Peptide-Functionalized Prussian Blue Nanomaterial for Antioxidant Stress and NIR Photothermal Therapy against Alzheimer's Disease

Excessive accumulations of reactive oxygen species (ROS) and amyloid-β (Aβ) protein are closely associated with the complex pathogenesis of Alzheimer's disease (AD). Therefore, approaches that synergistically exert elimination of ROS and dissociation of Aβ fibrils are effective therapeutic strategies for correcting the AD microenvironment. Herein, a novel near infrared (NIR) responsive Prussian blue-based nanomaterial (PBK NPs) is established with excellent antioxidant activity and photothermal effect. PBK NPs possess similar activities to multiple antioxidant enzymes, including superoxide dismutase, peroxidase, and catalase, which can eliminate massive ROS and relieve oxidative stress. Under the NIR irradiation, PBK NPs can generate local heat to disaggregate Aβ fibrils efficiently. By modifying CKLVFFAED peptide, PBK NPs display obvious targeting ability for blood–brain barrier penetration and Aβ binding. Furthermore, in vivo studies demonstrate that PBK NPs have outstanding ability to decompose Aβ plaques and alleviate neuroinflammation in AD mouse model. Overall, PBK NPs provide evident neuroprotection by reducing ROS levels and regulating Aβ deposition, and may accelerate the development of multifunctional nanomaterials for delaying the progression of AD.     

Preparation,characterization, in vivo biodistribution and pharmacokinetic studies of donepezil-loaded PLGA nanoparticles for brain targeting

Objective: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder manifested by cognitive, memory deterioration and variety of neuropsychiatric symptoms. Donepezil is a reversible cholinesterase inhibitor used for the treatment of AD. The purpose of this work is to prepare a nanoparticulate drug delivery system of donepezil using poly(lactic-co-glycolic acid) (PLGA) for sustained release and efficient brain targeting.

Materials and methods: PLGA nanoparticles (NPs) were prepared by the solvent emulsification diffusion–evaporation technique and characterized for particle size, particle-size distribution, zeta potential, entrapment efficiency, drug loading and interaction studies and in vivo studies using gamma scintigraphy techniques.

Results and discussion: The size of drug-loaded NPs (drug polymer ratio 1:1) was found to be 89.67?±?6.43?nm. The TEM and SEM images of the formulation suggested that particle size was within 20–100?nm and spherical in shape, smooth morphology and coating of Tween-80 on the NPs was clearly observed. The release behavior of donepezil exhibited a biphasic pattern characterized by an initial burst release followed by a slower and continuous sustained release. The biodistribution studies of donepezil-loaded PLGA NPs and drug solution via intravenous route revealed higher percentage of radioactivity per gram in the brain for the nanoparticulate formulation as compared with the drug solution (p?Conclusion: The high concentrations of donepezil uptake in brain due to coated NPs may help in a significant improvement for treating AD. But further, more extensive clinical studies are needed to check and confirm the efficacy of the prepared drug delivery system.     

Formulation and optimization of intranasal nanolipid carriers of pioglitazone for the repurposing in Alzheimer’s disease using Box-Behnken design

Growing evidence suggest that Alzheimer’s disease (AD), the most common cause of dementia among the elderly is a metabolic disorder associated with impaired brain insulin signaling. Hence, the diabetic drug can be a therapeutic option for the management AD. The researches in this area are ongoing and Pioglitazone (PIO) is one of the most investigated diabetic drug in AD. Eventhough PIO treatment was found to improve AD significantly in the preclinical models, the poor blood-brain barrier (BBB) permeability and serious peripheral side effects limited its success in the clinical trials. The objective of the present study was to formulate and optimize intranasal (IN) nano lipid carriers (NLC) of PIO for its targeted delivery to the brain. A Box-Behnken design was employed to optimize the effect of three independent variables on two dependent variables. The optimized formulation had a particle size (PS) of 211.4?±?3.54?nm and zeta potential of (ZP) of 14.9?±?1.09?mv. The polydispersibility index (PDI) and entrapment efficiency (EE) was found to be 0.257?±?0.108 and 70.18?±?4.5% respectively. Storage stability studies performed has confirmed the stability of NLCs at 4?°C and 25?°C. The in-vitro drug release study has exhibited a sustained release of drug from the NLC. The formulation was observed to improve the nasal permeability of PIO ex-vivo significantly. Toxicity studies were performed to confirm the safety of formulation for the in-vivo administration. In-vivo biodistribution study in rats has shown a direct transport of drug from the nose to brain from the IN-NLC.     

Detection of β‐Amyloid by Sialic Acid Coated Bovine Serum Albumin Magnetic Nanoparticles in a Mouse Model of Alzheimer's Disease

The accumulation and formation of β‐amyloid (Aβ) plaques in the brain are distinctive pathological hallmarks of Alzheimer's disease (AD). Designing nanoparticle (NP) contrast agents capable of binding with Aβ highly selectively can potentially facilitate early detection of AD. However, a significant obstacle is the blood brain barrier (BBB), which can preclude the entrance of NPs into the brain for Aβ binding. In this work, bovine serum albumin (BSA) coated NPs are decorated with sialic acid (NP‐BSA_x‐Sia) to overcome the challenges in Aβ imaging in vivo. The NP‐BSA_x‐Sia is biocompatible with high magnetic relaxivities, suggesting that they are suitable contrast agents for magnetic resonance imaging (MRI). The NP‐BSA_x‐Sia binds with Aβ in a sialic acid dependent manner with high selectivities toward Aβ deposited on brains and cross the BBB in an in vitro model. The abilities of these NPs to detect Aβ in vivo in human AD transgenic mice by MRI are evaluated without the need to coinject mannitol to increase BBB permeability. T₂*‐weighted MRI shows that Aβ plaques in mouse brains can be detected as aided by NP‐BSA_x‐Sia, which is confirmed by histological analysis. Thus, NP‐BSA_x‐Sia is a promising new tool for noninvasive in vivo detection of Aβ plaques.     

A Size-Changeable Collagenase-Modified Nanoscavenger for Increasing Penetration and Retention of Nanomedicine in Deep Tumor Tissue

The complex tumor microenvironment constitutes a variety of barriers to prevent nanoparticles (NPs) delivery and results in extremely low accumulation of nanomedicines in solid tumors. Here, a newly developed size-changeable collagenase-modified polymer micelle is employed to enhance the penetration and retention of nanomedicine in deep tumor tissue. The TCPPB micelle is first formed by self-assembly of maleimide-terminated poly(ethylene glycol)-block-poly(β-amino ester) (MAL-PEG-PBAE) and succinic anhydride-modified cisplatin-conjugated poly(ε-caprolactone)-block-poly(ethylene oxide)-triphenylphosphonium (CDDP-PCL-PEO-TPP). Next, Col-TCPPB NPs are prepared through a “click” chemical combination of thiolated collagenase and maleimide groups on TCPPB micelle. Finally, biocompatible chondroitin sulfate (CS) is coated to obtain CS/Col-TCPPB NPs for avoiding collagenase inactivation in blood circulation. In tumor acidic microenvironment, the hydrophobic PBAE segments of the resultant micelles become hydrophilic, leading to a dissociation and subsequent dissolution of partial collagenase-containing components (Col-PEG-PBAE) from NPs. The dissolved Col-PEG-PBAE promotes the digestion of collagen fibers in tumor tissue like a scavenger, which enhances the NPs penetration. Simultaneously, the increased hydrophilicity of residual Col-PEG-PBAE in the micellar matrix causes an expansion of the NPs, resulting in an enhanced intratumoral retention. In tumor cells, the NPs target to release the cisplatin drugs into mitochondria, achieving an excellent anticancer efficacy.     

Development of electrosprayed artesunate-loaded core–shell nanoparticles

Objective: Artesunate (ART) is proven to have potential anti-proliferative activities, but its instability and poor aqueous solubility limit its application as an anti-cancer drug. The present study was undertaken to develop coaxial electrospraying as a novel technique for fabricating nanoscale drug delivery systems of ART as the core–shell nanostructures.

Methods: The core–shell nanoparticles (NPs) were fabricated with coaxial electrospraying and the formation mechanisms of NPs were examined. The physical solid state and drug–polymer interactions of NPs were characterized by X-ray powder diffraction (XRPD) and Fourier transform infrared (FTIR) spectroscopy. The effects of materials and electrospraying process on the particle size and surface morphology of NPs were investigated by scanning electron microscopy (SEM). The drug release from NPs was determined in vitro by a dialysis method.

Results: The ART/poly(lactic-co-glycolic) acid (PLGA) chitosan (CS) NPs exhibited the mean particle size of 303?±?93?nm and relatively high entrapment efficiency (80.5%). The release pattern showed an initial rapid release within two hours followed by very slow extended release. The release pattern approached the Korsmeyer–Peppas model.

Conclusions: The present results suggest that the core–shell NPs containing PLGA and CS have a potential as carriers in the anticancer drug therapy of ART.     

3D nano-arrays of silver nanoparticles and graphene quantum dots with excellent surface-enhanced Raman scattering

Active surface-enhanced Raman scattering (SERS) substrates, 3D nano-arrays of Ag nanoparticles (NPs) and graphene quantum dots (GQDs), were prepared using a photochemical approach and an electrophoresis deposition technique with the formation mechanism addressed. The GQDs (ca. 6?nm average) fit into the inter-particle gaps between Ag NPs, as verified by their scanning electron microscopy and high-resolution transmission electron microscopy. This deliberately designed 3D assembly of Ag NPs and GQDs could promote the synergistic effects of both components to further enhance the SERS performances according to both electromagnetic mechanism and chemical mechanism. Preliminary experiments show that the 3D substrates exhibited strong SERS signals comparing with bare Si substrates. This work provides a promising way for 3D SERS substrates.     

Formulation and corneal permeation of ketorolac tromethamine-loaded chitosan nanoparticles

Abstract

The aim of this work was to formulate chitosan (CS)-based nanoparticles (NPs) loaded with ketorolac tromethamine (KT) intended for topical ocular delivery. NPs were prepared using ionic gelation method incorporating tri-polyphosphate (TPP) as cross-linker. Following the preparation, the composition of the system was optimized in terms of their particle size, zeta potential, entrapment efficiency (EE) and morphology, as well as performing structural characterization studies using Fourier transform infrared spectroscopy (FT-IR) and differential scanning calorimetry (DSC). The data suggested that the size of the NPs was affected by CS/TPP ratio where the diameter of the NPs ranged from 108.0?±?2.4?nm to 257.2?±?18.6?nm. A correlation between drug EE and the corresponding drug concentration added to the formulation was observed, where the EE of the NPs increased with increasing drug concentration, for up to 10?mg/mL. FT-IR and DSC revealed that KT was dispersed within the NPs where the phosphate groups of TPP were associated with the ammonium groups of CS. The in vitro release profile of KT from CS NPs showed significant differences (p?<?0.05) compared to KT solution. Furthermore, mucoadhesion studies revealed adhesive properties of the formulated NPs. The KT-loaded NPs were found to be stable when stored at different storage conditions for a period of 3 months. The ex vivo corneal permeation studies performed on excised porcine eye balls confirmed the ability of NPs in retaining the drug on the eye surface for a relatively longer time. These results demonstrate the potential of CS-based NPs for the ocular delivery of KT.     

Resistive Switching of Individual,Chemically Synthesized TiO2 Nanoparticles

Resistively switching devices are considered promising for next‐generation nonvolatile random‐access memories. Today, such memories are fabricated by means of “top–down approaches” applying thin films sandwiched between nanoscaled electrodes. In contrast, this work presents a “bottom–up approach” disclosing for the first time the resistive switching (RS) of individual TiO₂ nanoparticles (NPs). The NPs, which have sizes of 80 and 350 nm, respectively, are obtained by wet chemical synthesis and thermally treated under oxidizing or vacuum conditions for crystallization, respectively. These NPs are deposited on a Pt/Ir bottom electrode and individual NPs are electrically characterized by means of a nanomanipulator system in situ, in a scanning electron microscope. While amorphous NPs and calcined NPs reveal no switching hysteresis, a very interesting behavior is found for the vacuum‐annealed, crystalline TiO_2–x NPs. These NPs reveal forming‐free RS behavior, dominantly complementary switching (CS) and, to a small degree, bipolar switching (BS) characteristics. In contrast, similarly vacuum‐annealed TiO₂ thin films grown by atomic layer deposition show standard BS behavior under the same conditions. The interesting CS behavior of the TiO_2–x NPs is attributed to the formation of a core–shell‐like structure by re‐oxidation of the reduced NPs as a unique feature.     

Graphene Quantum Dots Nonmonotonically Influence the Horizontal Transfer of Extracellular Antibiotic Resistance Genes via Bacterial Transformation

Graphene quantum dots (GQDs) coexist with antibiotic resistance genes (ARGs) in the environment. Whether GQDs influence ARG spread needs investigation, since the resulting development of multidrug-resistant pathogens would threaten human health. This study investigates the effect of GQDs on the horizontal transfer of extracellular ARGs (i.e., transformation, a pivotal way that ARGs spread) mediated by plasmids into competent Escherichia coli cells. GQDs enhance ARG transfer at lower concentrations, which are close to their environmental residual concentrations. However, with further increases in concentration (closer to working concentrations needed for wastewater remediation), the effects of enhancement weaken or even become inhibitory. At lower concentrations, GQDs promote the gene expression related to pore-forming outer membrane proteins and the generation of intracellular reactive oxygen species, thus inducing pore formation and enhancing membrane permeability. GQDs may also act as carriers to transport ARGs into cells. These factors result in enhanced ARG transfer. At higher concentrations, GQD aggregation occurs, and aggregates attach to the cell surface, reducing the effective contact area of recipients for external plasmids. GQDs also form large agglomerates with plasmids and thus hindering ARG entrance. This study could promote the understanding of the GQD-caused ecological risks and benefit their safe application.     

Novel drug nanocarriers combining hydrophilic cyclodextrins and chitosan

The aim of this study was to explore the possibility of obtaining nanoparticles (NPs) containing high amounts of cyclodextrin (CD) derivatives such as carboxymethyl-β-CD and sulphobutyl ether-β-CD. The rationale used was to combine the drug solubilizing and stabilizing properties of cyclodextrins (CDs) with the mucoadhesive properties of chitosan (CS) in a unique nanoparticulate drug delivery system. The size of the resulting NPs was affected by the nature of the CDs, ranging between 275 and 550?nm, whereas the zeta potential of the NPs was always positive and close to +35?mV. The positive zeta values, together with the results from NMR studies, suggest that CS is the major compound on the surface of the NPs, while CD molecules are strongly associated with the NP matrix. The empirical composition of the NPs was quantified by elemental analysis and the results indicated that the amount of CD associated with the NPs was strictly dependent on its electrostatic charge. Finally, in vitro stability studies indicated that the presence of CDs in the NP structure can prevent the aggregation of this nanometric carrier system in simulated intestinal fluid. Overall, this new type of NP represents an attractive drug delivery platform of particular interest for the oral administration of drugs with low bioavailability.     

New method based on capillary electrophoresis with laser-induced fluorescence detection (CE-LIF) to monitor interaction between nanoparticles and the amyloid-β peptide

A novel application of capillary electrophoresis with laser-induced fluorescence detection (CE-LIF) was proposed to efficiently detect and monitor the interaction between polymeric nanoparticles and the β-Amyloid peptide (Aβ(1-42)), a biomarker for Alzheimer's Disease (AD), at concentrations close to physiological conditions. The CE-LIF method allowed the interaction between PEGylated poly(alkyl cyanoacrylate) nanoparticles (NPs) and the soluble Aβ(1-42) peptide monomers to be highlighted. These results were confirmed by surface plasmon resonance (SPR) and confocal laser scanning microscopy (CLSM). Whereas SPR showed an interaction between the NPs and the Aβ(1-42) peptide, CLSM allowed the formation of large aggregates/assemblies at high NP and peptide concentrations to be visualized. All these results suggested that these nanoparticles could bind the Aβ(1-42) peptide and influence its aggregation kinetics. Interestingly, the non-PEGylated poly(alkyl cyanoacrylate) NPs did not alter the aggregation kinetics of the Aβ(1-42) peptide, thus emphasizing the high level of discrimination of the CE-LIF method with respect to NPs.     

High‐Performance Flexible Organic Nano‐Floating Gate Memory Devices Functionalized with Cobalt Ferrite Nanoparticles

Nano‐floating gate memory (NFGM) devices are transistor‐type memory devices that use nanostructured materials as charge trap sites. They have recently attracted a great deal of attention due to their excellent performance, capability for multilevel programming, and suitability as platforms for integrated circuits. Herein, novel NFGM devices have been fabricated using semiconducting cobalt ferrite (CoFe₂O₄) nanoparticles (NPs) as charge trap sites and pentacene as a p‐type semiconductor. Monodisperse CoFe₂O₄ NPs with different diameters have been synthesized by thermal decomposition and embedded in NFGM devices. The particle size effects on the memory performance have been investigated in terms of energy levels and particle–particle interactions. CoFe₂O₄ NP‐based memory devices exhibit a large memory window (≈73.84 V), a high read current on/off ratio (read I_on/I_off) of ≈2.98 × 10³_, and excellent data retention. Fast switching behaviors are observed due to the exceptional charge trapping/release capability of CoFe₂O₄ NPs surrounded by the oleate layer, which acts as an alternative tunneling dielectric layer and simplifies the device fabrication process. Furthermore, the NFGM devices show excellent thermal stability, and flexible memory devices fabricated on plastic substrates exhibit remarkable mechanical and electrical stability. This study demonstrates a viable means of fabricating highly flexible, high‐performance organic memory devices.     

Neuroprotective Effect of Nerve Growth Factor Loaded in Porous Silicon Nanostructures in an Alzheimer's Disease Model and Potential Delivery to the Brain

Nerve growth factor (NGF) plays a vital role in reducing the loss of cholinergic neurons in Alzheimer's disease (AD). However, its delivery to the brain remains a challenge. Herein, NGF is loaded into degradable oxidized porous silicon (PSiO₂) carriers, which are designed to carry and continuously release the protein over a 1 month period. The released NGF exhibits a substantial neuroprotective effect in differentiated rat pheochromocytoma PC12 cells against amyloid‐beta (Aβ)‐induced cytotoxicity, which is associated with Alzheimer's disease. Next, two potential localized administration routes of the porous carriers into murine brain are investigated: implantation of PSiO₂ chips above the dura mater, and biolistic bombardment of PSiO₂ microparticles through an opening in the skull using a pneumatic gene gun. The PSiO₂‐implanted mice are monitored for a period of 8 weeks and no inflammation or adverse effects are observed. Subsequently, a successful biolistic delivery of these highly porous microparticles into a live‐mouse brain is demonstrated for the first time. The bombarded microparticles are observed to penetrate the brain and reach a depth of 150 µm. These results pave the way for using degradable PSiO₂ carriers as potential localized delivery systems for NGF to the brain.     

Evaluation of liposomal behavior in the gastrointestinal tract after oral administration using real-time in vivo imaging

Liposomes are regarded as promising drug carriers for enhancing the pharmacological effects of poorly absorbed drugs, such as peptides, following oral administration. Liposomal surface modifications by mucoadhesive polymers could improve drug absorption through interactions with the mucus layer. The main purpose of this study was to establish a method of monitoring the behavior of liposomes within the body after oral administration, particularly in the gastrointestinal (GI) tract, using a real-time in vivo imaging system (IVIS) to elucidate the behavior of surface-modified liposomes. Indocyanine green (ICG) was used as a near-infrared dye to label chitosan (CS) or glycol CS (GCS)-modified liposomes, and to observe the dynamic behavior of the liposomes in rats by noninvasive IVIS after oral administration. First, we validated IVIS results of the rat abdomens by comparing them to quantitative measurements of ICG fluorescence intensity in tissue homogenates. Nano-sized small unilamellar vesicles were retained longer than micro-sized multilamellar vesicles in the GI tract. Furthermore, surface-modified liposomes showed longer-term retention in the GI tract than unmodified liposomes in fasted rats. Moreover, surface modification by CS or GCS effectively prevented the excretion of liposomes from the GI tract and prolonged retention in fed rats.     

A Reactive Oxygen Species-Responsive Targeted Nanoscavenger to Promote Mitophagy for the Treatment of Alzheimer's Disease

Mitophagy modulators are proposed as potential therapeutic intervention that enhance neuronal health and brain homeostasis in Alzheimer's disease (AD). Nevertheless, the lack of specific mitophagy inducers, low efficacies, and the severe side effects of nonselective autophagy during AD treatment have hindered their application. In this study, the P@NB nanoscavenger is designed with a reactive-oxygen-species-responsive (ROS-responsive) poly(l -lactide-co-glycolide) core and a surface modified with the Beclin1 and angiopoietin-2 peptides. Notably, nicotinamide adenine dinucleotide (NAD⁺) and Beclin1, which act as mitophagy promoters, are quickly released from P@NB in the presence of high ROS levels in lesions to restore mitochondrial homeostasis and induce microglia polarization toward the M2-type, thereby enabling it to phagocytose amyloid-peptide (Aβ). These studies demonstrate that P@NB accelerates Aβ degradation and alleviates excessive inflammatory responses by restoring autophagic flux, which ameliorates cognitive impairment in AD mice. This multitarget strategy induces autophagy/mitophagy through synergy, thereby normalizing mitochondrial dysfunction. Therefore, the developed method provides a promising AD-therapy strategy.     

RES‐loaded pegylated CS NPs: for efficient ocular delivery

The objective of this study is to develop resveratrol (RES) loaded polyethylene glycols (PEGs) modified chitosan (CS) nanoparticles (NPs) by ionic gelation method for the treatment of glaucoma. While increasing the concentration of PEG, the particle size and polydispersity index of the formulations increased. Entrapment efficiency and RES loading (RL) of NPs decreased while increasing PEG concentration. The in vitro release of NPs showed an initial burst release of RES (45%) followed by controlled release. Osmolality of formulations revealed that the prepared NPs were iso‐osmolar with the tear. Ocular tolerance of the NPs was evaluated using hen''s egg test on the chorioallantoic membrane and it showed that the NPs were non‐irritant. RES‐loaded PEG‐modified CS NPs shows an improved corneal permeation compared with RES dispersion. Fluorescein isothiocyanate loaded CS NPs accumulated on the surface of the cornea but the PEG‐modified CS NPs crossed the cornea and reached retinal choroid. RES‐loaded PEG‐modified CS NPs reduced the intra‐ocular pressure (IOP) by 4.3 ± 0.5 mmHg up to 8 h in normotensive rabbits. These results indicate that the developed NPs have efficient delivery of RES to the ocular tissues and reduce the IOP for the treatment of glaucoma.Inspec keywords: conducting polymers, nanoparticles, nanomedicine, drug delivery systems, particle size, nanofabrication, organic compounds, biomembranes, cellular biophysics, eye, vision defects, biological tissuesOther keywords: RES‐loaded pegylated CS NP, efficient ocular delivery, resveratrol loaded polyethylene glycol modified chitosan nanoparticles, ionic gelation method, glaucoma treatment, particle size, polydispersity index, entrapment efficiency, RES loading, PEG concentration, in vitro release, osmolality formulations, ocular tolerance, hen egg testing, chorioallantoic membrane, improved corneal permeation, RES dispersion, fluorescein isothiocyanate loaded CS NP, cornea surface, reached retinal choroid, intraocular pressure, normotensive rabbits, RES delivery, ocular tissues     

Nonvolatile memory characteristics of solution-processed oxide thin-film transistors using Ag nanoparticles

We developed a nonvolatile memory device based on a solution-processed oxide thin-film transistor (TFT) with Ag nanoparticles (NPs) as the charge trapping layer. We fabricated the device using a soluble MgInZnO active channel on a SiO₂ gate dielectric, Ag NPs as a charge trapping site at the gate insulator-channel interface, and Al for source and drain electrodes.The transfer characteristics of the device showed a high level of clockwise hysteresis that can be used to demonstrate its memory function, due to electron trapping in the Ag NPs charge trapping layer. A large memory window (?V_th) was observed with a forward and backward gate voltage sweep, and this memory window was increased in size by increasing the gate voltage sweep. These results show the potential application of memory on displays and disposable electronics.     

Brain pharmacokinetics of neurotoxin-loaded PLA nanoparticles modified with chitosan after intranasal administration in awake rats

Context: Neurotoxin (NT), an analgesic peptide which was separated from the venom of Naja naja atra, is endowed an exceptional specificity of action that blocks transmission of the nerve impulse by binding to the acetylcholine receptor in the membrane. However, it has limited permeability across the blood-brain barrier (BBB).

Objective: The purpose of this study was to encapsulate NT within polylactic acid (PLA) nanoparticles (NPs) modified with chitosan (NT-PLA-cNPs) and to evaluate their brain pharmacokinetic behaviors after intranasal (i.n.) administration using a microdialysis technique in free-moving rats.

Methods: NT-PLA-cNPs (NT labeled with fluorescein isothiocyanate) were prepared and characterized. Then, NT-PLA-cNPs were i.n. administered to rats and the fluorescence intensity in the periaqueductal gray (PAG) was monitored for up to 480?min, with NT-PLA-NPs and NT solution as control groups.

Results: The NPs prepared were spherical with a homogenous size distribution. The mean particle size, zeta potential, and entrapment efficiency were 140.5?±?5.4?nm, +33.71?±?3.24 mV, and 83.51?±?2.65%, respectively. The brain transport results showed that T_max of NT-PLA-cNPs was equal with that of NT-PLA-NPs after i.n. administration (150?min). The C_max and AUC_{0–8 h} of each group followed the following order: NT-PLA-cNPs > NT-PLA-NPs. The corresponding absolute bioavailability (F_abs) of NT-PLA-cNPs was about 151% with NT-PLA-NPs as reference preparations.

Conclusion: These results suggest that NPs modified with chitosan have better brain targeting efficiency and are a promising approach for i.n. delivery of large hydrophilic peptides and proteins in improving the treatment of central nervous system (CNS) disorders.     

A novel vehicle for local protein delivery to the inner ear: injectable and biodegradable thermosensitive hydrogel loaded with PLGA nanoparticles

Delivery of biomacromolecular drugs into the inner ear is challenging, mainly because of their inherent instability as well as physiological and anatomical barriers. Therefore, protein-friendly, hydrogel-based delivery systems following local administration are being developed for inner ear therapy. Herein, biodegradable poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) containing interferon α-2?b (IFN α-2?b) were loaded in chitosan/glycerophosphate (CS/GP)-based thermosensitive hydrogel for IFN delivery by intratympanic injection. The injectable hydrogel possessed a physiological pH and formed semi-solid gel at 37?°C, with good swelling and deswelling properties. The CS/GP hydrogel could slowly degrade as visualized by scanning electron microscopy (SEM). The presence of NPs in CS/GP gel largely influenced in vitro drug release. In the guinea pig cochlea, a 1.5- to 3-fold increase in the drug exposure time of NPs-CS/GP was found than those of the solution, NPs and IFN-loaded hydrogel. Most importantly, a prolonged residence time was attained without obvious histological changes in the inner ear. This biodegradable, injectable, and thermosensitive NPs-CS/GP system may allow longer delivery of protein drugs to the inner ear, thus may be a potential novel vehicle for inner ear therapy.