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Exploiting the local heat on the surface of magnetic nanoparticles (MNPs) upon exposure to an alternating magnetic field (AMF) to cleave thermal labile bonds represents an interesting approach in the context of remotely triggered drug delivery. Here, taking advantages of a simple and scalable two-step ligand exchange reaction, we have prepared iron oxide nanocubes (IONCs) functionalized with a novel multifunctional polymer ligand having multiple catechol moieties, furfuryl pendants, and polyethylene glycol (PEG) side chains. Catechol groups ensure a strong binding of the polymer ligands to the IONCs surface, while the PEG chains provide good colloidal stability to the polymer-coated IONCs. More importantly, furfuryl pendants on the polymer enable to click the molecules of interest (either maleimide–fluorescein or maleimide–doxorubicin) via a thermal labile Diels–Alder adduct. The resulting IONCs functionalized with a fluorescein/doxorubicin-conjugated polymer ligand exhibit good colloidal stability in buffer saline and serum solution along with outstanding heating performance in aqueous solution or even in viscous media (81% glycerol/water) when exposed to the AMF of clinical use. The release of conjugated bioactive molecules such as fluorescein and doxorubicin could be boosted by applying AMF conditions of clinical use (16 kAm–1 and 110 kHz). It is remarkable that the magnetic hyperthermia-mediated release of the dye/drug falls in the concentration range 1.0–5.0 μM at an IONCs dose as low as 0.5 gFe/L and at no macroscopical temperature change. This local release effect makes this magnetic nanoplatform a potential tool for drug delivery with remote magnetic hyperthermia actuation and with a dose-independent action of MNPs. This work was partially supported by the Marie Sklodowska-Curie Innovative training network MSCA-ITN-ETN (HeatNMof project, GA 860942), partially by the AIRC Foundation (AIRC IG-14527 to T.P.), partially by the European Research Council (starting grant ICARO, Contract No. 678109), and partially by ERC proof of concept Hypercube, Contract No. 899661).

Active packaging materials, biodegradable and from renewable resources, are the most promising substitutes of nonbiodegradable, petroleum-based plastics, toward green and sustainable packaging solutions. In this study, an innovative bioplastic system, composed of carbon dioxide-derived poly(propylene carbonate) (PPC) and nature-originated cellulose acetate (CA), was developed. The extract from oregano waste was incorporated into the bioplastics as a low-cost and effective antioxidant resource. Thin, freestanding, and flexible PPC.CA bioplastic films were obtained by a simple, easily scalable solvent casting technique. The pristine films, without the oregano extract, featured good transparency and high water vapor barrier ability, along with suitable mechanical and thermal properties that are comparable to commercial plastics used for packaging. Interestingly, the incorporation of oregano waste extract added to the bioplastics high UV protection and high antioxidant activity, suitable features for active food packaging applications, without compromising the intriguing properties of the pristine films. The biocomposite films were not only biocompatible but also started biodegrading after just 1 week in seawater. The reported biocomposites are foreseen as promising candidates for several packaging applications, but in particular for sustainable active food packaging.

This protocol describes a solvothermal-based process to prepare gram-scale ferrite nanoparticles with well-defined shapes (nanocubes, nanostarts, faceted nanoparticles and nanospheres) having heating properties specifically appealing for magnetic hyperthermia applications of clinical used.

Magnetic hyperthermia (MHT) is a therapeutic modality for the treatment of solid tumors that has now accumulated more than 30 years of experience. In the ongoing MHT clinical trials for the treatment of brain and prostate tumors, iron oxide nanoparticles are employed as intra-Tumoral MHT agents under a patient-safe 100 kHz alternating magnetic field (AMF) applicator. Although iron oxide nanoparticles are currently approved by FDA for imaging purposes and for the treatment of anemia, magnetic nanoparticles (MNPs) designed for the efficient treatment of MHT must respond to specific physical-chemical properties in terms of magneto-energy conversion, heat dose production, surface chemistry and aggregation state. Accordingly, in the past few decades, these requirements have boosted the development of a new generation of MNPs specifically aimed for MHT. In this review, we present an overview on MNPs and their assemblies produced via different synthetic routes, focusing on which MNP features have allowed unprecedented heating efficiency levels to be achieved in MHT and highlighting nanoplatforms that prevent magnetic heat loss in the intracellular environment. Moreover, we review the advances on MNP-based nanoplatforms that embrace the concept of multimodal therapy, which aims to combine MHT with chemotherapy, radiotherapy, immunotherapy, photodynamic or phototherapy. Next, for a better control of the therapeutic temperature at the tumor, we focus on the studies that have optimized MNPs to maintain gold-standard MHT performance and are also tackling MNP imaging with the aim to quantitatively assess the amount of nanoparticles accumulated at the tumor site and regulate the MHT field conditions. To conclude, future perspectives with guidance on how to advance MHT therapy will be provided. This journal is

Multi-dentate ligands enabling a quick and high yield water transfer of inorganic nanocrystals (NCs) via a ligand exchange process is of great interest to promote the applications of NCs in the biomedical field. Here, we describe a facile two-step protocol for the synthesis of polymeric multi-dentate ligands that are suitable for the water transfer of hydrophobic colloidal inorganic nanocrystals (NCs). This protocol first exploits the photo-induced atom transfer radical (photo-ATRP) copolymerization of ester-activated N-succinimidyl methacrylate and oligoethylene glycol methyl ether methacrylate. A high monomer conversion rate along with a fair control over the polymerization is confirmed by size exclusion chromatography and nuclear magnetic resonance spectroscopy. In the second step, the activated carboxyl moieties of the copolymers are reacted with nucleophilic agents such as 2-aminoethylphosphonic acid or histamine dihydrochloride via a post-polymerization reaction to generate phosphonic- or amino-based multi-dentate ligands, respectively. As shown here, polymers comprising poly-phosphonic acid moieties are suitable as multi-dentate ligands for water transfer of multiple varieties of NCs with distinct compositions including iron oxide nanoparticles, CdSe@CdS quantum dots (QDs) and up-converting nanoparticles (UCNPs). Meanwhile the polymers containing histamine groups are also able to strongly coordinate to the surface of semiconductor QDs, thus enabling their water transfer. Notably, the NCs exhibit long-term stability in physiological media (saline) upon water transfer, while their size, shape, magnetic properties, and optical properties were also maintained. The UCNPs could be imaged when excited under an infrared laser while the QDs show a bright fluorescence signal under UV irradiation. QDs coated with a poly-phosphonic acid-based ligand resulted in a more homogeneous coating as demonstrated by the narrow band on gel electrophoresis, along with a higher quantum yield (QY ∼48%) in comparison with the polyimidazole-based ones (QY ∼31%). The aqueous IONPs instead were proven to provide a transversal relaxation making them useful as contrast agents in magnetic resonance imaging. The water transfer procedure is straightforward thanks to the full solubility of the amphiphilic polymer in the NC chloroform solution. This enables the right interaction between the anchoring moieties on the polymer chains and the surface of NCs, thus replacing the surfactant molecules. The gram scale production of the polymer together with the very simple steps of the water transfer protocol enables a quick translation of the protocol for large scale production of aqueous stabilized nanoparticles.

We report a one-step synthesis of halide perovskite nanocrystals embedded in amphiphilic polymer (poly(acrylic acid)-block-poly(styrene), PAA-b-PS) micelles, based on injecting a dimethylformamide solution of PAA-b-PS, PbBr2, ABr (A = Cs, formamidinium, or both) and “additive” molecules in toluene. These bifunctional or trifunctional short chain organic molecules improve the nanocrystal–polymer compatibility, increasing the nanocrystal stability against polar solvents and high flux irradiation (the nanocrystals retain almost 80% of their photoluminescence after 1 h of 3.2 w/cm2 irradiation). If the nanocrystals are suspended in toluene, the coil state of the polymer allows the nanocrystals to undergo halide exchange, enabling emission color tunability. If the nanocrystals are suspended in methanol, or dried as powders, the polymer is in the globule state, and they are inert to halide exchange. By mixing three primary colors we could prepare stable, multicolor emissive samples (for example, white emitting powders) and a UV-to-white color converting layer for light-emitting diodes entirely made of perovskite nanocrystals.

Herein, we have developed pH-responsive shape-persistent polymersomes made of well-defined amphiphilic poly(ethylene oxide)-block-poly(diisopropylaminoethyl methacrylate-co-furfuryl methacrylate)s PEO-b-P(DPAco- FMA) by exploiting Diels-Alder chemistry as a robust and simple crosslinking method. Using Photo-induced Copper Mediated Reversible Deactivation Radical Polymerization, we synthesized PEO-b-P(DPA-co-FMA) with optimal block ratios that favor the formation of polymersomes in aqueous media having pH-responsive P(DPAco- FMA) membranes. Owing to the existence of furfuryl pendant groups within the polymersome membranes, the crosslinking of pH-responsive P(DPA-co-FMA) chains can be achieved via Diels-Alder chemistry. Interestingly, the resulting crosslinked polymersomes swell when the pH in the solution is decreased so that it lies in a biologically relevant range, as was demonstrated by cryogenic transmission electron microscopy. Here, the polymersomes' ability to swell can be controlled by adjusting the amount of crosslinker. A minimum threshold of crosslinking density is needed for the polymersomes to swell while an excess amount of crosslinker quenched their ability to swell. Furthermore, crosslinked polymersomes are capable of encapsulating hydrophilic model drug, such as Rhodamine B. At pH 7.20, due to the compact and hydrophobic membrane, the diffusion of the dye from the interior of the polymersomes to the media is minimized, while the pronation of PDPA at an acidic pH of 4.00, enables a permeable membrane, allowing the loaded cargo to leak much more quickly. The shape-persistent polymersomes that we developed herein, are a promising nano-platform for use in drug delivery applications.

Herein, by studying a stepwise phase transformation of 23 nm FeO–Fe3O4core–shell nanocubes into Fe3O4, we identify a composition at which the magnetic heating performance of the nanocubes is not affected by the medium viscosity and aggregation. Structural and magnetic characterizations reveal the transformation of the FeO–Fe3O4nanocubes from having stoichiometric phase compositions into Fe2+-deficient Fe3O4phases. The resultant nanocubes contain tiny compressed and randomly distributed FeO subdomains as well as structural defects. This phase transformation causes a 10-fold increase in the magnetic losses of the nanocubes, which remain exceptionally insensitive to the medium viscosity as well as aggregation unlike similarly sized single-phase magnetite nanocubes. We observe that the dominant relaxation mechanism switches from Néel in fresh core–shell nanocubes to Brownian in partially oxidized nanocubes and once again to Néel in completely treated nanocubes. The Fe2+deficiencies and structural defects appear to reduce the magnetic energy barrier and anisotropy field, thereby driving the overall relaxation into Néel process. The magnetic losses of these nanoparticles remain unchanged through a progressive internalization/association to ovarian cancer cells. Moreover, the particles induce a significant cell death after being exposed to hyperthermia treatment. Here, we present the largest heating performance that has been reported to date for 23 nm iron oxide nanoparticles under intracellular conditions. Our findings clearly demonstrate the positive impacts of the Fe2+deficiencies and structural defects in the Fe3O4structure on the heating performance into intracellular environment.

Cancer stem cells (CSCs) are the tumor cell subpopulation responsible for resistance to chemotherapy, tumor recurrence, and metastasis. An efficient therapy must act on low proliferating quiescent-CSCs (q-CSCs). We here investigate the effect of magnetic hyperthermia (MHT) in combination with local chemotherapy as a dual therapy to inhibit patient-derived colorectal qCR-CSCs. We apply iron oxide nanocubes as MHT heat mediators, coated with a thermoresponsive polymer (TR-Cubes) and loaded with DOXO (TR-DOXO) as a chemotherapeutic agent. The thermoresponsive polymer releases DOXO only at a temperature above 44 °C. In colony-forming assays, the cells exposed to TR-Cubes with MHT reveal that qCR-CSCs struggle to survive the heat damage and, with a due delay, restart the division of dormant cells. The eradication of qCR-CSCs with a complete stop of the colony formation was achieved only with TR-DOXO when exposed to MHT. The in vivo tumor formation study confirms the combined effects of MHT with heat-mediated drug release: only the group of animals that received the CR-CSCs pretreated, in vitro, with TR-DOXO and MHT lacked the formation of tumor even after several months. For DOXO-resistant CR-CSCs cells, the same results were shown, in vitro, when choosing the drug oxaliplatin rather than DOXO and applying MHT. These findings emphasize the potential of our nanoplatforms as an effective patient-personalized cancer treatment against qCR-CSCs.

Active packaging materials, biodegradable and from renewable resources, are the most promising substitutes of nonbiodegradable, petroleum-based plastics, toward green and sustainable packaging solutions. In this study, an innovative bioplastic system, composed of carbon dioxide-derived poly(propylene carbonate) (PPC) and nature-originated cellulose acetate (CA), was developed. The extract from oregano waste was incorporated into the bioplastics as a low-cost and effective antioxidant resource. Thin, freestanding, and flexible PPC.CA bioplastic films were obtained by a simple, easily scalable solvent casting technique. The pristine films, without the oregano extract, featured good transparency and high water vapor barrier ability, along with suitable mechanical and thermal properties that are comparable to commercial plastics used for packaging. Interestingly, the incorporation of oregano waste extract added to the bioplastics high UV protection and high antioxidant activity, suitable features for active food packaging applications, without compromising the intriguing properties of the pristine films. The biocomposite films were not only biocompatible but also started biodegrading after just 1 week in seawater. The reported biocomposites are foreseen as promising candidates for several packaging applications, but in particular for sustainable active food packaging.

Combining hard matter, like inorganic nanocrystals, and soft materials, like polymers, can generate multipurpose materials with a broader range of applications with respect to the individual building blocks. Given their unique properties at the nanoscale, magnetic nanoparticles (MNPs) have drawn a great deal of interest due to their potential use in the biomedical field, targeting several applications such as heat hubs in magnetic hyperthermia (MHT, a heat-damage based therapy), contrast agents in magnetic resonance imaging (MRI), and nanocarriers for targeted drug delivery. At the same time, polymers, with their versatile macromolecular structure, can serve as flexible platforms with regard to constructing advanced functional materials. Advances in the development of novel polymerization techniques has enabled the preparation of a large portfolio of polymers that have intriguing physicochemical properties; in particular, those polymers that can undergo conformational and structural changes in response to their surrounding environmental stimuli. Therefore, merging the unique features of MNPs with polymer responsive properties, such as pH and thermal stimuli activation, enables smart control of polymer properties operated by the MNPs andvice versaat an unprecedented level of sophistication. These magnetic-stimuli-responsive nanosystems will impact the cancer field by combining magnetic hyperthermia with stimuli-dependent controlled drug delivery toward multimodal therapies. In this approach, a malignant tumor may be destroyed by a combination of the synergic effects of thermal energy generated by MNPs and the controlled release of antitumoral agents, activated by means of either heat or pH changes, finally leading to a much more effective cancer treatment than those available today. Also, taking advantage of such a triggered chemotherapy will overcome the notorious drawbacks of classic chemotherapy. Nevertheless, tracking the changes in the magnetic properties of such pH-responsive magnetic nanoparticles, which are provided by changes in relaxation signals of water molecules surrounding the nanoplatform, is a novel approach to the detection of pathological conditions (such as pH-changes at the ischemic and tumor sites). Despite great efforts by chemists to fabricate different featured materials, there have been few successful preclinical studies to date. A clinical translation of magnetic stimuli-responsive systems would require overcoming the actual nanosystem limitations and the joint efforts of an interdisciplinary scientific community. In this Account, we have framed state of the art magnetic stimuli-responsive systems, focusing on thermo- and pH-responsive behavior, following an organization based on the response mechanisms of polymers. By evaluating the features of the most representative and advanced nanosystems that already exist in literature, we present the challenges to overcome, the future directions to undertake for the development of magnetic stimuli-responsive nanoplatforms that will work under clinical operating conditions and have biodegradable and biocompatible features, and a consideration of the technical aspects.

The use of magnetic nanoparticles in oncothermia has been investigated for decades, but an effective combination of magnetic nanoparticles and localized chemotherapy under clinical magnetic hyperthermia (MH) conditions calls for novel platforms. In this study, we have engineered magnetic thermoresponsive iron oxide nanocubes (TR-cubes) to merge MH treatment with heat-mediated drug delivery, having in mind the clinical translation of the nanoplatform. We have chosen iron oxide based nanoparticles with a cubic shape because of their outstanding heat performance under MH clinical conditions, which makes them benchmark agents for MH. Accomplishing a surface-initiated polymerization of strongly interactive nanoparticles such as our iron oxide nanocubes, however, remains the main challenge to overcome. Here, we demonstrate that it is possible to accelerate the growth of a polymer shell on each nanocube by simple irradiation of a coppermediated polymerization with a ultraviolet light (UV) light, which both speeds up the polymerization and prevents nanocube aggregation. Moreover, we demonstrate herein that these TR-cubes can carry chemotherapeutic doxorubicin (DOXO-loaded- TR-cubes) without compromising their thermoresponsiveness both in vitro and in vivo. In vivo efficacy studies showed complete tumor suppression and the highest survival rate for animals that had been treated with DOXO-loaded-TR-cubes, only when they were exposed to MH. The biodistribution of intravenously injected TR-cubes showed signs of renal clearance within 1 week and complete clearance after 5 months. This biomedical platform works under clinical MH conditions and at a low iron dosage, which will enable the translation of dual MH/heat-mediated chemotherapy, thus overcoming the clinical limitation of MH: i.e., being able to monitor tumor progression post-MH-treatment by magnetic resonance imaging (MRI).

Herein, by studying a stepwise phase transformation of 23 nm FeO-Fe

Sickle cell disease is a hemoglobinopathy that results in paroxysmal arteriolar occlusion and tissue infarction that can manifest in a plurality of tissues. Rarely, these infarcted crises manifest in the bony orbit. Orbital infarction usually presents with acute onset of periorbital tenderness, swelling, erythema, and pain. Soft tissue swelling can result in proptosis and attenuation of extraocular movements. Expedient diagnosis of sickle cell orbital infarction is crucial because this is a potentially sight-threatening entity. Diagnosis can be delayed since the presentation has physical and radiographic findings mimicking various infectious and traumatic processes. We describe a patient who presented with sickle cell orbital crisis without pain. This case highlights the importance of maintaining a high index of suspicion in patients with known sickle cell disease or of African descent born outside the United States in a region where screening for hemoglobinopathy is not routine, even when the presentation is not classic.

In this study, a new strategy for the utilization of cocoa shell waste, a by-product of cocoa industry, is presented for the development of new bioelastomers. The cocoa shell waste (CSW) is first micronized and then incorporated into single component acetoxy-poly(dimethylsiloxane) (acetoxy-PDMS) macromolecular matrix by a mixing process to produce bioelastomer composites with tunable properties. A detailed study is carried out to investigate the influence of micronized cocoa waste concentration on the curing process and on the properties of final materials. It is found that addition of CSWs has a strong effect on the curing behavior of PDMS due to establishment of an intermolecular hydrogen bond network between the two components. CSW bioelastomers are hydrophobic and exhibit good water barrier properties. In addition, the bioelastomers show effective antioxidant scavenging activity against 2,2-diphenyl-1-picrylhydrazyl free radical (DPPH•) and 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) radical cation (ABTS•+). The incorporation of micronized CSW into PDMS is also found to significantly enhance the Young's modulus of the elastomers. Hence, these antioxidant bioelastomers originating from food industry waste can be highly suitable as materials for active food packaging applications.

We report a one-step synthesis of halide perovskite nanocrystals embedded in amphiphilic polymer (poly(acrylic acid)-block-poly(styrene), PAA-b-PS) micelles, based on injecting a dimethylformamide solution of PAA-b-PS, PbBr2, ABr (A = Cs, formamidinium, or both) and "additive" molecules in toluene. These bifunctional or trifunctional short chain organic molecules improve the nanocrystal-polymer compatibility, increasing the nanocrystal stability against polar solvents and high flux irradiation (the nanocrystals retain almost 80% of their photoluminescence after 1 h of 3.2 w/cm2 irradiation). If the nanocrystals are suspended in toluene, the coil state of the polymer allows the nanocrystals to undergo halide exchange, enabling emission color tunability. If the nanocrystals are suspended in methanol, or dried as powders, the polymer is in the globule state, and they are inert to halide exchange. By mixing three primary colors we could prepare stable, multicolor emissive samples (for example, white emitting powders) and a UV-to-white color converting layer for light-emitting diodes entirely made of perovskite nanocrystals.