Mucopenetrating polymer - Lipid hybrid nanovesicles as subunits in alginate beads as an oral formulation.

Crossing the intestinal mucus layer remains a great hurdle in oral drug delivery. The viscous mucus gel protects the body from pathogens but simultaneously traps many types of delivery vehicles, limiting their therapeutic efficacy. We report the assembly of mucopenetrating PEG-based polymer-lipid hybrid vesicles encapsulated in mucoadhesive alginate carriers aiming to increase their residence time in the intestine. The stability of the formulations was evaluated in simulated gastrointestinal conditions, showing negligible subunit leakage in the gastric fluid but a substantial release in the intestinal fluid. Mucopenetration of the free and encapsulated subunits was first demonstrated in vitro in a microfluidic set-up filled with reconstituted porcine mucus and in a mucus-covered co-culture of Caco-2 cells and HT29-MTX-E12 cells. Finally, the free and encapsulated subunits remained adhered in close proximity to the intestinal epithelium after oral administration to rats while the alginate carriers were washed away. In conclusion, the double-encapsulated system with combined mucoadhesive and mucopenetrating properties is a promising alternative drug carrier for oral delivery.

Recent Advancements in Using Polymers for Intestinal Mucoadhesion and Mucopenetration.

Oral administration of actives is the most desired form of delivery, but the formulations need to overcome a variety of barriers including the intestinal mucus. This feature article summarizes the developments from the past 2-3 years in this context focusing on polymer-based formulations. The progress in assembling mucopenetrating nanoparticles is outlined considering coatings using noninteracting polymers as well as virus-like particles and charge-shifting particles. Next, polymers and their modification to enhance mucoadhesion are discussed, followed by providing examples of double-encapsulation systems that aim to combine mucopenetration with mucoadhesion in the same formulation. Finally, a short outlook is provided highlighting a few of the most pressing challenges to address.

Microswimmers with Heat Delivery Capacity for 3D Cell Spheroid Penetration.

Micro- and nanoswimmers are a fast emerging concept that changes how colloidal and biological systems interact. They can support drug delivery vehicles, assist in crossing biological barriers, or improve diagnostics. We report microswimmers that employ collagen, a major extracellular matrix (ECM) constituent, as fuel and that have the ability to deliver heat via incorporated magnetic nanoparticles when exposed to an alternating magnetic field (AMF). Their assembly and heating properties are outlined followed by the assessment of their calcium-triggered mobility in aqueous solution and collagen gels. It is illustrated that the swimmers in collagen gel in the presence of a steep calcium gradient exhibit fast and directed mobility. The experimental data are supported with theoretical considerations. Finally, the successful penetration of the swimmers into 3D cell spheroids is shown, and upon exposure to an AMF, the cell viability is impaired due to the locally delivered heat. This report illustrates an opportunity to employ swimmers to enhance tissue penetration for cargo delivery via controlled interaction with the ECM.

Interaction of cells with patterned reactors.

Surface coatings that allow externally controlled interaction with cells are of interested for diverse biomedical applications. We fabricated particle patterns and assessed the interaction of these substrates with endothelial cells and hepatocytes. The particles were turned into subcompartmentalized reactors by immobilizing glucose oxidase loaded liposomes sandwiched between polymer layers. The reactor activities depending on the number of liposome deposition steps were confirmed in solution and on patterned surfaces. Finally, reduced viability of hepatocytes adhering to the reactor patterned surfaces in the presence of glucose was observed due to the local production of hydrogen peroxide. This first report on patterned reactors in combination with cells opens up vast opportunities to assemble interactive nanobiointerfaces.

Platinum Nanoparticle-Based Microreactors as Support for Neuroblastoma Cells.

Excitotoxicity is a common phenomenon in several neurological diseases, associated with an impaired clearance of synaptically released glutamate, which leads to an overactivation of postsynaptic glutamate receptors. This will, in turn, start an intracellular cascade of neurotoxic events, which include exacerbated production of reactive oxygen species and ammonia toxicity. We report the assembly of microreactors equipped with platinum nanoparticles as artificial enzymes and polymer terminating layers including poly(dopamine). The biological response to these microreactors is assessed in human neuroblastoma cell culture. The microreactors' function to deplete hydrogen peroxide (H2O2) and ammonia is confirmed. While the proliferation of the cells depends on the number of microreactors present, no inherent toxicity is found. Furthermore, the microreactors are able to ameliorate the effects of excitotoxicity in cell culture by scavenging H2O2 and ammonia, thus having the potential to provide a therapeutic approach for several neurological diseases in which excitotoxicity is observed.

Mucopenetrating micelles with a PEG corona.

Crossing the intestinal mucus layer is a long-standing challenge for orally delivered nanoparticles carrying therapeutic cargo. We report the assembly of mucopenetrating cargo-loaded micelles using block copolymers consisting of either linear poly(ethylene glycol) (PEG) or bottle-brush poly(oligo(ethylene glycol)methacrylate) (PEGb) as the hydrophilic block and poly(caprolactone) (PCL) or poly(cholesteryl methacrylate) (PCMA) as the hydrophobic extension. The micelles were shown to preserve their stability and retain ∼50% of their cargo in simulated gastric fluid. The ability of micelles to diffuse through reconstituted porcine mucus was assessed in a microfluidic set-up. Finally, the delivery of Nile Red as a hydrophobic model cargo across a mucus layer produced by epithelial cells was demonstrated. These engineered mucopenetrating micelles have potential to be developed into efficient absorption enhancers, contributing a nanotechnology solution to oral drug delivery.

A Polymer Chemistry Point of View on Mucoadhesion and Mucopenetration.

Although oral is the preferred route of administration of pharmaceutical formulations, the long-standing challenge for medically active compounds to efficiently cross the mucus layer barrier limits its wider applicability. Efforts in nanomedicine to overcome this hurdle consider mucoadhesive and mucopenetrating drug carriers by selectively designing (macromolecular) building blocks. This review highlights and critically discusses recent strategies developed in this context including poly(ethylene glycol)-based modifications, cationic and thiolated polymers, as well as particles with high charge density, zeta-potential shifting ability, or mucolytic properties. The latest advances in ex vivo test platforms are also reviewed.

Droplet-microfluidics towards the assembly of advanced building blocks in cell mimicry.

Therapeutic cell mimicry is an approach in nanomedicine aiming at substituting for missing or lost cellular functions employing nature-inspired concepts. Pioneered decades ago, only now is this technology empowered with the arsenal of nanotechnological tools and ready to provide radically new solutions such as assembling synthetic organelles and artificial cells. One of these tools is droplet microfluidics (D-µF), which provides the flexibility to generate cargo-loaded particles with tunable size and shape in a fast and reliable manner, an essential requirement in cell mimicry. This minireview aims at outlining the developments in D-µF from the past four years focusing on the assembly of nanoparticles, Janus-shaped and other non-spherical particles as well as their loading with biological payloads.