle structure can also be flexibly altered to Janus-patchy, triple, quadruple or core-shell type. Phase transition of the chosen lipid from solid to liquid would occur under physiological temperature, which was applied for rapid release of the loaded drug. The polymer compartment would undergo a slow degradation process in physiological environment, facilitating sustained drug release. Paclitaxel was loaded into Janus particles during preparation, and staged release was achieved, leading to a combination of rapid and sustained release, which is highly desired in target drug delivery. This study would start the application of hybrid Janus particles of polymer-lipid type with novel release kinetics in drug delivery systems.
Anisotropic polymer particles have promising applications in various fields, whereas their preparation usually suffers from tedious procedures. Here, we introduce a facile strategy to fabricate novel shape-anisotropic particles with varied internal structures via self-assembly of block copolymers (BCPs) with perfluorooctane (PFO) as liquid template in emulsion droplets. By increasing the volume ratio of PFO to polystyrene-block-poly(4-vinylpyridine) (PS-b-P4VP) or decreasing the initial concentration of the BCPs, the self-assembled polymer particles change from spherical core-shell structures to anisotropic particles. Moreover, the anisotropic shape and internal structure of the polymer particles, including cone-like particles with alternative PS and P4VP lamellas, crescent-shaped particles with cylindrical P4VP domains, and plate-like particles with spherical P4VP domains, can be obtained by changing block ratio, molecular weight, or adding hydrogen bonding agent. Based on the in-situ optical microscopy investigation on the morphology evolution of emulsion droplet, we conclude that both kinetic and thermodynamic factors during emulsion evolution determine the formation of shape-anisotropic polymeric particles with controllable internal structures.
Hybrid nanosystem with impeccable cellular imaging and antioxidant functionality is demonstrated. The microwave-irradiation derived molybdenum trioxide nanoparticles (MoO3 NPs) were surface functionalized with cationic dye molecule, methylene blue (MB), which enables superior UV-visible absorbance and fluorescence emission wavelengths potential for bioimaging. Radical scavenging property of the pristine MoO3 NPs and MoO3-MB NPs were studied in vivo using Caenorhabditis elegans as model system. Heat shock induced oxidative stress in the C. elegans was significantly resolved by the MoO3-MB NPs, in agreement with in vitro radical scavenging study by electron paramagnetic resonance spectroscopy. Hybrid nanostructures of MoO3-MB demonstrate synergistic benefits in the intracellular imaging with intrinsic biocompatibility and antioxidant behavior, which can facilitate application as advanced healthcare materials toward bioimaging and clinical therapeutics.
The brain as a target for drug delivery is a challenge in pharmaceutical research. Among the several proposed strategies, the intranasal route represents a good strategy to deliver drugs to the brain. The goal of this study was to investigate the potential use of oxcarbazepine (OXC) to enhance brain targeting efficiency after intranasal (IN) administration. As well as attempting to use as low a dose as possible to obtain therapeutic effect. Our results showed that, after IN administrations, the dose of OXC that was effective in controlling epileptic seizures was 0.5 mg/kg (1 dose, every 20 min for 1 h) in rodents, confirmed by Cerebral Spinal Fluid (CSF) bioavailability. With the aim of reducing the number of administrations, sustaining drug release and increasing brain targeting, OXC was loaded into poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs). The selected nanoformulation for in vivo studies was obtained re-suspending the freeze-dried and cryo-protected OXC loaded PLGA NPs. The translocation of 1-1′-Dioctadecyl-3,3,3′,3′-tetramethylindotricarbocyanine Iodide loaded PLGA NPs, from nose to the brain, was confirmed by Fluorescence Molecular Tomography, which also evidenced an accumulation of NPs in the brain after repeated IN administrations.
IN administrations of OXC loaded PLGA NPs reduced the number of administrations to 1 over 24 h compared to the free drug thus controlling seizures in rats. Immunohistochemical evaluations (anti-neurofilament, anti-beta tubulin, and anti-caspase3) demonstrated a neuroprotective effect of OXC PLGA NPs after 16 days of treatment. These encouraging results confirmed the possibility of developing a novel non-invasive nose to brain delivery system of OXC for the treatment of epilepsy.
Most recent studies on Janus particles have concentrated on amphiphilic Janus particles. Herein, a facile and efficient method based on polymerization-induced phase separation is presented to fabricate Janus particles with different morphologies. Theses novel hydrophilic Janus particles with two distinct hydrophilic domains have been prepared by combination of distillation precipitation polymerization (DPP) and seeded emulsion polymerization. Crosslinked poly(2-hydroxyehtyl methacrylate) (PHEMA) cores were synthesized via DPP and used as seed particles. Also, methacrylic acid (MAA) was used as second hydrophilic monomer. Effect of feeding approach, and reaction medium were investigated on the morphology of fabricated composite particles. Different morphologies such as cauliflower-like, dumbbell-like, and core-shell toward cauliflower-like structures were obtained by varying feeding approach and polymerization medium. The morphology of resultant particles was observed by means of FE-SEM and TEM images and their particle sizes were confirmed by DLS. Fabricated composite particles were used to simultaneously carry both DOX and ibuprofen. Drug release studies showed that Janus particles can be used in loading and release of two drugs simultaneously. However, release behaviors of DOX and ibuprofen were different at different pH values. Also, release behavior was significantly affected by the structure of composite particles.
New mixed cationic liposomes based on L-α-phosphatidylcholine and dihexadecylmethylhydroxyethylammonium bromide (DHDHAB) were designed to overcome the BBB crossing by using the intranasal route. Synthesis and self-assembly of DHDHAB were performed. A low critical association concentration (0.01 mM), good solubilization properties toward hydrophobic dye Orange OT and antimicrobial activity against gram-positive bacteria Staphylococcus aureus (MIC=7.8 μg mL-1) and Bacillus cereus (MIC=7.8 μg mL-1), low hemolytic activities against human red blood cells (less than 10%) were achieved. Conditions for preparation of cationic vesicles and mixed liposomes with excellent colloidal stability at room temperature were determined. The intranasal administration of rhodamine B-loaded cationic liposomes was shown to increase bioavailability into the brain in comparison to the intravenous injection. The cholinesterase reactivator, 2-PAM, was used as model drug for the loading in cationic liposomes. 2-PAM-loaded cationic liposomes displayed high encapsulation efficiency (∼ 90%) and hydrodynamic diameter close to 100 nm. Intranasally administered 2-PAM-loaded cationic liposomes were effective against paraoxon-induced acetylcholinesterase inhibition in the brain. 2-PAM-loaded liposomes reactivated 12 ± 1% of brain acetylcholinesterase. This promising result opens the possibility to use marketed positively charged oximes in medical countermeasures against organophosphorus poisoning for reactivation of central acetylcholinesterase by implementing a non-invasive approach, via the "nose-brain" pathway.
Central nervous system (CNS) disorders (e.g., multiple sclerosis, Alzheimer's disease, etc.) represent a growing public health issue, primarily due to the increased life expectancy and the aging population. The treatment of such disorders is notably elaborate and requires the delivery of therapeutics to the brain in appropriate amounts to elicit a pharmacological response. However, despite the major advances both in neuroscience and drug delivery research, the administration of drugs to the CNS still remains elusive. It is commonly accepted that effectiveness-related issues arise due to the inability of parenterally administered macromolecules to cross the Blood-Brain Barrier (BBB) in order to access the CNS, thus impeding their successful delivery to brain tissues. As a result, the direct Nose-to-Brain delivery has emerged as a powerful strategy to circumvent the BBB and deliver drugs to the brain. The present review article attempts to highlight the different experimental and computational approaches pursued so far to attain and enhance the direct delivery of therapeutic agents to the brain and shed some light on the underlying mechanisms involved in the pathogenesis and treatment of neurological disorders.
Mucus is a hydrogel that exhibits complex selective permeability, permitting the passage of some particles while restricting the passage of other particles including important therapeutics. In this review, we discuss biochemical mechanisms underlying mucus penetration and mucus binding, emphasizing the importance of steric, electrostatic, and hydrophobic interactions. We discuss emerging techniques for engineering nanoparticle surface chemistries for mucus penetration as well as recent advances in tuning mucus interactions with small molecule, peptide, or protein therapeutics. Finally, we highlight recent work suggesting that mucus permeability can serve as a biomarker for disease and physiological states such as pregnancy.
A quantitative analysis has cast doubt over the limited advantages provided by particles for nose-to-brain (NTB) drug delivery. Thus, it is imperative to identify the role of nanovehicles in NTB drug delivery. If nanocarriers are used merely as an option to improve various properties of the drugs or the formulations, it is difficult for them to outperform conventional formulations, such as solutions or gels. However, nanovehicles bring about special features, such as maintenance of the solubilized state of drugs, sustained or delayed release, and enhanced penetration because of surface modifications, all of which lead to enhanced NTB delivery efficiency.
It is known that rod-like nanoparticles (NPs) can achieve higher diffusivity than their spherical counterparts in biological porous media such as mucus and tumor interstitial matrix, but the underlying mechanisms still remain elusive. Here, we present a joint experimental and theoretical study to show that the aspect ratio (AR) of NPs and their adhesive interactions with the host medium play key roles in such anomalous diffusion behaviors of nanorods. In an adhesive polymer solution/gel (e.g., mucus), hopping diffusion enables nanorods to achieve higher diffusivity than spherical NPs with diameters equal to the minor axis of the rods, and there exists an optimal AR that leads to maximum diffusivity. In contrast, the diffusivity of nanorods decreases monotonically with increasing AR in a non-adhesive polymer solution/gel (e.g., hydroxyethyl cellulose, HEC). Our theoretical model, which captures all the experimental observations, generalizes the so-called obstruction-scaling model by incorporating the effects of the NPs/matrix interaction via the mean first passage time (MFPT) theory. This work reveals the physical origin of the anomalous diffusion behaviors of rod-like NPs in biological gels and may provide guidelines for a range of applications that involve NPs diffusion in complex porous media.