Enrico Miceli

Stimuli-responsive nanogel composites and their application in nanomedicine

Nanogels are nanosized crosslinked polymer networks capable of absorbing large quantities of water. Specifically, smart nanogels are interesting because of their ability to respond to biomedically relevant changes like pH, temperature, etc. In the last few decades, hybrid nanogels or composites have been developed to overcome the ever increasing demand for new materials in this field. In this context, a hybrid refers to nanogels combined with different polymers and/or with nanoparticles such as plasmonic, magnetic, and carbonaceous nanoparticles, among others. Research activities are focused nowadays on using multifunctional hybrid nanogels in nanomedicine, not only as drug carriers but also as imaging and theranostic agents. In this review, we will describe nanogels, particularly in the form of composites or hybrids applied in nanomedicine.

Lewis Acid Trapping of an Elusive Copper–Tosylnitrene Intermediate Using Scandium Triflate

High-valent copper-nitrene intermediates have long been proposed to play a role in copper-catalyzed aziridination and amination reactions. However, such intermediates have eluded detection for decades, preventing the unambiguous assignments of mechanisms. Moreover, the electronic structure of the proposed copper-nitrene intermediates has also been controversially discussed in the literature. These mechanistic questions and controversy have provided tremendous motivation to probe the accessibility and reactivity of Cu(III)-NR/Cu(II)N(•)R species. In this paper, we report a breakthrough in this field that was achieved by trapping a transient copper-tosylnitrene species, 3-Sc, in the presence of scandium triflate. The sufficient stability of 3-Sc at -90 °C enabled its characterization with optical, resonance Raman, NMR, and X-ray absorption near-edge spectroscopies, which helped to establish its electronic structure as Cu(II)N(•)Ts (Ts = tosyl group) and not Cu(III)NTs. 3-Sc can initiate tosylamination of cyclohexane, thereby suggesting Cu(II)N(•)Ts cores as viable reactants in oxidation catalysis.

A High‐Valent Heterobimetallic [CuIII(μ‐O)2NiIII]2+ Core with Nucleophilic Oxo Groups

A heterobimetallic CuNi bis(μ-oxo) diamond core is shown to possess nucleophilic oxo groups, and has been demonstrated for the first time as a viable intermediate during the deformylation of fatty aldehydes by cyanobacterial aldehyde decarbonylase.

Mechanism of phenol oxidation by heterodinuclear Ni Cu bis(μ-oxo) complexes involving nucleophilic oxo groups

Oxidation of phenols by heterodinuclear Cu(III)(μ-O)2Ni(III) complexes containing nucleophilic oxo groups occurs by both proton coupled electron transfer (PCET) and hydrogen atom transfer (HAT) mechanisms; the exact mechanism depends on the nature of the phenol as well as the substitution pattern of the ligand bound to Cu.

Rational design of dendritic thermoresponsive nanogels that undergo phase transition under endolysosomal conditions

In the last few decades, the synthesis of nanodevices has become a very active research field with many applications in biochemistry, biotechnology, and biomedicine. However, there is still a great need for smart nanomaterials that can sense and respond to environmental changes. Temperature- and pH-responsive nanogels (NGs), which are prepared in a one-pot synthesis from N-isopropylacrylamide (NiPAm) and a Newkome-type dendron (ABC) bearing carboxylic acid groups, are being investigated as multi-responsive drug carriers. As a result, NGs have been developed that are able to undergo a reversible volume phase transition triggered by acidic conditions, like the ones found in endolysosomal compartments of cancer cells. The NGs have been thoroughly characterized using dynamic light scattering and spectroscopies, such as infrared, nuclear magnetic resonance, UV-visible, and stimulated Raman. Strong hydrogen bonds have been detected when the ABC moieties are deprotonated, which has led to changes in the transition temperatures of the NGs and a reversible, pH-dependent aggregation. This pH-dependent phase change was exploited for the effective encapsulation and sustained release of the anticancer drug cisplatin and resulted in a faster release of the drug at endolysosomal pH values. The cisplatin-loaded NGs have exhibited high toxicities against A549 cells in vitro, while the unloaded NGs have been found to be not cytotoxic and hemocompatible.

Understanding the elusive protein corona of thermoresponsive nanogels

AIM We analyzed the protein corona of thermoresponsive, poly(N-isopropylacrylamide)- or poly(N-isopropylmethacrylamide)-based nanogels. MATERIALS & METHODS Traces of protein corona detected after incubation in human serum were characterized by proteomics and dynamic light scattering in undiluted serum. RESULTS Apolipoprotein B-100 and albumin were the main components of the protein coronae. For dendritic polyglycerol-poly(N-isopropylacrylamide) nanogels at 37°C, an increase in adsorbed immunoglobulin light chains was detected, followed by partially reversible nanogel aggregation. All nanogels in their hydrophilic state are colloidally stable in serum and bear a dysopsonin-rich protein corona. CONCLUSION We observed strong changes in NG stability upon slight alterations in the composition of the protein coronae according to nanogel solvation state. Nanogels in their hydrophilic state possess safe protein coronae.

Semi-interpenetrated, dendritic, dual-responsive nanogels with cytochrome c corona induce controlled apoptosis in HeLa cells

Dendritic thermoresponsive nanogels loaded with cytochrome c corona induce controlled apoptosis upon sample cooling. ABSTRACT The use of thermoresponsive nanogels (NGs) allows the controlled release of therapeutic molecules upon a thermal switch. Usually, this strategy involves the use of temperature increase to activate cargo expulsion from shrinking NGs. In this study, poly(N‐isopropylacrylamide) (pNIPAM)‐based NGs were involved in the release of a therapeutic protein corona by temperature decrease. NGs based on dendritic polyglycerol (dPG) and thermoresponsive pNIPAM were semi‐interpenetrated with poly(4‐acryloylamine‐4‐(carboxyethyl)heptanodioic acid) (pABC). The resulting semi‐interpenetrated NGs retain the thermoresponsive properties of pNIPAM, together with pH‐responsive, dendritic pABC as a secondary network, in one single nanoparticle. Semi‐interpenetrated polymer network (SIPN) NGs are stable in physiological conditions, exhibit a reversible phase transition at 35°C, together with tunable electrophoretic mobilities around the body temperature. The binding of cytochrome c (cyt c) was successful on SIPN NGs in their collapsed state at 37°C. Upon cooling of the samples to room temperature, the swelling of the NG effectively boosted the release of cyt c, as compared with the same kept at constant 37°C. These responsive SIPN NGs were able to deliver cyt c to cancer cells and specifically induce apoptosis at 30°C, while the cells remained largely unaffected at 37°C. In this way, we show therapeutic efficacy of thermoresponsive NGs as protein carriers and their efficacy triggered by temperature decrease. We envision the use of such thermal trigger as relevant for the treatment of superficial tumors, in which induction of apoptosis can be controlled by the application of local cooling agents.