Mucoadhesive maleimide-functionalised liposomes for drug delivery to urinary bladder

Intravesical drug administration is used to deliver chemotherapeutic agents via a catheter to treat bladder cancer. The major limitation of this treatment is poor retention of the drug in the bladder due to periodic urine voiding. In this work, maleimide-functionalised PEGylated liposomes (PEG-Mal) were explored as mucoadhesive vehicles for drug delivery to the urinary bladder. The retention of these liposomes on freshly excised porcine bladder mucosa in vitro was compared with conventional liposomes, PEGylated liposomes, two controls (dextran and chitosan), and evaluated through Wash Out50 (WO50) values. PEG-Mal liposomes exhibited greater retention on mucosal surfaces compared to other liposomes. The penetration abilities of conventional, PEG-Mal-functionalised and PEGylated liposomal dispersions with encapsulated fluorescein sodium into the bladder mucosa ex vivo were assessed using a fluorescence microscopy technique. PEGylated liposomes were found to be more mucosa-penetrating compared to other liposomes. All liposomes were loaded with fluorescein sodium salt as a model drug and the in vitro release kinetics was evaluated. Longer drug release was observed from PEG-Mal liposomes

Chitosan/Poly(2-ethyl-2-oxazoline) films with ciprofloxacin for application in vaginal drug delivery

Chitosan (CHI) and chitosan/poly(2-ethyl-2-oxazoline) (CHI/POZ)-based films were prepared by casting from aqueous solutions of polymer blends with different compositions. Ciprofloxacin was used as a model drug in these formulations. The weight, thickness, folding endurance and transparency of blend films were measured and characterised. All films had a uniform thickness (0.06 ± 0.01 mm) and exhibited sufficient flexibility. The surface pHs of films ranged from 3.76 ± 0.49 to 4.14 ± 0.32, which is within the pH range suitable for vaginal applications. The cumulative release of the drug from the films in experiments in vitro was found to be 42 ± 2% and 56 ± 1% for pure CHI and CHI/POZ (40:60) films, respectively. Drug-free chitosan/poly(2-ethyl-2-oxazoline) films showed weak antimicrobial activity against Escherichia coli. Drug-loaded CHI and CHI/POZ films showed good antimicrobial properties against both Gram-positive Staphylococcus aureus and Gram-negative bacteria Escherichia coli. Mucoadhesive properties of these films with respect to freshly excised sheep vaginal mucosa were evaluated using a tensile method. It was established that all films were mucoadhesive, but an increase in POZ content in the blend resulted in a gradual reduction of their ability to stick to vaginal mucosa. These films could potentially find applications in vaginal drug delivery

Maleimide-functionalised PLGA-PEG nanoparticles as mucoadhesive carriers for intravesical drug delivery

Low permeability of the urinary bladder epithelium, poor retention of the chemotherapeutic agents due to dilution and periodic urine voiding as well as intermittent catheterisations are the major limitations of intravesical drug delivery used in the treatment of bladder cancer. In this work, maleimide-functionalised poly(lactide-co-glycolide)-block-poly(ethylene glycol) (PLGA-PEG-Mal) nanoparticles were developed. Their physicochemical characteristics, including morphology, architecture and molecular parameters have been investigated by means of dynamic light scattering, transmission electron microscopy and small-angle neutron scattering techniques. It was established that the size of nanoparticles was dependent on the solvent used in their preparation and molecular weight of PEG, for example, 105 ± 1 nm and 68 ± 1 nm particles were formed from PLGA20K-PEG5K in dimethyl sulfoxide and acetone, respectively. PLGA-PEG-Mal nanoparticles were explored as mucoadhesive formulations for drug delivery to the urinary bladder. The retention of fluorescein-loaded nanoparticles on freshly excised lamb bladder mucosa in vitro was evaluated and assessed using a flow-through fluorescence technique and Wash Out50 (WO50) quantitative method. PLGA-PEG-Mal nanoparticles (NPs) exhibited greater retention on urinary bladder mucosa (WO50 = 15 mL) compared to maleimide-free NPs (WO50 = 5 mL). The assessment of the biocompatibility of PEG-Mal using the slug mucosal irritation test revealed that these materials are non-irritant to mucosal surfaces

Synthesis and evaluation of methacrylated poly(2-ethyl-2-oxazoline) as a mucoadhesive polymer for nasal drug delivery

Methacrylated poly(2-ethyl-2-oxazoline) (PEOZ) was synthesized by partial hydrolysis of 500 kDa PEOZ, and the resulting poly[(2-ethyl-2-oxazoline)-co-ethylenimine] P(EOZ-co-EI) was subsequently reacted with methacrylic anhydride. The successful synthesis of methacrylated PEOZ (MAPEOZ) was confirmed by proton nuclear magnetic resonance (1H NMR), infrared spectroscopy, and differential scanning calorimetry. The degrees of hydrolysis and methacrylation were determined by 1H NMR spectra. MAPEOZ exhibited temperature-responsive properties, which were dependent on the degree of methacrylation. On that basis, three soluble MAPEOZ derivatives with different degrees of methacrylation were selected and investigated in cell toxicity studies, showing no significant cytotoxicity against the HEK293 cell line. A slug mucosal irritation assay showed that PEOZ and MAPEOZ do not cause mucosal irritation. The presence of methacryloyl groups and residual amines had a remarkable synergistic effect on the mucoadhesive properties of these polymers. These poly(2-ethyl-2-oxazoline) derivatives have excellent potential as mucoadhesive materials for developing formulations for drug delivery via mucosal routes of administration

Supramolecular hybrid structures and gels from host–guest interactions between α-cyclodextrin and PEGylated organosilica nanoparticles

Polypseudorotaxanes are polymer chains threaded by molecular rings that are free to unthread; these “pearl-necklace” can self-assemble further, leading to higher-order supramolecular structures with interesting functionalities. In this work, the complexation between α-cyclodextrin (α-CD), a cyclic oligosaccharide of glucopyranose units, and poly(ethylene glycol) (PEG) grafted to silica nanoparticles was studied. The threading of α-CD onto the polymeric chains leads to their aggregation into bundles, followed by either the precipitation of the inclusion complex or the formation of a gel phase, in which silica nanoparticles are incorporated. The kinetics of threading, followed by turbidimetry, revealed a dependence of the rate of complexation on the following parameters: the concentration of α-CD, temperature, PEG length (750, 4000, and 5000 g mol–1), whether the polymer is grafted or free in solution, and the density of grafting. Complexation is slower, and temperature has a higher impact on PEG grafted on silica nanoparticles compared to PEG free in solution. Thermodynamic parameters extracted from the transition-state theory showed that inclusion complex formation is favored with grafted PEG compared to free PEG and establishes a ratio of complexation of five to six ethylene oxide units per cyclodextrin. The complexation yields, determined by gravimetry, revealed that much higher yields are obtained with longer chains and higher grafting density. Thermogravimetric analysis and Fourier transform infrared spectroscopy on the inclusion complex corroborate the number of macrocycles threaded on the chains. A sol–gel transition was observed with the longer PEG chain (5k) at specific mixing ratios; oscillatory shear rheology measurements confirmed a highly solid-like behavior, with an elastic modulus G′ of up to 25 kPa, higher than that in the absence of silica. These results thus provide the key parameters dictating inclusion complex formation between cyclodextrin and PEG covalently attached to colloidal silica and demonstrate a facile route toward soft nanoparticle gels based on host–guest interactions

Aldehyde-functional thermoresponsive diblock copolymer worm gels exhibit strong mucoadhesion

A series of thermoresponsive diblock copolymer worm gels is prepared via reversible addition–fragmentation chain transfer (RAFT) aqueous dispersion polymerization of 2-hydroxypropyl methacrylate using a water-soluble methacrylic precursor bearing pendent cis-diol groups. Selective oxidation using an aqueous solution of sodium periodate affords the corresponding aldehyde-functional worm gels. The aldehyde groups are located within the steric stabilizer chains and the aldehyde content can be adjusted by varying the periodate/cis-diol molar ratio. These aldehyde-functional worm gels are evaluated in terms of their mucoadhesion performance with the aid of a fluorescence microscopy-based assay. Using porcine urinary bladder mucosa as a model substrate, we demonstrate that these worm gels offer a comparable degree of mucoadhesion to that afforded by chitosan, which is widely regarded to be a ‘gold standard’ positive control in this context. The optimum degree of aldehyde functionality is approximately 30%: lower degrees of functionalization lead to weaker mucoadhesion, whereas higher values compromise the desirable thermoresponsive behavior of these worm gels

Enhancing mucoadhesive properties of gelatin through chemical modification with unsaturated anhydrides

Gelatin is a water-soluble natural polyampholyte with poor mucoadhesive properties. It has traditionally been used as a major ingredient in many pharmaceuticals, including soft and hard capsules, suppositories, tissue engineering, and regenerative medicine. The mucoadhesive properties of gelatin can be improved by modifying it through conjugation with specific adhesive unsaturated groups. In this study, gelatin was modified by reacting with crotonic, itaconic, and methacrylic anhydrides in varying molar ratios to yield crotonoylated-, itaconoylated-, and methacryloylated gelatins (abbreviated as Gel-CA, Gel-IA, and Gel-MA, respectively). The successful synthesis was confirmed using 1H NMR, FTIR spectroscopies, and colorimetric TNBSA assay. The effect of chemical modification on the isoelectric point was studied through viscosity and electrophoretic mobility measurements. The evolution of the storage (G′) and loss (G′′) moduli was employed to determine thermoreversible gelation points of modified and unmodified gelatins. The safety of modified gelatin derivatives was assessed with an in vivo slug mucosal irritation test (SMIT) and an in vitro MTT assay utilizing human pulmonary fibroblasts cell line. Two different model dosage forms, such as physical gels and spray-dried microparticles, were prepared and their mucoadhesive properties were evaluated using a flow-through technique with fluorescent detection and a tensile test with ex vivo porcine vaginal tissues and sheep nasal mucosa. Gelatins modified with unsaturated groups exhibited superior mucoadhesive properties compared to native gelatin. The enhanced ability of gelatin modified with these unsaturated functional groups is due to the formation of covalent bonds with cysteine-rich subdomains present in the mucin via thiol–ene click Michael-type addition reactions occurring under physiologically relevant conditions

Chitosan/poly(2-ethyl-2-oxazoline) films for ocular drug delivery: Formulation, miscibility, in vitro and in vivo studies

Polymeric films were prepared based on chitosan and its blends with poly(2-ethyl-2-oxazoline) by casting from aqueous solutions. These materials were characterised using a number of physicochemical techniques, including Fourier-transform infrared spectroscopy, thermal gravimetric analysis, differential scanning calorimetry, wide angle x-ray diffraction, tensile testing and scanning electron microscopy. All these studies indicate that there is a weak intermacromolecular hydrogen bonding between these polymers, which facilitates their complete miscibility in solid state. These films were formulated with sodium fluorescein as a model drug and were evaluated for their potential application in ocular drug delivery both in vitro and in vivo. It was established that the films are biocompatible and mucoadhesive; they are capable of providing a sustained drug release when administered topically on the cornea

Supramolecular hybrid structures and gels from host-guest interactions between alpha-cyclodextrin and PEGylated organosilica nanoparticles

Polypseudorotaxanes are polymer chains threaded by molecular rings that are free to unthread; these "pearl-necklace" can self-assemble further, leading to higher-order supramolecular structures with interesting functionalities. In this work, the complexation between alpha-cyclodextrin (alpha-CD), a cyclic oligosaccharide of glucopyranose units, and poly(ethylene glycol) (PEG) grafted to silica nanoparticles was studied. The threading of alpha-CD onto the polymeric chains leads to their aggregation into bundles, followed by either the precipitation of the inclusion complex or the formation of a gel phase, in which silica nanoparticles are incorporated. The kinetics of threading, followed by turbidimetry, revealed a dependence of the rate of complexation on the following parameters: the concentration of alpha-CD, temperature, PEG length (750, 4000, and 5000 g mol(-1)), whether the polymer is grafted or free in solution, and the density of grafting. Complexation is slower, and temperature has a higher impact on PEG grafted on silica nanoparticles compared to PEG free in solution. Thermodynamic parameters extracted from the transition-state theory showed that inclusion complex formation is favored with grafted PEG compared to free PEG and establishes a ratio of complexation of five to six ethylene oxide units per cyclodextrin. The complexation yields, determined by gravimetry, revealed that much higher yields are obtained with longer chains and higher grafting density

The creation of the technology of biodegradable films based on cornstarch

Materials able to decompose safely are very important for solving the environmental problems. In this paper the preparation conditions of biodegradable film based on polyvinyl alcohol (PVA) and starch were studied. IR-spectroscopy analysis showed that during the synthesis copolymers connect with each other due to the hydrogen bonds. The films synthesized on the basis of PVA and starch have been subjected to γ-radiation. They have shown the improved characteristics on strength, elasticity and durability in various solvents at the expense of the polymeric components sewed by hydrogen bonds. Opportunities of application of the films as a biodegradable material were shown