Polymeric nanofibers as novel carriers for the delivery of therapeutic molecules

Nanotechnology and nanoscience are relatively new technological endeavors that encompass the study, control, manipulation, and assembly of multifarious nanoscale components into materials, systems and devices to serve human interest and needs. Among the various currently used nanostructures for high technology applications polymeric nanofibers have received immense interest due to the ease of fabrication, controllable size/shape, and properties. Polymeric nanofibers have been extensively investigated for diversified applications, including filtration, barrier fabrics, wipes, personal care, biomedical, and pharmaceutical applications. This review mainly focuses on the fabrication of therapeutic agent loaded polymeric nanofibers and their controlled/sustained release behavior for the delivery of these active agents for various therapeutic applications. The nonwoven biodegradable polymeric nanofiber matrices are currently being reported as topical/local therapeutic agent delivery systems and as resorbable/biodegradable gauze for wound healing applications.     

Polymeric micelles modified by folate-PEG-lipid for targeted drug delivery to cancer cells in vitro

A novel technique was developed for the formation of ligand-targeted polymeric micelles that can be applicable to various ligands. For tumor-specific drug delivery, camptothecin (CPT)-loaded polymeric micelles were modified by folate to produce a folate-receptor-targeted drug carrier. Folate-linked PEG5000-distearoylphosphatidylethanolamine (folate-PEG5000-DSPE) was added when preparations of drug-loaded polymeric micelles, resulting in folate ligands exposed to the surface. Folate-modified CPT-loaded polymeric micelles (F-micelle) were evaluated by measuring cellular uptake using a flow cytometer, fluorescence microscopy, and confocal laser scanning microscopy, and by cytotoxicity measurement. The results revealed that F-micelle showed higher cellular uptake in KB cells overexpressing folate receptor (FR) and higher cytotoxicity compared with non-folate modified CPT-loaded polymeric micelles (plain micelles) in KB cells, but not in FR-negative HepG2 cells. This result indicated that polymeric micelles were successfully modified by the folate-linked lipid.     

Functionalized nano-magnetic particles for an in vivo delivery system

Nanotechnologies to allow the nondisruptive introduction of carriers in vivo have wide potential for therapeutic delivery system. We have prepared functional nano-magnetic particles (d = 3 nm) by silanization with (3-aminopropyl) triethoxysilane. For the purpose of functionalizing the surface of the nanoparticles with amino groups for subsequent cross-linking with pharmaceuticals and biomolecules. The extremely small particles were successfully introduced into living cells without any further modification to enhance endocytic internalization, such as the use of a cationic help. The cells containing the internalized particles continued to thrive, indicating that the particles have no inhibition effect for mitosis. In addition, the particles could be incorporated into the subcutaneous tissue of mouse's ear from ear skin and were able to be localized upon application of an external magnetic field. The functionalized nano-magnetic particles are expected to be useful as a new delivery tool.     

Increased absorption of mangiferin in the gastrointestinal tract and its mechanism of action by absorption enhancers in rats

The therapeutic efficiency of mangiferin is restricted by its low intestinal permeability. In order to improve the oral absorption of mangiferin, potential of enhancers, including TPGS, sodium deoxycholate and Carbopol 974P, were investigated in a series of in vivo experiments. After administration of mangiferin at a dose of 30?mg/kg combining with sodium deoxycholate, the bioavailability of mangiferin increased four-fold, and this may be due to sodium deoxycholate weakening the compactness between lecithin molecules and increased the paracellular permeability. When Carbopol 974P (100?mg/kg) was combined with mangiferin, the oral bioavailability of it increased seven-fold compared with the control group, and this may be related to the mucoadhesive properties of Carbopol 974P and paracellular drug permeation. However, following coadministration of TPGS (50?mg/kg), the oral absorption of mangiferin increased slightly compared with that of the control group (p > 0.05). The increased oral absorption by the three coexcipients was in the order of Carbopol 974P > sodium deoxycholate > TPGS. The absolute bioavailability of mangiferin in the three different doses following oral administration were evaluated based on the AUC_(0–t) of the intravenous dose and there was no increase from low doses to high doses (25?mg/kg to 100?mg/kg). The above results show that the low absorption of mangiferin was due to presence of a narrow absorption window, which may also exist in these compounds, which have structures similar to mangiferin including three fused aromatic rings with polyphenolic hydroxyl groups. Bioadhesion polymers are effective enhancers of the absorption of mangiferin in the gastrointestinal tract.     

Bio-inspired solutions for locomotion in the gastrointestinal tract: background and perspectives

This paper illustrates a bio-inspired approach to effective, smooth and safe navigation in the human body and, in particular, in the gastrointestinal tract. This idea originates from the medical need to develop more powerful tools for microendoscopy, which is one of the most challenging frontiers of modern medicine. Understanding motion and perception systems of lower animal forms, such as parasites, worms, insects and snakes, can help to design and fabricate bio-inspired robots able to navigate in tortuous, slippery and difficult-to-access cavities of the human body. A preliminary study of a biomimetic adhesion system for the human tissues is presented in this work and some technological implementations are illustrated and discussed. Finally, some issues concerning the goals of smart and reactive locomotion are considered and the most promising and relevant enabling technologies are discussed.     

用于肺部给药的壳聚糖空心微球的制备

采用壳聚糖为壁材、烷基多糖苷为赋形剂通过喷雾干燥的方法成功制备出了可用于肺部给药的空心载药微球,其粒径在10μm左右。采用扫描电子纤维镜观察了所得粒子的形貌,并分析了喷雾干燥条件下得到这种薄壁空心结构的原理。     

Evaluation of microporous polycaprolactone matrices for controlled delivery of antiviral microbicides to the female genital tract

Acyclovir (ACV) as a model antiviral microbicide, was incorporated in controlled-release polycaprolactone (PCL) matrices designed for application as intra-vaginal ring inserts (IVRs). Microporous materials incorporating acyclovir up to a level of ~10 % w/w were produced by rapidly cooling suspensions of drug powder in PCL solution followed by solvent extraction from the hardened matrices. Around 21, 50 and 78 % of the drug content was gradually released from matrices over 30 days in simulated vaginal fluid at 37 °C, corresponding to drug loadings of 5.9, 7.0 and 9.6 % w/w. The release behaviour of matrices having the lowest drug loading followed a zero order model, whereas, the release kinetics of 7.0 and 9.6 % ACV-loaded PCL matrices could be described effectively by the Higuchi model, suggesting that Fickian diffusion is controlling drug release. Corresponding values of the diffusion co-efficient for ACV in the PCL matrices of 3.16 × 10^?9 and 1.07 × 10^?8 cm²/s were calculated. Plaque reduction assays provided an IC₅₀ value of 1.09 μg/mL for acyclovir against HSV-2 and confirmed the antiviral activity of released acyclovir against HSV-2 replication in primate kidney cells (Vero) at levels ~70 % that of non-formulated acyclovir at day 30. Estimated minimum in vivo acyclovir concentrations produced by a PCL IVR (19 μg/mL) exceeded by a factor of 20 the IC₅₀ value against HSV-2 and the reported ACV vaginal concentrations in women (0.5–1.0 μg/mL) following oral administration. These findings recommend further investigations of PCL matrices for vaginal delivery of antiviral agents in the treatment and prevention of sexually transmitted infections such as AIDS.     

Novel electrohydrodynamic preparation of porous chitosan particles for drug delivery

Uniform spherical chitosan particles of size <10 μm in diameter are important in drug delivery applications due to their excellent biocompability and biodegradability. A high concentration of chitosan in the particles can help to control the release of drugs and methods for processing high viscosity chitosan solutions are therefore required. In principle, any type of polymer, whether hydrophobic or hydrophilic, can be electrosprayed to obtain monodisperse particles of diameter <10 μm. In practice, however, electrospraying of biopolymers having viscosities of >100 mPa s results in particles >10 μm diameter. In this study, by reducing surface tension of a high viscosity chitosan suspension, it was found that smaller diameter particles could be prepared. Chitosan solutions were electrosprayed in the stable cone-jet mode to systematically study the relationship between particle diameter, viscosity and surface tension. Increasing viscosity resulted in larger diameter particles with a broad size distribution, but decreasing surface tension had the opposite effect. Results show that a chitosan solution having a viscosity of ~80 mPa s can be used to prepare chitosan particles of diameter ~2.5 μm which on drying reduced to particles of 500 nm.     

Biomechanical functional and sensory modelling of the gastrointestinal tract

The aim of this review is to describe the biomechanical, functional and sensory modelling work that can be used to integrate the physiological, anatomical and medical knowledge of the gastrointestinal (GI) system. The computational modelling in the GI tract was designed, implemented and evaluated using a series of information and communication technologies-based tools. These tools modelled the morphometry, biomechanics, functions and sensory aspects of the human GI tract. The research presented in this review is based on the virtual physiological human concept that pursues a holistic approach to representation of the human body. Such computational modelling combines imaging data, GI physiology, the gut-brain axis, geometrical and biomechanical reconstruction, and computer graphics for mechanical, electronic and pain analysis. The developed modelling will aid research and ensure that medical professionals benefit through the provision of relevant and precise information about a patient's condition. It will also improve the accuracy and efficiency of the medical procedures that could result in reduced cost for diagnosis and treatment.     

Preparation and characterization of thermosensitive submicron particles for gene delivery

In this study, a new thermosensitive material was proposed as a carrier for gene delivery. The thermosensitive submicron particles were synthesized by the dispersion copolymerization of N-isopropylacylamide (NIPA) with a relatively new, cationic comonomer, N-3-dimethylaminopropylmethacrylamide (DMAPM) with higher ionization ability with respect to the commonly used cationic comonomers. To achieve particle sizes smaller than 1 microm, suitable for gene delivery, the total monomer concentration in the dispersion copolymerization was kept at a sufficiently low level. The size of poly(NIPA-co-DMAPM) particles was determined as 454 nm, by AFM in dry state. The poly(NIPA-co-DMAPM) particles showed both temperature and pH sensitivity in the aqueous media.The plasmid DNA adsorption onto the thermosensitive cationic particles was investigated at different temperatures and pHs. The adsorbed amount of plasmid DNA onto the particles was significantly increased by the introduction of cationic comonomer. The equilibrium plasmid DNA adsorptions up to 13 mg/g dry particles were achieved at physiological pH. Approximately 36% w/w of adsorbed plasmid could be desorbed from the cationic nanolatex. The results of biocompatibility studies performed with mouse fibroblast cells showed the suitability of thermosensitive cationic particles for intended application.     

Adsorption of nonlamellar nanostructured liquid-crystalline particles to biorelevant surfaces for improved delivery of bioactive compounds

The adsorption of nanostructured lyotropic liquid-crystal particles, cubosomes and hexosomes, at surfaces was investigated for potential use in surface-specific agrochemical delivery. Adsorption of phytantriol (PHYT) and glyceryl monooleate (GMO)-based cubosomes and hexosomes, stabilized using Pluronic F127, at tristearin-coated (model leaf surface) and uncoated zinc selenide surfaces was studied using attenuated total reflectance Fourier transform IR (ATR-FTIR) spectroscopy, by quantifying the IR absorbance due to the lipid components of the particles over time. The delivery of an encapsulated hydrophobic model herbicide [dichlorodiphenyldichloroethylene (DDE)] was also examined on the model and real leaf surfaces. The adsorption behavior of the particles by ATR-FTIR was dependent on the internal nanostructure and lipid composition, with PHYT cubosomes adsorbing more avidly at tristearin surfaces than GMO-based cubosomes or hexosomes. There was a direct correlation between DDE associated with the surfaces and the particle adsorption observed in the ATR-FTIR study, strongly implicating particle adsorption with the delivery efficiency. Differences between the mode of interaction of the Pluronic stabilizer with the different lipids and particle nanostructures were proposed to lead to differences in the particle adsorption behavior.     

Two-layered dissolving microneedles for percutaneous delivery of sumatriptan in rats

A novel transdermal delivery of sumatriptan (ST) was attempted by application of dissolving microneedle (DM) technology. Dextran DM (d-DM) and hyaluronate DM (h-DM) were prepared by adding ST solution to dextran solution or hyaluronic acid solution. One DM chip, 1.0?×?1.0?cm, contains 100 microneedle arrays in a 10?×?10 matrix. The mean lengths of DMs were 496.6?±?2.9 μm for h-DM and 494.5?±?1.3 μm for d-DM. The diameters of the array basement were 295.9?±?3.9 μm (d-DM) and 291.7?±?3.0 μm (h-DM), where ST contents were 31.6?±?4.5?μg and 24.1?±?0.9?μg. These results suggest that ST was stable in h-DM. Each DM was administered to rat abdominal skin. The maximum plasma ST concentrations, Cmax, and the areas under the plasma ST concentration versus time curves (AUC) were 44.6?±?4.9?ng/ml and 24.6?±?3.9?ng · h/ml for h-DM and 38.4?±?2.7?ng/ml and 14.1?±?1.5?ng · h/ml for d-DM. The bioavailabilities of ST from DMs were calculated as 100.7?±?18.8% for h-DM and 93.6?±?10.2% for d-DM. Good dose dependency was observed on Cmax and AUC. The stability study of ST in DM was performed for 3 months under four different conditions, ?80, 4, 23, and 50°C. At the end of incubation period, they were, respectively, 100.0?±?0.3%, 97.8?±?0.2%, 98.8?±?0.2%, and 100.7?±?0.1%. These suggest the usefulness of DM as a noninvaisive transdermal delivery system of ST to migraine therapy.     

Two-layered dissolving microneedles for percutaneous delivery of sumatriptan in rats

A novel transdermal delivery of sumatriptan (ST) was attempted by application of dissolving microneedle (DM) technology. Dextran DM (d-DM) and hyaluronate DM (h-DM) were prepared by adding ST solution to dextran solution or hyaluronic acid solution. One DM chip, 1.0?×?1.0?cm, contains 100 microneedle arrays in a 10?×?10 matrix. The mean lengths of DMs were 496.6?±?2.9 μm for h-DM and 494.5?±?1.3 μm for d-DM. The diameters of the array basement were 295.9?±?3.9 μm (d-DM) and 291.7?±?3.0 μm (h-DM), where ST contents were 31.6?±?4.5?μg and 24.1?±?0.9?μg. These results suggest that ST was stable in h-DM. Each DM was administered to rat abdominal skin. The maximum plasma ST concentrations, C_max, and the areas under the plasma ST concentration versus time curves (AUC) were 44.6?±?4.9?ng/ml and 24.6?±?3.9?ng · h/ml for h-DM and 38.4?±?2.7?ng/ml and 14.1?±?1.5?ng · h/ml for d-DM. The bioavailabilities of ST from DMs were calculated as 100.7?±?18.8% for h-DM and 93.6?±?10.2% for d-DM. Good dose dependency was observed on C_max and AUC. The stability study of ST in DM was performed for 3 months under four different conditions, ?80, 4, 23, and 50°C. At the end of incubation period, they were, respectively, 100.0?±?0.3%, 97.8?±?0.2%, 98.8?±?0.2%, and 100.7?±?0.1%. These suggest the usefulness of DM as a noninvaisive transdermal delivery system of ST to migraine therapy.     

Stress intensity factor for a three-layered plate with a crack in the center layer

The objective of this study is to model the laminated composite as a multilayered plate each layer being made of a different material. With a crack in the mid-layer of the laminate, the stresses can vary in all three space coordinate directions and the problem is recognized as a three-dimensional one. A laminate plate theory is developed by application of the minimum complementary energy theorem in variational calculus such that the qualitative three-dimensional character of the crack edge stresses is retained while approximations are made in a quantitative sense on the stress intensity factor.Numerical values of the stress intensity factors for different construction of the laminate are reported and compared with the same size plate made of a single homogeneous material. When the modulus of elasticity of the middle layer which contains the crack is lower than that of the outer layers, the load transmission to the crack site as measured by the stress intensity factor can be reduced significantly. The present model assumes failure by crack propagation in only one layer of the laminate. Other possible modes of failure such as cohesive and/or adhesive fracture in laminated structures have yet to be explored.     

1,3-Dicyclohexyl urea nanosuspension for intravenous steady-state delivery in rats

Aqueous insolubility is recognized throughout the pharmaceutical industry as a major hurdle for pre-clinical and clinical drug delivery. Pre-clinical, early efficacy, and proof of concept studies oftentimes rely on model compounds that have less than ideal physiochemical properties, and the in vivo results from these studies often have critical impact on the future of the project. As such, effective delivery of prototype compounds with sub-optimal properties is important in target validation. 1,3-Dicyclohexyl urea (DCU), a potent inhibitor of soluble epoxide hydrolase (sEH) has been shown to lower systemic blood pressure in spontaneously hypertensive rats. This compound has limited aqueous solubility that makes in vivo delivery difficult. In such situations, co-solvents, complexation reagents, and emulsions are commonly used to increase the bioavailability of a prototype compound. However, these approaches are often limited by their capacity to get and keep a compound in solution and can have unwanted placebo effects, which can confound the interpretation of animal efficacy results. Nanosuspension formulations of DCU have been utilized for both intravenous injection and infusion to reach steady-state (Css) plasma concentrations in rat enabling the investigation of the target, chemistry space, and PK/PD in a timely manner without encountering confounding efficacy results.     

Formulation and in vivo evaluation of effervescent inhalable carrier particles for pulmonary delivery of nanoparticles

The purpose of this study was to evaluate the safety of a new inhalable effervescent carrier preparation containing model nanoparticles. Spray-freeze drying was used to prepare inhalable powders containing butylcyanoacrylate nanoparticles. The particle size of the nanoparticles before incorporation into the effervescent carrier and after dissolving the carrier powder was measured using laser light scattering. The particle size distribution of the effervescent carrier aerosol particles was measured using a cascade impactor. The prepared powder was tested in vivo using five Balb/c nude mice. The animals were treated with 1 mg of inhalable powder every week for 4 weeks. The body weight and morbidity score of the mice were observed over an 8-week period. The effervescent activity of the inhalable nanoparticle powder was observed when the powder was exposed to humidity. The particle size of the nanoparticles did not change significantly after spray-freeze drying. The mass median aerodynamic diameter (MMAD) of the prepared powder was 4.80 +/- 2.12 microm, which is suitable for lung delivery. The animals that were treated with effervescent powder tolerated the administration without any changes in their morbidity scores. Our pilot study demonstrates that pulmonary nanoparticle delivery via effervescent carrier particles appears safe in the present animal model.     

Nano-carrier mediated co-delivery of methyl prednisolone and minocycline for improved post-traumatic spinal cord injury conditions in rats

Objective: The objective of this study is to investigate the fate of albumin coupled nanoparticulate system over non-targeted drug carrier in the treatment of hemisectioned spinal cord injury (SCI).

Significance: Targeted delivery of methyl prednisolone (MP) and minocycline (MC) portrayed improved therapeutic efficacy as compared with non-targeted nanoparticles (NPS).

Methods: Albumin coupled, chitosan stabilized, and cationic NPS (albumin-MP?+?MC???NPS) of poly-(lactide-co-glycolic acid) were prepared using the emulsion solvent evaporation method. Prepared NPS were characterized for drug entrapment efficiency, particle size, poly-dispersity index (PDI), zeta potential, and morphological characteristics. Their evaluation was done based on the pharmaceutical, toxicological, and pharmacological parameters.

Results and discussion: In vitro release of MP?+?MC from albumin-MP?+?MC???NPS and MP?+?MC???NPS was observed to be very controlled for the period of eight days. Cell viability study portrayed non-toxic nature of the developed NPS. Albumin-MP?+?MC???NPS showed prominent anti-inflammatory potential as compared with non-targeted NPS (MP?+?MC???NPS) when studied in LPS-induced inflamed astrocytes. Albumin-MP?+?MC???NPS reduced lesional volume and improved behavioral outcomes significantly in rats with SCI (hemisectioned injury model) when compared with that of MP?+?MC???NPS.

Conclusions: Albumin-coupled NPS carrier offered an effective method of SCI treatment following safe co-administration of MP and MC. The in vitro and in vivo effectiveness of MP?+?MC was improved tremendously when compared with the effectiveness showed by MP?+?MC???NPS. That could be attributed to the site specific, controlled release of MP?+?MC to the inflammatory site.     

Effect of simulated gastrointestinal conditions on drug release from pectin/ethylcellulose as film coating for drug delivery to the colon

The aim of this work was to investigate the effect of acidic pH representative of gastric fluid on the release of 5-aminosalicylic acid from beads coated with pectin/ethylcellulose as film coating intended for drug delivery to the colon, in media mimicking the lower gastrointestinal (GI) tract and representative of colonic conditions. In this work, the in vitro incubation of the beads in acid medium was found to influence the hydration and the swelling characteristics of pectin after transfer into simulated intestinal fluid and simulated cecal fluid containing pectinolytic enzymes. Moreover, the drug release profiles from the beads in simulated intestinal fluid after incubation for 2 h or 30 min in simulated gastric fluid vs. no acid incubation were found to be very different. The in vitro degradation of pectin in the coat by pectinolytic enzymes in simulated cecal fluid depended on whether the beads were placed in simulated gastric fluid prior to testing in simulated intestinal fluid. The percentage drug release also depended on the ratio of pectin to ethylcellulose in the coat.