Biocompatibility and biofunctionalization of mesoporous silicon particles

Several of the newly developed drug molecules experience poor biopharmaceutical behavior, which hinders their effective delivery at the proper site of action. Among the several strategies employed in order to overcome this obstacle, mesoporous silicon-based materials have emerged as promising drug carriers due to their ability to improve the dissolution behavior of several poorly water-soluble drugs compounds confined within their pores. In addition to improve the dissolution behavior of the drugs, we report that porous silicon (PSi) nanoparticles have a higher degree of biocompatibility than PSi microparticles in several cell lines studied. In addition, the degradation of the nanoparticles showed its potential to fast clearance in the body. After oral delivery, the PSi particles were also found to transit the intestines without being absorbed. These results constituted the first quantitative analysis of the behavior of orally administered PSi nanoparticles compared with other delivery routes in rats. The self-assemble of a hydrophobin class II (HFBII) protein at the surface of hydrophobic PSi particles endowed the particles with greater biocompatibility in different cell lines, was found to reverse their hydrophobicity and also protected a drug loaded within its pores against premature release at low pH while enabling subsequent drug release as the pH increased. These results highlight the potential of HFBII-coating for PSi-based drug carriers in improving their hydrophilicity, biocompatibility and pH responsiveness in drug delivery applications. In conclusion, mesoporous silicon particles have been shown to be a versatile platform for improving the dissolution behavior of poorly water-soluble drugs with high biocompatibility and easy surface modification. The results of this study also provide information regarding the biofunctionalization of the THCPSi particles with a fungal protein, leading to an improvement in their biocompatibility and endowing them with pH responsive and mucoadhesive properties.Heikot biofarmaseuttiset ominaisuudet vaikeuttavat uusien lääkemolekyylien keksintää ja kehittämistä, mikä estää molekyylien tehokasta annostelua vaikutuspaikkaansa elimistössä. Tämän ongelman ratkaisemiseksi on tutkittu useita menetelmiä ja materiaaleja, joista yksi lupaavimmista perustuu mesohuokoisten silikonipohjaisten (PSi) materiaalien käyttöön lääkeannostelussa. PSi-pohjaiset lääkekantajat parantavat niukkaliukoisten lääkeaineiden liukenemisnopeutta, mikä perustuu mesohuokosten pieneen kokoon ja suureen pinta-alaan. Useissa solulinjoissa tehdyissä kokeissa havaittiin, että huokoisesta piistä valmistetut nanopartikkelit ovat biologiselta yhteensopivuudeltaan parempia kuin vastaavat PSi-mikropartikkelit. PSi-nanopartikkelien etuna on lisäksi nopea hajoaminen ja sitä kautta nopea poistuminen elimistöstä. Väitöskirjatyössä annosteltiin radio-leimattuja PSi-nanopartikkeleita rotan laskimoverenkiertoon, jolloin ne kohdentuivat nopeasti koe-eläimen maksaan ja pernaan ilman näkyviä toksisia vaikutuksia. Suun kautta annosteltuina PSi-nanopartikkelit kulkeutuivat suoliston läpi. PSi-partikkelien biologista yhteensopivuutta tutkituissa solulinjoissa parannettiin päällystämällä ne itsejärjestäytyvillä hydrofobiini-proteiineilla (hydrofobiini-luokka II, HFBII), mikä muutti hydrofobiset PSi-partikkelit hydrofiilisemmiksi. Päällystäminen myös suojasi PSi-partikkeleita ennenaikaiselta lääkeaineen vapautumiselta matalassa pH:ssa; kun ympäristön pH nousi, myös lääkevapautuminen nopeutui. Tulosten perusteella HFBII-päällystetyt PSi-pohjaiset lääkekantajat paransivat materiaalin hydrofiilisyyttä, biologista yhteensopivuutta ja pH-herkkyyttä, mitä voidaan käyttää hyväksi erilaisissa lääkeannosteluun liittyvissä sovellutuksissa. Yhteenvetona väitöskirjan tuloksista voidaan todeta, että biologisesti hyvin yhteensopivat mesohuokoiset silikonipohjaiset mikro- ja nanopartikkelit soveltuvat erinomaisesti niukkaliukoisten lääkemolekyylien liukoisuusnopeuden parantamiseen. Lääkeannostelua ja biologista yhteensopivuutta voidaan edelleen helposti parantaa ja säädellä partikkelien pintaa muokkaamalla. Hydrofobiini-proteiinien kanssa suoritetut PSi-partikkelien biofunktionalisoinnit mahdollistavat lääkekantajan pH-herkkyyteen ja mukoadhesiivisuuteen perustuvan säädellyn lääkeannostelun

Crystallisation behaviour of pharmaceutical compounds confined within mesoporous silicon

The poor aqueous solubility of new and existing drug compounds represents a significant challenge in pharmaceutical development, with numerous strategies currently being pursued to address this issue. Amorphous solids lack the repeating array of atoms in the structure and present greater free energy than their crystalline counterparts which in turn enhances the solubility of the compound. The loading of drug compounds into porous materials has been described as a promising approach for the stabilisation of the amorphous state but is dependent on many factors including pore size and surface chemistry of the substrate material. This review looks at the applications of mesoporous materials in the confinement of pharmaceutical compounds to increase their dissolution rate or modify their release, and the influence of varying pore size to crystallise metastable polymorphs. We focus our attention on mesoporous silicon, due to the ability of its surface to be easily modified, enabling it to be stabilised and functionalised for the loading of various drug compounds. The use of neutron and synchrotron X-ray to examine compounds and the mesoporous materials in which they are confined is also discussed, moving away from the conventional analysis methods

Microfibre-functionalised silk hydrogels

Silk hydrogels have shown potential for tissue engineering applications, but several gaps and challenges, such as a restricted ability to form hydrogels with tuned mechanics and structural features, still limit their utilisation. Here, Bombyx mori and Antheraea mylitta (Tasar) silk microfibres were embedded within self-assembling B. mori silk hydrogels to modify the bulk hydrogel mechanical properties. This approach is particularly attractive because it creates structured silk hydrogels. First, B. mori and Tasar microfibres were prepared with lengths between 250 and 500 μm. Secondary structure analyses showed high beta-sheet contents of 61% and 63% for B. mori and Tasar microfibres, respectively. Mixing either microfibre type, at either 2% or 10% (w/v) concentrations, into 3% (w/v) silk solutions during the solution–gel transition increased the initial stiffness of the resulting silk hydrogels, with the 10% (w/v) addition giving a greater increase. Microfibre addition also altered hydrogel stress relaxation, with the fastest stress relaxation observed with a rank order of 2% (w/v) > 10% (w/v) > unmodified hydrogels for either fibre type, although B. mori fibres showed a greater effect. The resulting data sets are interesting because they suggest that the presence of microfibres provided potential ‘flow points’ within these hydrogels. Assessment of the biological responses by monitoring cell attachment onto these two-dimensional hydrogel substrates revealed greater numbers of human induced pluripotent stem cell-derived mesenchymal stem cells (iPSC-MSCs) attached to the hydrogels containing 10% (w/v) B. mori microfibres as well as 2% (w/v) and 10% (w/v) Tasar microfibres at 24 h after seeding. Cytoskeleton staining revealed a more elongated and stretched morphology for the cells growing on hydrogels containing Tasar microfibres. Overall, these findings illustrate that hydrogel stiffness, stress relaxation and the iPSC-MSC responses towards silk hydrogels can be tuned using microfibres

Self-Assembly of Amphiphilic Janus Dendrimers into Mechanically Robust Supramolecular Hydrogels for Sustained Drug Release

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Biocompatibility of Thermally Hydrocarbonized Porous Silicon Nanoparticles and their Biodistribution in Rats

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Pulmonary administration of a dry powder formulation of the antifibrotic drug tilorone reduces silica-induced lung fibrosis in mice

The aim of this work was to study the antifibrotic effect of pulmonary administration of tilorone to lung fibrosis. L-leucine coated tilorone particles were prepared and their aerosolization properties were analyzed using two dry powder inhalers (Easyhaler and Twister). In addition, the biological activity and cell monolayer permeation was tested. The antifibrotic effect of tilorone delivered by oropharyngeal aspiration was studied in vivo using a silica-induced model of pulmonary fibrosis in mice in a preventive setting. When delivered from the Easyhaler in an inhalation simulator, the emitted dose and fine particle fraction were independent from the pressure applied and showed dose repeatability. However, with Twister the aerosolization was pressure-dependent indicating poor compatibility between the device and the formulation. The formulation showed more consistent permeation through a differentiated Calu-3 cell monolayer compared to pristine tilorone. Tilorone decreased the histological fibrosis score in vivo in systemic and local administration, but only systemic administration decreased the mRNA expression of type I collagen. The difference was hypothesized to result from 40-fold higher drug concentration in tissue samples in the systemic administration group. These results show that tilorone can be formulated as inhalable dry powder and has potential as an oral and inhalable antifibrotic drug.Peer reviewe

Functionalising silk hydrogels with hetero- and homotypic nanoparticles

Despite many reports detailing silk hydrogels, the development of composite silk hydrogels with homotypic and heterotypic silk nanoparticles and their impact on material mechanics and biology have remained largely unexplored. We hypothesise that the inclusion of nanoparticles into silk-based hydrogels enables the formation of homotropic and heterotropic material assemblies. The aim was to explore how well these systems allow tuning of mechanics and cell adhesion to ultimately control the cell–material interface. We utilised nonporous silica nanoparticles as a standard reference and compared them to nanoparticles derived from Bombyx mori silk and Antheraea mylitta (tasar) silk (approximately 100–150 nm in size). Initially, physically cross-linked B. mori silk hydrogels were prepared containing silica, B. mori silk nanoparticles, or tasar silk nanoparticles at concentrations of either 0.05% or 0.5% (w/v). The initial modulus (stiffness) of these nanoparticle-functionalised silk hydrogels was similar. Stress relaxation was substantially faster for nanoparticle-modified silk hydrogels than for unmodified control hydrogels. Increasing the concentrations of B. mori silk and silica nanoparticles slowed stress relaxation, while the opposite trend was observed for hydrogels modified with tasar nanoparticles. Cell attachment was similar for all hydrogels, but proliferation during the initial 24 h was significantly improved with the nanoparticle-modified hydrogels. Overall, this study demonstrates the manufacture and utilisation of homotropic and heterotropic silk hydrogels

Pressure-induced superelastic behaviour of isonicotinamide

Dynamic organic crystals have come to the fore as potential lightweight alternatives to inorganic actuators providing high weight-to-force ratios. We have observed pressure-induced superelastic behaviour in Form I of isonicotinamide. The reversible single-crystal to single-crystal transformation exhibited by the system is an important component for functioning actuators. Crucially, our observations have enabled us to propose a mechanism for the molecular movement supported by Pixel energy calculations, that may pave the way for the future design and development of functioning dynamic crystals

Exploring the thermal behaviour of the solvated structures of Nifedipine

Abstract: Understanding the solvation of pharmaceutical materials is an important part of materials discovery and development. The isolation and desolvation pathways can provide routes to new polymorphs as well as providing important information of intermolecular interactions that can be formed. Providing detailed in-situ structural data is vital to be able to fully characterise changes that may occur in the system. In this paper, we describe the isolation and characterisation of seven solvates of the L-type calcium channel antagonist, nifedipine using variable temperature powder X-ray diffraction so that the structural evolution as a function of temperature can be followed. The solvates reported herein can be split into those that are structurally similar to the previously reported DMSO and Dioxane solvates and those that have a unique crystal structure. Of particular note is the solvate with THF which has a hydrogen-bonding motif between the nifedipine molecules very similar to the metastable β-nifedipine. In addition to variable-temperature X-ray diffraction, the stability of the solid-forms was assessed using differential scanning calorimetry and thermogravimetric analysis and indicate that in all cases desolvation results in the thermodynamically stable α-polymorph of nifedipine even the THF solvate. From the diffraction data the pathway of desolvation during heating of the DMF solvate showed conversion to another likely 1:1 polymorph before desolvation to α-nifedipine. The desolvation of this material indicated a two-stage process; first the initial loss of 90% of the solvent before the last 10% on melting. The methanol solvate shows interesting negative-thermal expansion on heating, which is rarely reported in organic materials, but this behaviour can be linked back to the winerack-type hydrogen bonding pattern of the nifedipine molecules

High-Generation Amphiphilic Janus-Dendrimers as Stabilizing Agents for Drug Suspensions

Pharmaceutical nanosuspensions are formed when drug crystals are suspended in aqueous media in the presence of stabilizers. This technology offers a convenient way to enhance the dissolution of poorly water-soluble drug compounds. The stabilizers exert their action through electrostatic or steric interactions, however, the molecular requirements of stabilizing agents have not been studied extensively. Here, four structurally related amphiphilic Janus-dendrimers were synthesized and screened to determine the roles of different macromolecular domains on the stabilization of drug crystals. Physical interaction and nanomilling experiments have substantiated that Janus-dendrimers with fourth generation hydro- philic dendrons were superior to third generation analogues and Poloxamer 188 in stabilizing indomethacin suspensions. Contact angle and surface plasmon resonance measurements support the hypothesis that Janus-dendrimers bind to indomethacin surfaces via hydrophobic interactions and that the number of hydrophobic alkyl tails determines the adsorption kinetics of the Janus-dendrimers. The results showed that amphiphilic Janus-dendrimers adsorb onto drug particles and thus can be used to provide steric stabilization against aggregation and recrystallization. The modular synthetic route for new amphiphilic Janus-dendrimers offers, thus, for the first time a versatile platform for stable general-use stabilizing agents of drug suspensions.Peer reviewe