Maleimide-bearing nanogels as novel mucoadhesive materials for drug delivery

Novel maleimide-functionalised nanogels have been synthesised via the polymerisation of 2,5-dimethylfuran-protected 3-maleimidoethyl butylacrylate in the presence of presynthesised poly(N-vinylpyrrolidone) (PVP) nanogel scaffolds using surfactant-free emulsion polymerisation techniques. The protected maleimide nanogels were subsequently deprotected to generate the reactive maleimide group via a retro-Diels-Alder reaction. These activated nanogels were found to exhibit excellent mucoadhesive properties on ex vivo conjunctival tissue when compared to the known mucoadhesive chitosan. In order to determine the viability of the materials as drug carriers, nanogels were loaded with a model drug compound and the in vitro release kinetics were analysed. The nanogels could sustain the release of a model drug compound over several hours owing to the swellable hydrophilic nanogel structure, exhibiting first order release kinetics. As a consequence, these findings support the potential of these maleimide-bearing nanogels as a novel platform for sustained ocular drug delivery

Synthesis of thiolated and acrylated nanoparticles using thiol-ene click chemistry: towards novel mucoadhesive materials for drug delivery

Thiol- and acrylate-functionalized nanoparticles have been synthesized from pentaerythritol tetrakis(3-mercapto-propionate) and pentaerythritol tetraacrylate using thiol-ene click chemistry. Using Raman and 1H NMR spectroscopy as well as Ellman's assay, it was demonstrated that excess pentaerythritol tetraacrylate in the feed mixture led to nanoparticles with free acrylate groups on their surface, whereas nanoparticles with thiolated surfaces could be synthesized using feed mixtures with excess pentaerythritol tetrakis(3-mercapto-propionate). The possibility of fluorescent labelling of thiolated nanoparticles has been demonstrated through their reaction with fluorescein-5-maleimide. The thiolated nanoparticles were found to be mucoadhesive and exhibited retention on mucosal surface of porcine urinary bladder

Thermodynamic, rheological and structural properties of edible oils structured with LMOGs: Influence of gelator and oil phase

Supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/j.foostr.2018.03.003.The effect of different oil phases and low molecular weight organogelators (LMOGs) structures on edible oils was investigated through differential scanning calorimetry (DSC), rheology and small-angle X-ray scattering (SAXS). Different gelators (glyceryl tristearateGT; sorbitan tristearateST; sorbitan monostearateSM and glyceryl monostearate-GM) were tested in medium-chain triglycerides and high oleic sunflower (named MCT and LCT). Systems were thermoreversible and their thermodynamic properties were dependent on the combined effect of the interactions of structurants polar head with other constituents and the sterical effect of their hydrophobic tails. The crystallization onset temperature was higher for GM and SM, possibly due to the lower sterical effect of their tails. However, the corresponding enthalpy and entropy change values were influenced by the hydrophilic head group: glycerol-based organogelator molecules were able to interact strongly than sorbitans, increasing these values. Rheological studies showed that gels produced with LCT were stronger than with MCT. Moreover, cooling and heating cycles showed more than one transition and shear dependence. Stronger structures were more sensitive to temperature, possibly because of their more organized structure that destabilizes more easily with the increase of molecular mobility. These results were in agreement with the SAXS analyses. At 50°C, the stronger networks lost their initial structure, and at 70°C they collapsed. Thus, molecular interactions and structurant self-assembly were dependent on the structurant+solvent combination, leading to different physicochemical properties and thermal stability. It is expected that these results will allow customizing properties of structured oil for diverse applications, spanning from food to cosmetic and pharmaceutical industries.LuizH.FasolinthanksthescholarshipCapes/FCTprogram(349/13) for the research exchange and Rosiane Lopes Cunha thanks CNPq (CNPq 307168/2016-6) for the productivity grant. The authors also would like to thank Fapesp (EMU 09/54137-1), CNPq and Capes for their financial support and the Brazilian Synchrotron Light Laboratory (LNLS) for the opportunity to carry out SAXS measurements. This study was also supported by the Portuguese Foundation for Science and Technology (FCT) under the scope of the strategic funding of UID/BIO/ 04469/2013 unit and COMPETE 2020 (POCI-01-0145-FEDER-006684) and BioTecNorte operation (NORTE-01-0145-FEDER-000004) funded by the European Regional Development Fund under the scope of Norte2020 – Programa Operacional Regional do Norte. and of the Project RECI/BBB-EBI/0179/2012 (FCOMP-01-0124-FEDER-027462).info:eu-repo/semantics/publishedVersio

Synthesis of mucoadhesive thiol-bearing microgels from 2-(acetylthio)ethylacrylate and 2-hydroxyethylmethacrylate: novel drug delivery systems for chemotherapeutic agents to the bladder

Thiol-bearing microgels have been synthesised from copolymerisation of 2-(acetylthio)ethylacrylate and 2-hydroxyethylmethacrylate, and subsequent deprotection using sodium thiomethoxide. The concentration of thiol groups on these microgels could be tailored by use of different molar ratios of the two monomers. These thiol-bearing microgels were shown to adhere to ex vivo porcine urinary bladder, which was correlated with their level of thiolation. By simply mixing solutions of thiol-bearing microgels and doxorubicin, high levels of drug loading into the microgels could be achieved. Thiol-bearing microgels controlled the release of doxorubicin in a time-dependent manner over several hours. These doxorubicin-loaded thiol-bearing microgels could have application in the treatment of early-stage bladder cancers. The method used represents a new ‘bottom-up’ approach for the synthesis of novel mucoadhesive microgels

Side chain variations radically alter the diffusion of poly(2-alkyl-2-oxazoline) functionalised nanoparticles through a mucosal barrier

Functionalised nanomaterials are gaining popularity for use as drug delivery vehicles and, in particular, mucus penetrating nanoparticles may improve drug bioavailability via the oral route. To date, few polymers have been investigated for their muco-penetration, and the effects of systematic structural changes to polymer architectures on the penetration and diffusion of functionalised nanomaterials through mucosal tissue have not been reported. We investigated the influence of poly(2-oxazoline) alkyl side chain length on nanoparticle diffusion; poly(2-methyl-2-oxazoline), poly(2-ethyl-2-oxazoline), and poly(2-n-propyl-2-oxazoline) were grafted onto the surface of thiolated silica nanoparticles and characterised by FT-IR, Raman and NMR spectroscopy, thermogravimetric analysis, and small angle neutron scattering. Diffusion coefficients were determined in water and in a mucin dispersion (using Nanoparticle Tracking Analysis), and penetration through a mucosal barrier was assessed using an ex vivo fluorescence technique. The addition of a single methylene group in the side chain significantly altered the penetration and diffusion of the materials in both mucin dispersions and mucosal tissue. Nanoparticles functionalised with poly(2-methyl-2-oxazoline) were significantly more diffusive than particles with poly(2-ethyl-2-oxazoline) while particles with poly(2-n-propyl-2-oxazoline) showed no significant increase compared to the unfunctionalised particles. These data show that variations in the polymer structure can radically alter their diffusive properties with clear implications for the future design of mucus penetrating systems

New biomaterial based on cotton with incorporated biomolecules

The aim of this study was to investigate a method of embedding l-cysteine (l-cys), an antimicrobial agent, between layers of chitosan (CH) and sodium alginate (ALG) onto cotton samples obtained via a layer-by-layer electrostatic deposition technique via several embedding methods. The results show that the best way to incorporate l-cys into the layers was the one that used the property of gelling ALG. To monitor the l-cys embedding into the CH/ALG multilayer film, different methods were used: energy-dispersive X-ray spectrometry analysis to assess the presence of sulfur on the sample, Ellman's reagent method to analyze l-cys release from the sample, and attenuated total reflectance (ATR) Fourier transform infrared spectroscopy (FTIR) to compare the ATR–FTIR spectra of the pure l-cys and l-cys embedded in the CH/ALG multilayer film to study the interaction between the l-cys and the CH/ALG multilayer films. Functionalized CH/ALG cotton samples were also investigated for their antibacterial properties toward Staphylococcus aureus andKlebsiella pneumonia with the Japanese Industrial Standard method JIS L 1902:2002, and the results show an enhancement of the antibacterial effect due to the presence of l-cys.The authors thank Fundação para a Ciência e Tecnologia for the funding granted concerning the project PTDC/EBB-BIO/113671/ 2009 (FCOMP-01-0124-FEDER-014752). Also, they thank Fundo Europeu de Desenvolvimento Regional through COMPETE—Programa Operacional Factores de Competitividade for cofunding

Advances in intravesical drug delivery systems to treat bladder cancer

Chemotherapeutic agents administered intravesically to treat bladder cancer have limited efficacy due to periodic dilution and wash-out during urine formation and elimination. This review describes the pathophysiology, prevalence and staging of bladder cancer, and discusses several formulation strategies used to improve drug residence within the bladder. These include the use of amphiphilic copolymers, mucoadhesive formulations, hydrogels, floating systems, and liposomes. Various in vitro and in vivo models recently employed for intravesical drug delivery studies are discussed. Some of the challenges that have prevented the clinical use of some promising formulations are identified

Innovative Methods and Applications in Mucoadhesion Research.

The present review is aimed at elucidating relatively new aspects of mucoadhesion/mucus interaction and related phenomena that emerged from a Mucoadhesion workshop held in Munster on 2-3 September 2015 as a satellite event of the ICCC 13th-EUCHIS 12th. After a brief outline of the new issues, the focus is on mucus description, purification, and mucus/mucin characterization, all steps that are pivotal to the understanding of mucus related phenomena and the choice of the correct mucosal model for in vitro and ex vivo experiments, alternative bio/mucomimetic materials are also presented. Then a selection of preparative techniques and testing methods are described (at molecular as well as micro and macroscale) that may support the pharmaceutical development of mucus interactive systems and assist formulators in the scale-up and industrialization steps. Recent applications of mucoadhesive systems (including medical devices) intended for different routes of administration (oral, gastrointestinal, vaginal, nasal, ocular, and intravesical) and for the treatment of difficult to treat pathologies or the alleviation of symptoms are described