Analytical characterization of chitosan nanoparticles for peptide drug delivery applications

Chitosan-cyclodextrin hybrid nanoparticles (NPs) were obtained by the ionic gelation process in the presence of glutathione (GSH), chosen as a model drug. NPs were characterized by means of transmission electron microscopy and zeta-potential measurements. Furthermore, a detailed X-ray photoelectron spectroscopy study was carried out in both conventional and depth-profile modes. The combination of controlled ion-erosion experiments and a scrupulous curve-fitting approach allowed for the first time the quantitative study of the GSH in-depth distribution in the NPs. NPs were proven to efficiently encapsulate GSH in their inner cores, thus showing promising perspectives as drug carriers.     

Surface modification of quantum dots and magnetic nanoparticles with PEG-conjugated chitosan derivatives for biological applications

In this paper, amphiphilic chitosan derivatives (N-octyl-N-mPEG-chitosan, mPEG = poly(ethylene glycol) monomethyl ether; OPEGC) were successfully synthesised via the Schiff base reduction reaction of chitosan and mPEG-aldehyde, or octanal, with chitosan acting as the backbone of the grafted copolymers, and mPEG-aldehyde providing the hydrophilic chain or octanal providing the hydrophobic alkyl chain. The synthesis was confirmed by characterisation employing Fourier transform infrared spectroscopy (FTIR) and ¹H NMR. In the subsequent procedure, water-soluble quantum dots (QDs) and iron(II,III) oxide (IO) nanoparticles, widely used as nanoprobes in medical applications, were produced by the incorporation of QDs or IO inside the polymeric micelle core. Finally, the optical properties of QDs incorporated into OPEGC (OPEGC@QDs) were characterised by UV-VIS spectroscopy, fluorescence spectroscopy, cell viability was obtained through MTT, and the morphology of their assembly formed in water were observed by atomic force microscope (AFM) and transmission electron microscope (TEM) and the QDs content of OPEGC@QDs was calculated following thermo gravimetric analysis (TGA). In addition, the properties of IO incorporated into OPEGC (OPEGC@IO) were characterised by vibrating sample magnetometry (VSM), FT-IR, MTT, TGA, AFM, and TEM. The results indicated that the OPEGC composite nanoparticles with size narrowly distributed, good water solubility, and low cytotoxicity were prepared here, which represented a high quantum yield or good super-paramagnetism.     

Surface modification of cellulose with plant triglycerides for hydrophobicity

Hydrophobic cotton was achieved by surface modification of the cellulose with triglycerides from several plant oils including soybean, rapeseed, olive and coconut oils. These oils were delivered to the cellulose substrates in homogeneous solutions of ethanol or acetone as well as aqueous emulsions. Surface modification was facilitated by solvent evaporation followed by heating between 110 and 120 °C for 60 min. All oils, except for coconut, produced hydrophobic and less water-absorbing cotton, supporting the desirable role of higher unsaturation in the fatty acids to achieve crosslinked network. The most hydrophobic surfaces were obtained by the reaction with 1% soybean oil in acetone. On both bleached and scoured cotton, a water contact angle of 80° and water absorption value of 0.82 μL/mg were achieved. The acquired hydrophobicity was not only retained after water washing but also improved with subsequent exposures to elevated temperatures. The surface tension of scoured cotton cellulose was lowered from 63.81 mJ/m² to 25.74 mJ/m² when modified by soybean oil delivered in acetone, which is lower than that of poly(ethylene terephthalate). An aqueous emulsion of soybean oil also rendered the scoured cotton hydrophobic, which shows promise for a green chemistry and bio-based approach to achieve water repellency on cellulosic materials.     

Surface chemical modification of microfibrillated cellulose: improvement of barrier properties for packaging applications

Heterogeneous acetylation of microfibrillated cellulose (MFC) was carried out to modify its physical properties and at the same time to preserve the morphology of cellulose fibrils. The overall reaction success was assessed by FTIR together with the degree of substitution (DS) defined by titration and the degree of surface substitution (DSS) evaluated by means of XPS. Dynamic contact angle measurements confirmed the hydrophobicity improvement relative to non-modified samples. The increase of contact angle upon reaching a certain reaction time and some decrease following the further acetylation was confirmed. Mechanical properties of MFC films made from chemically modified material were evaluated using tensile strength tests which showed no significant reduction of tensile strength. According to SEM images, dimension analysis and tensile strength data, the acetylation seemed not to affect the morphology of cellulose fibrils.     

Surface modification of natural cellulose substances:toward functional materials and applications

Combining various synthetic chemical processes and biological assemblies provides a promising strategy for the design and fabrication of functional materials with tailored structures and properties.The unique multilevel structures and morphologies of natural cellulose substances such as ordinary commercial laboratory filter paper make them ideal platforms for the self-assemblies of various functional guest molecules that are to be deposited on the surfaces of their fine structures,and the resulting composite matters show significant potentials for various applications.The surface sol-gel process was employed to deposit ultrathin metal-oxide(e.g.,titania and zirconia)gel films to coat the cellulose nanofibers in bulk filter papers;thereafter,monolayers of specific guest substrates were immobilized onto the surfaces of the metal-oxide gel films.Highly selective,sensitive,and reversible chemosensors based on the surface modification of filter paper were obtained toward the fluorescence and colorimetric detection of various analytes such as heavy-metal ions,inorganic anions,amino acids,and gases.Cellulosebased composite materials with superhydrophobic,antibacterial,or luminescent properties were fabricated by self-assembly approaches toward practical applications.     

Surface modification of Mitoxantrone-loaded PLGA nanospheres with chitosan

The purpose of this research was to develop polylactic-co-glycolic acid (PLGA) nanospheres surface modified with chitosan (CS). Mitoxantrone- (MTO-) loaded PLGA nanospheres were prepared by a solvent evaporation technique. The PLGA nanospheres surface was modified with CS by two strategies (adsorption and covalent binding). PLGA nanospheres of 248.4 ± 21.0 nm in diameter characterized by the laser light scattering technique, scanning electron microscopy (SEM) are spherical and its drug encapsulation efficiency is 84.1 ± 3.4%. Zeta potential of unmodified nanospheres was measured to be negative −21.21 ± 2.13 mV. The positive zeta potential of modified nanospheres reveals the presence of CS on the surface of the modified nanospheres. Modified nanospheres were characterized for surface chemistry by X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared (FT-IR). FT-IR spectra exhibited peaks at 3420 cm⁻¹ and 1570 cm⁻¹, XPS spectra shows the N 1s (atomic orbital 1s of nitrogen) region of the surface of the nanospheres, corresponding to the primary amide of CS. In vitro drug release demonstrated that CS-modified nanospheres have many advantages such as prolonged drug release property and decreased the burst release over the unmodified nanospheres, and the modified nanospheres by covalent binding method could achieve the release kinetics of a relatively constant release. These data demonstrate high potential of CS-modified PLGA nanospheres for the anticancer drug carrier.     

Hydrophobic modification of cellulose nanocrystal via covalently grafting of castor oil

Hydrophobic cellulose nanocrystals (CNs) have been prepared by grafting isocyanate-terminated castor oil, a kind of natural vegetable oil, onto their surface. The existence of castor oil component in the modified cellulose nanocrystals was verified by Fourier transform infrared spectroscopy, solid-state ¹³C NMR spectra and X-ray photoelectron spectroscopy. At the same time, X-ray diffraction and transmission electron micrographs further proved that the crystalline structure and large aspect ratio of cellulose nanocrystals were essentially preserved after chemical grafting. Furthermore, the surface of modified cellulose nanocrystals appeared to be hydrophobic as indicated by contact angle measurements. The value of the polar component of surface energy decreased from 21.5 mJ/m² to almost zero via grafting castor oil. These novel hydrophobic castor oil-grafted cellulose nanocrystals appear as valuable alternatives to formulate bionanocomposites with non-polar polymers for optimized performances.     

Surface modification using photocrosslinkable chitosan for improving hemocompatibility

Immobilization of the anticoagulative or antithrombogenic biomolecule has been considered as one of the important methods to improve the blood compatibility of artificial biomaterials. In this study, a novel immobilization reaction scheme was utilized to incorporate O-butyrylchitosan (OBCS) onto the activated glass surface with an aim to develop an anticoagulative substrate. Activation of the glass surface was carried out by silanization and then OBCS was grafted to the silanized surface via a radiation grafting technique. The OBCS-grafted glass surfaces were characterized by electron spectroscopy for chemical analysis (ESCA) and atomic force microscopy (AFM). The blood compatibility of the OBCS-grafted glass was evaluated by platelet rich plasma (PRP) contacting experiments and protein adsorption experiments in vitro. These results have demonstrated that the surface with immobilized OBCS shows much less platelet adhesive and fibrinogen adsorption compared to the control surface. Therefore, the novel reaction scheme proposed here is very promising for future development of an anticoagulative glass substrate.     

Surface modification of RGD-liposomes for selective drug delivery to monocytes/neutrophils in brain

In the present study, RGD peptide was coupled with ferulic acid (FA) liposomes for binding to monocytes and neutrophils in peripheral blood for brain targeting in response to leukocyte recruitment. Cholesterol (Ch) was esterified with succinic anhydride to introduce a carboxylic end group (Ch-COOH). Soybean phosphatidylcholine, cholesterol and Ch-COOH were in a molar ratio of 1 : 0.23 : 0.05. FA was loaded into liposomes with 80.2+/-5.2% entrapment efficiency (EE) using a calcium acetate gradient method since it was difficult to load FA by other methods. RGD peptide was a novel compound coupled with Ch-COOH via carbodiimide and N-hydroxysulfosuccinimide. The results of the in vitro flow cytometric study showed that RGD conjugation liposomes (RGD-liposomes) could bind to monocytes/neutrophils efficiently. The rats were subjected to intrastriatal microinjections of 100 microl of human recombinant IL-1beta to produce brain inflammation and subsequently sacrificed after 15, 30, 60 and 120 min of administration of three formulations (FA solution, FA liposome, RGD-coated FA liposome). The body distribution results showed that RGD-liposomes could be directed to the target site, i.e. the brain, by cell selectivity in case of an inflammatory response. For RGD coated liposomes, the concentration of FA in brain was 6-fold higher than that of FA solution and 3-fold higher than that of uncoated liposomes. MTT assay and flow cytometry were used in the pharmacodynamic studies where it was found that FA liposomes exhibited greater antioxidant activity to FA solution on U937 cell.     

Surface only modification of bacterial cellulose nanofibres with organic acids

Bacterial cellulose (BC) nanofibres were modified only on their surface using an esterification reaction with acetic acid, hexanoic acid or dodecanoic acid. This reaction rendered the extremely hydrophilic surfaces of BC nanofibres hydrophobic. The hydrophobicity of BC increased with increasing carbon chain length of the organic acids used for the esterification reaction. Streaming (zeta-) potential measurements showed a slight shift in the isoelectric point and a decrease in ζ_plateau was also observed after the esterification reactions. This was attributed to the loss of acidic functional groups and increase in hydrophobicity due to esterification of BC with organic acids. A method based on hydrogen/deuterium exchange was developed to evaluate the availability of surface hydroxyl groups of neat and modified BC. The thermal degradation temperature of modified BC sheets decreased with increasing carbon chain length of the organic acids used. This is thought to be a direct result of the esterification reaction, which significantly reduces the packing efficiency of the nanofibres because of a reduction in the number of effective hydrogen bonds between them.     

Folate binding protein—Outlook for drug delivery applications

Serum proteins represent an important class of drug and imaging agent delivery vectors. In this minireview, key advantages of using serum proteins are discussed, followed by the particular advantages and challenges associated with employing soluble folate binding protein. In particular, approaches employing drugs that target folate metabolism are reviewed. Additionally, the slow-onset, tightbinding interaction of folate with folate binding protein and the relationship to a natural oligomerization mechanism is discussed. These unique aspects of folate binding protein suggest interesting applications for the protein as a vector for further drug and imaging agent development.     

Designing responsive microgels for drug delivery applications

Microgels based on thermally responsive polymers have been widely investigated in the context of controlled release applications, with increasing recent interest on developing a clearer understanding of what physical, chemical, and biological parameters must be considered to rationally design a microgel to deliver a specific drug at a specific rate in a specific physiological context. In this contribution, we outline these key design parameters associated with engineering responsive microgels for drug delivery and discuss several recent examples of how these principles have been applied to the synthesis of microgels or microgel-based composites. Overall, we suggest that in vivo assessment of these materials is essential to bridge the existing gap between the fascinating properties observed in the lab and the practical use of microgels in the clinic. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013, 51, 3027–3043     

Application of cellulose acetate butyrate-based membrane for osmotic drug delivery

The release rate of drugs from an OROS^® is controlled by semipermeable membranes composed typically of cellulose acetate (CA) with various flux enhancers. Cellulose acetate butyrate (CAB) was identified as a viable alternative. The CAB membrane matched the CA membrane in robustness but had superior drying properties, offering particular advantages for thermolabile formulations. Studies were conducted to characterize CAB membrane properties with respect to performance of OROS^® systems. Four different membrane formulations with varying plasticizer type and concentration were investigated. The CAB based membranes exhibited superior drying characteristics and similar functionality to the CA:polyethylene glycol (PEG) membranes used as a control. A linear relationship was observed between the level of flux enhancer and release rate. The stability of the membrane was evaluated based on release profiles after system storage at various conditions. The CAB membranes appeared to have stability comparable to the standard CA membrane. A linear relationship between membrane weight and release rate as well as the time required to release 90% of a drug from the system [T₉₀] for a model formulation was observed. In conclusion, the newly identified alternative membrane composition allows for the use of thinner membranes, thereby reducing cost of goods, coating time and, most importantly, membrane drying time.     

Nanofibrillated cellulose: surface modification and potential applications

Interest in nanofibrillated cellulose has been increasing exponentially because of its relatively ease of preparation in high yield, high specific surface area, high strength and stiffness, low weight and biodegradability etc. This bio-based nanomaterial has been used mainly in nanocomposites due to its outstanding reinforcing potential. Solvent casting, melt mixing, in situ polymerization and electrospinning are important techniques for the fabrication of nanofibrillated cellulose-based nanocomposites. Due to hydrophilic character along with inherent tendency to form strong network held through hydrogen-bonding, nanofibrillated cellulose cannot uniformly be dispersed in most non-polar polymer matrices. Therefore, surface modification based on polymer grafting, coupling agents, acetylation and cationic modification was used in order to improve compatibility and homogeneous dispersion within polymer matrices. Nanofibrillated cellulose opens the way towards intense and promising research with expanding area of potential applications, including nanocomposite materials, paper and paperboard additive, biomedical applications and as adsorbent.     

A chameleonic macrocyclic peptide with drug delivery applications

Head-to-tail cyclized peptides are intriguing natural products with unusual properties. The PawS-Derived Peptides (PDPs) are ribosomally synthesized as part of precursors for seed storage albumins in species of the daisy family, and are post-translationally excised and cyclized during proteolytic processing. Here we report a PDP twice the typical size and with two disulfide bonds, identified from seeds of Zinnia elegans. In water, synthetic PDP-23 forms a unique dimeric structure in which two monomers containing two β-hairpins cross-clasp and enclose a hydrophobic core, creating a square prism. This dimer can be split by addition of micelles or organic solvent and in monomeric form PDP-23 adopts open or closed V-shapes, exposing different levels of hydrophobicity dependent on conditions. This chameleonic character is unusual for disulfide-rich peptides and engenders PDP-23 with potential for cell delivery and accessing novel targets. We demonstrate this by conjugating a rhodamine dye to PDP-23, creating a stable, cell-penetrating inhibitor of the P-glycoprotein drug efflux pump.

The cyclic peptide PDP-23 adopts a different structure depending on conditions. In water it forms a dimer, but can unfold allowing its hydrophobic core to interact with membranes. PDP-23 shows promise as a cell penetrating scaffold for drug delivery.     

Uniform chitosan microspheres for potential application to colon-specific drug delivery

Uniform chitosan microspheres have been fabricated and weakly crosslinked for potential applications in colon-specific drug delivery. The effects of microsphere size, crosslinking density and electrostatic interactions between the drug and chitosan on drug release were studied, employing model drugs of different acidities. When the drug was basic, all chitosan spheres exhibited 100% release within 30 min. As the acidity of the drug increased, the release slowed down and depended on the crosslinking density and microsphere size. The release of weakly acidic drug was most suppressed for large spheres (35-38 microm), while the small spheres (23-25 microm) with higher crosslinking exhibited the most retention of highly acidic drug, indicating that they are a promising candidate for colon-specific delivery.     

The potential of TEMPO-oxidized nanofibrillar cellulose beads for cell delivery applications

The advanced development of cell carriers for regenerative medicine and cell therapy demands materials able to sustain cell viability prior to their delivery to the target tissue, an ability that can be controlled by the shape, size and degradability of the matrix. TEMPO-oxidized nanofibrillar cellulose (ToNFC) macromolecules are negatively charged and therefore can be easily formulated by ionotropic gelation into beads of varying sizes that can release their payload through an erosion-controlled process. We report here for the first time on the preparation of ToNFC beads via ionic gelation using CaCl₂ and on their loading with OSTEO-1 rat bone cells, with a view to examine their capacity of sustaining the cell viability and of releasing the bone cells in a controlled manner. The initial results obtained demonstrate that ToNFC is able to protect the OSTEO-1 cells and to maintain their viability for at least 2 weeks. Following gradual disintegration of the beads, a significant cell release and subsequent proliferation was observed after 7 days. These results indicate the considerable potential of nanofibrillar cellulose (ToNFC) for applications in cell therapy and regenerative medicine.     

Surface modification of cellulose nanowhiskers for application in thermosetting epoxy polymers

Cellulose nanowhiskers (CNWs) were chemically modified with dodecenyl succinic anhydride to obtain hydrophobic CNWs called DCNWs. Surface modification was confirmed by infrared spectroscopy, transmission electron microscopy, and X-ray diffraction. The surface substitution degree determined by X-ray photoelectron spectroscopy was 0.30. Nanocomposites were prepared by incorporating different amounts of DCNWs pre-dispersed in a small amount of acetone into an epoxy matrix. Scanning electron microscope demonstrated that DCNWs dispersed well in the epoxy matrix. A strong interaction was proved between the DCNWs and epoxy matrix, as results of which the nanocomposites exhibited an obvious increase in T _g by about 30 °C, simultaneous increases in tensile strength, Young’s modulus, and strain at break; and an improvement in the hydrothermal properties. Compared with the neat epoxy, the nanocomposite containing 3.5 wt% of DCNWs exhibited an increase in tensile strength by 82 %, Young’s modulus by 21 %, and a strain at break by 198 %.     

TEMPO-mediated oxidation of microcrystalline cellulose: limiting factors for cellulose nanocrystal yield

Cellulose nanocrystal (CNC) production suffers, among other problems, from low yields. The focus of this study was to investigate the universal effect of charge density, centrifugation, and mechanical treatment as limiting causes of yield. Microcrystalline cellulose (MCC) was used as the starting material in order to eliminate the relatively arbitrary yield losses caused by the hydrolysis conditions. To disintegrate MCC into nanocrystals, high surface charge in the form of carboxylic groups was introduced by TEMPO-mediated oxidation, after which the material was mechanically treated, and separated into fine and coarse fractions. The fine fraction collected as supernatant after separation by centrifugation had a yield of 17–20% independent of the mechanical treatment method or time used. The particle sizes of these fractions did not significantly differ from each other, which raises questions on the efficiency of the mechanical treatment (sonication) and centrifugation in traditional CNC production. The results imply that radically new approaches in preparation are needed for truly meaningful increases in the CNC yield.