Translating innovative nanomaterials to medical products requires efficient manufacturing techniques that enable large-scale high-throughput synthesis and high reproducibility. Drug carriers in... Show moreTranslating innovative nanomaterials to medical products requires efficient manufacturing techniques that enable large-scale high-throughput synthesis and high reproducibility. Drug carriers in medicine embrace a complex subset of tasks calling for multi-functionality. Here, we report the synthesis of pro-drug-loaded core cross-linked polymeric micelles (CCPMs) in a continuous flow process, which combines the commonly separated steps of micelle formation, core cross-linking, functionalization, and purification into a single process. Redox-responsive CCPMs are formed from thiol-reactive polypept(o)ides of polysarcosine-block-poly(S-ethylsulfonyl-l-cysteine) and functional cross-linkers based on dihydrolipoic acid hydrazide for pH-dependent release of paclitaxel. The precisely controlled microfluidic self-assembly and purification process allows the production of spherical micelles (Dh = 35 nm) with low polydispersity values (PDI<0.1) while avoiding toxic organic solvents and additives with unfavorable safety profiles. Self-assembly and cross-linking via slit interdigital micromixers produce 350-700 mg of CCPMs/h per single system, while purification by online tangential flow filtration successfully removes impurities (unimer ≤ 0.5%). The formed paclitaxel-loaded CCPMs possess the desired pH-responsive release profile, display stable drug encapsulation, an improved toxicity profile compared to Abraxane, and therapeutic efficiency in the B16F1-xenotransplanted zebrafish model. The combination of reactive polymers, functional cross-linkers, and microfluidics enables the continuous-flow synthesis of therapeutically active CCPMs in a single process. This article is protected by copyright. All rights reserved. Show less
Lipid nanoparticles (LNPs) are the leading nonviral technologies for the delivery of exogenous RNA to target cells in vivo. As systemic delivery platforms, these technologies are exemplified by... Show moreLipid nanoparticles (LNPs) are the leading nonviral technologies for the delivery of exogenous RNA to target cells in vivo. As systemic delivery platforms, these technologies are exemplified by Onpattro, an approved LNP-based RNA interference therapy, administered intravenously and targeted to parenchymal liver cells. The discovery of systemically administered LNP technologies capable of preferential RNA delivery beyond hepatocytes has, however, proven more challenging. Here, preceded by comprehensive mechanistic understanding of in vivo nanoparticle biodistribution and bodily clearance, an LNP-based messenger RNA (mRNA) delivery platform is rationally designed to preferentially target the hepatic reticuloendothelial system (RES). Evaluated in embryonic zebrafish, validated in mice, and directly compared to LNP-mRNA systems based on the lipid composition of Onpattro, RES-targeted LNPs significantly enhance mRNA expression both globally within the liver and specifically within hepatic RES cell types. Hepatic RES targeting requires just a single lipid change within the formulation of Onpattro to switch LNP surface charge from neutral to anionic. This technology not only provides new opportunities to treat liver-specific and systemic diseases in which RES cell types play a key role but, more importantly, exemplifies that rational design of advanced RNA therapies must be preceded by a robust understanding of the dominant nano-biointeractions involved. Show less
Lipid nanoparticles (LNPs) are the leading nonviral technologies for the delivery of exogenous RNA to target cells in vivo. As systemic delivery platforms, these technologies are exemplified by... Show moreLipid nanoparticles (LNPs) are the leading nonviral technologies for the delivery of exogenous RNA to target cells in vivo. As systemic delivery platforms, these technologies are exemplified by Onpattro, an approved LNP-based RNA interference therapy, administered intravenously and targeted to parenchymal liver cells. The discovery of systemically administered LNP technologies capable of preferential RNA delivery beyond hepatocytes has, however, proven more challenging. Here, preceded by comprehensive mechanistic understanding of in vivo nanoparticle biodistribution and bodily clearance, an LNP-based messenger RNA (mRNA) delivery platform is rationally designed to preferentially target the hepatic reticuloendothelial system (RES). Evaluated in embryonic zebrafish, validated in mice, and directly compared to LNP-mRNA systems based on the lipid composition of Onpattro, RES-targeted LNPs significantly enhance mRNA expression both globally within the liver and specifically within hepatic RES cell types. Hepatic RES targeting requires just a single lipid change within the formulation of Onpattro to switch LNP surface charge from neutral to anionic. This technology not only provides new opportunities to treat liver-specific and systemic diseases in which RES cell types play a key role but, more importantly, exemplifies that rational design of advanced RNA therapies must be preceded by a robust understanding of the dominant nano-biointeractions involved. Show less
Electrochemical sensors for detecting micromolecule organics are desirable for improving the perception of environmental quality and human health. However, currently, the electrochemical sensors... Show moreElectrochemical sensors for detecting micromolecule organics are desirable for improving the perception of environmental quality and human health. However, currently, the electrochemical sensors for formaldehyde are substantially limited on the market due to the long-term unsolved problems of the low electrooxidation efficiency and CO poisoning issue of commercial Pd catalysts. Here, a 2D Cr-doped Pd metallene (Cr-Pdene) with few atomic layers is shown as an advanced catalyst for ultrasensitive and selective sensing of formaldehyde via a highly efficient formaldehyde electrooxidation. It is found that the doping of Cr into Pd metallene can efficiently optimize the electronic structure of Pd and weaken the interaction between Pd and CO, providing an anti-poisoning means to favor CO2 production and suppress CO adsorption. The Cr-Pdene-based electrochemical sensor exhibits one order of magnitude higher detection range and, especially, much higher anti-interference for formaldehyde than that of the conventional sensors. Most importantly, it is demonstrated that the Cr-Pdene can be integrated into commercializable wireless sensor networks or handheld instruments for promising applications relating to the environment, health, and food. Show less
Zhou, X.Q.; Mytiliniou, M.; Hilgendorf, J.; Zeng, Y.; Papadopoulou, P.; Shao, Y.; ... ; Bonnet, S. 2021
Many drug delivery systems end up in the lysosome because they are built from covalent or kinetically inert supramolecular bonds. To reach other organelles, nanoparticles hence need to either be... Show moreMany drug delivery systems end up in the lysosome because they are built from covalent or kinetically inert supramolecular bonds. To reach other organelles, nanoparticles hence need to either be made from a kinetically labile interaction that allows re-assembly of the nanoparticles inside the cell following endocytic uptake, or, be taken up by a mechanism that short-circuits the classical endocytosis pathway. In this work, the intracellular fate of nanorods that self-assemble via the Pt horizontal ellipsis Pt interaction of cyclometalated platinum(II) compounds, is studied. These deep-red emissive nanostructures (638 nm excitation, approximate to 700 nm emission) are stabilized by proteins in cell medium. Once in contact with cancer cells, they cross the cell membrane via dynamin- and clathrin-dependent endocytosis. However, time-dependent confocal colocalization and cellular electron microscopy demonstrate that they directly move to mitochondria without passing by the lysosomes. Altogether, this study suggests that Pt horizontal ellipsis Pt interaction is strong enough to generate emissive, aggregated nanoparticles inside cells, but labile enough to allow these nanostructures to reach the mitochondria without being trapped in the lysosomes. These findings open new venues to the development of bioimaging nanoplatforms based on the Pt horizontal ellipsis Pt interaction. Show less
Hendrikse, H.C.; Weijden, A. van der; Ronda-Lloret, M.; Yang, T.; Bliem, R.; Raveendran Shiju, N.; ... ; Noorduin, W.L. 2020
Direct electrical probing of molecular materials is often impaired by their insulating nature. Here, graphene is interfaced with single crystals of a molecular spin crossover complex, [Fe(bapbpy)... Show moreDirect electrical probing of molecular materials is often impaired by their insulating nature. Here, graphene is interfaced with single crystals of a molecular spin crossover complex, [Fe(bapbpy)(NCS)2], to electrically detect phase transitions in the molecular crystal through the variation of graphene resistance. Contactless sensing is achieved by separating the crystal from graphene with an insulating polymer spacer. Next to mechanical effects, which influence the conductivity of the graphene sheet but can be minimized by using a thicker spacer, a Dirac point shift in graphene is observed experimentally upon spin crossover. As confirmed by computational modeling, this Dirac point shift is due to the phase‐dependent electrostatic potential generated by the crystal inside the graphene sheet. This effect, named as chemo‐electric gating, suggests that molecular materials may serve as substrates for designing graphene‐based electronic devices. Chemo‐electric gating, thus, opens up new possibilities to electrically probe chemical and physical processes in molecular materials in a contactless fashion, from a large distance, which can enhance their use in technological applications, for example, as sensors. Show less
The spatial resolution and signal-to-noise ratio (SNR) attainable in magnetic resonance microscopy (MRM) are limited by intrinsic probe losses and probe-sample interactions. In this work, the... Show moreThe spatial resolution and signal-to-noise ratio (SNR) attainable in magnetic resonance microscopy (MRM) are limited by intrinsic probe losses and probe-sample interactions. In this work, the possibility to exceed the SNR of a standard solenoid coil by more than a factor-of-two is demonstrated theoretically and experimentally. This improvement is achieved by exciting the first transverse electric mode of a low-loss ceramic resonator instead of using the quasi-static field of the metal-wire solenoid coil. Based on theoretical considerations, a new probe for microscopy at 17 T is developed as a dielectric ring resonator made of ferroelectric/dielectric low-loss composite ceramics precisely tunable via temperature control. Besides the twofold increase in SNR, compared with the solenoid probe, the proposed ceramic probe does not cause static-field inhomogeneity and related image distortion. Show less
Maruccio, G.; Biasco, A.; Visconti, P.; Bramanti, A.; Pompa, P. P.; Calabi, F.; ... ; Canters, G. W. 2005
A protein field-effect transistor (Pro-FET) based on the blue-copper protein azurins (see Figure) and operating at room temperature and ambient pressure is demonstrated. The transfer... Show moreA protein field-effect transistor (Pro-FET) based on the blue-copper protein azurins (see Figure) and operating at room temperature and ambient pressure is demonstrated. The transfer characteristics of the Pro-FET exhibit a pronounced resonance due to the switch from behaving as a n-metal oxide semiconductor FET (n-MOSFET) to a p-MOSFET. Carrier transport through the device is explained in terms of an equilibrium between the two possible oxidation states of the redox site (Cu1+ and Cu2+). Show less
