Molecular and cellular cues governing nanomaterial-mucosae interactions: from nanomedicine to nanotoxicology.

Mucosal tissues constitute the largest interface between the body and the surrounding environment and they regulate the access of molecules, supramolecular structures, particulate matter, and pathogens into it. All mucosae are characterized by an outer mucus layer that protects the underlying cells from physicochemical, biological and mechanical insults, a mono-layered or stratified epithelium that forms tight junctions and controls the selective transport of solutes across it and associated lymphoid tissues that play a sentinel role. Mucus is a gel-like material comprised mainly of the glycoprotein mucin and water and it displays both hydrophilic and hydrophobic domains, a net negative charge, and high porosity and pore interconnectivity, providing an efficient barrier for the absorption of therapeutic agents. To prolong the residence time, absorption and bioavailability of a broad spectrum of active compounds upon mucosal administration, mucus-penetrating and mucoadhesive particles have been designed by tuning the chemical composition, the size, the density, and the surface properties. The benefits of utilizing nanomaterials that interact intimately with mucosae by different mechanisms in the nanomedicine field have been extensively reported. To ensure the safety of these nanosystems, their compatibility is evaluated in vitro and in vivo in preclinical and clinical trials. Conversely, there is a growing concern about the toxicity of nanomaterials dispersed in air and water effluents that unintentionally come into contact with the airways and the gastrointestinal tract. Thus, deep understanding of the key nanomaterial properties that govern the interplay with mucus and tissues is crucial for the rational design of more efficient drug delivery nanosystems (nanomedicine) and to anticipate the fate and side-effects of nanoparticulate matter upon acute or chronic exposure (nanotoxicology). This review initially overviews the complex structural features of mucosal tissues, including the structure of mucus, the epithelial barrier, the mucosal-associated lymphatic tissues and microbiota. Then, the most relevant investigations attempting to identify and validate the key particle features that govern nanomaterial-mucosa interactions and that are relevant in both nanomedicine and nanotoxicology are discussed in a holistic manner. Finally, the most popular experimental techniques and the incipient use of mathematical and computational models to characterize these interactions are described.

Selective Accumulation of Galactomannan Amphiphilic Nanomaterials in Pediatric Solid Tumor Xenografts Correlates with GLUT1 Gene Expression.

In this work, we designed, characterized, and investigated the performance of hydrolyzed galactomannan (hGM)-based amphiphilic nanoparticles for selective intratumoral accumulation in pediatric patient-derived sarcomas. To create a self-assembly amphiphilic copolymer, the side chain of hGM was hydrophobized with poly(methyl methacrylate) (PMMA) by utilizing a graft free radical polymerization reaction. Different hGM and MMA weight feeding ratios were used to adjust the critical aggregation concentration and the size and size distribution of the nanoparticles. The ability to actively target glucose transporter-1 (GLUT-1) was studied by fluorescence confocal microscopy and imaging flow cytometry in vitro on Rh30 (rhabdomyosarcoma) and patient-derived Ewing sarcoma (HSJD-ES-001) cell lines with different expression levels of GLUT-1. Results confirmed that the nanoparticles are internalized by ∼100% of the cells at 37 °C. Furthermore, we investigated the biodistribution of the nanoparticles in pediatric patient-derived models of two deadly musculoskeletal tumors, rhabdomyosarcoma and Ewing sarcoma. Outstandingly, the intratumoral accumulation of the nanoparticles correlated very well with the expression level of GLUT1 gene in each patient-derived tumor (P = 0.0141; Pearson's correlation test). Finally, we demonstrated the encapsulation capacity of these nanoparticles by loading 7.5% (w/w) of the hydrophobic first-generation tyrosine kinase inhibitor imatinib. These findings point out the potential of this new type of nanoparticle to target GLUT-1-expressing tumors and selectively deliver anticancer agents.

Electrohydrodynamic atomization and spray-drying for the production of pure drug nanocrystals and co-crystals.

In recent years, nanotechnology has offered attractive opportunities to overcome the (bio)pharmaceutical drawbacks of most drugs such as low aqueous solubility and bioavailability. Among the numerous methodologies that have been applied to improve drug performance, a special emphasis has been made on those that increase the dissolution rate and the saturation solubility by the reduction of the particle size of pure drugs to the nanoscale and the associated increase of the specific surface area. Different top-down and bottom-up methods have been implemented, each one with its own pros and cons. Over the last years, the latter that rely on the dissolution of the drug in a proper solvent and its crystallization or co-crystallization by precipitation in an anti-solvent or, conversely, by solvent evaporation have gained remarkable impulse owing to the ability to adjust features such as size, size distribution, morphology and to control the amorphous/crystalline nature of the product. In this framework, electrohydrodynamic atomization (also called electrospraying) and spray-drying excel due to their simplicity and potential scalability. Moreover, they do not necessarily require suspension stabilizers and dry products are often produced during the formation of the nanoparticles what ensures physicochemical stability for longer times than liquid products. This review overviews the potential of these two technologies for the production of pure drug nanocrystals and co-crystals and discusses the recent technological advances and challenges for their implementation in pharmaceutical research and development.