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.
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.
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 (HO) 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 HO and ammonia, thus having the potential to provide a therapeutic approach for several neurological diseases in which excitotoxicity is observed.
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) (PEG) 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.
Biocatalytic intracellular active nanoreactors (artificial organelles) aim to support their host cells. Here, we report the first successful micelle-based artificial organelles containing a salen−manganese complex (EUK) as catalase mimic with intracellular activity in HepG2 cells to act as reactive oxygen species (ROS) scavengers. Four different EUKs were synthesized and compared in their ability to convert hydrogen peroxide to water and oxygen as free compounds and when encapsulated into micelles assembled from the amphiphilic block copolymer poly(cholesteryl methacrylate)-block-poly(2-(dimethylamino)ethyl methacrylate). An EUK candidate with an asymmetric substitution of chemical groups at the ortho and the meta position (EUK-B) was identified as lead candidate. HepG2 cells continued proliferating when preincubated with low concentrations of EUK-B-containing micelles (M B ). Importantly, HepG2 cells equipped with M B showed improved viability compared to the controls when stressed with paraquat, a compound that induces ROS generation. The intracellular activity of M B was supported by lower amounts of intracellular detectable ROS. This first report on the combination of artificial enzymes and artificial organelles further extends the opportunities in therapeutic cell mimicry.
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