CuFeS2 Nanoparticles Functionalized with a Thermoresponsive Polymer for Photothermia and Externally Controlled Drug Delivery.

CuFeS2 chalcopyrite nanoparticles (NPs) can generate heat under exposure to near-infrared laser irradiation. Here, we develop a protocol to decorate the surface of CuFeS2 NPs (13 nm) with a thermoresponsive (TR) polymer based on poly(ethylene glycol methacrylate) to combine heat-mediated drug delivery and photothermal heat damage. The resulting TR-CuFeS2 NPs feature a small hydrodynamic size (∼75 nm), along with high colloidal stability and a TR transition temperature of 41 °C in physiological conditions. Remarkably, TR-CuFeS2 NPs, when exposed to a laser beam (in the range of 0.5 and 1.5 W/cm2) at NP concentrations as low as 40-50 µg Cu/mL, exhibit a high heating performance with a rise in the solution temperature to hyperthermia therapeutic values (42-45 °C). Furthermore, TR-CuFeS2 NPs worked as nanocarriers, being able to load an appreciable amount of doxorubicin (90 µg DOXO/mg Cu), a chemotherapeutic agent whose release could then be triggered by exposing the NPs to a laser beam (through which a hyperthermia temperature above 42 °C could be reached). In an in vitro study performed on U87 human glioblastoma cells, bare TR-CuFeS2 NPs were proven to be nontoxic at a Cu concentration up to 40 µg/mL, while at the same low dose, the drug-loaded TR-CuFeS2-DOXO NPs displayed synergistic cytotoxic effects due to the combination of direct heat damage and DOXO chemotherapy, under photo-irradiation by a 808 nm laser (1.2 W/cm2). Finally, under a 808 nm laser, the TR-CuFeS2 NPs generated a tunable amount of reactive oxygen species depending on the applied power density and NP concentration.

Intranasal Polymeric and Lipid-Based Nanocarriers for CNS Drug Delivery.

Nanomedicine is currently focused on the design and development of nanocarriers that enhance drug delivery to the brain to address unmet clinical needs for treating neuropsychiatric disorders and neurological diseases. Polymer and lipid-based drug carriers are advantageous for delivery to the central nervous system (CNS) due to their safety profiles, drug-loading capacity, and controlled-release properties. Polymer and lipid-based nanoparticles (NPs) are reported to penetrate the blood-brain barrier (BBB) and have been extensively assessed in in vitro and animal models of glioblastoma, epilepsy, and neurodegenerative disease. Since approval by the Food and Drug Administration (FDA) of intranasal esketamine for treatment of major depressive disorder, intranasal administration has emerged as an attractive route to bypass the BBB for drug delivery to the CNS. NPs can be specifically designed for intranasal administration by tailoring their size and coating with mucoadhesive agents or other moieties that promote transport across the nasal mucosa. In this review, unique characteristics of polymeric and lipid-based nanocarriers desirable for drug delivery to the brain are explored in addition to their potential for drug repurposing for the treatment of CNS disorders. Progress in intranasal drug delivery using polymeric and lipid-based nanostructures for the development of treatments of various neurological diseases are also described.

Scale-up approach for the preparation of magnetic ferrite nanocubes and other shapes with benchmark performance for magnetic hyperthermia applications.

Magnetic nanoparticles are increasingly used in medical applications, including cancer treatment by magnetic hyperthermia. This protocol describes a solvothermal-based process to prepare, at the gram scale, ferrite nanoparticles with well-defined shape, i.e., nanocubes, nanostars and other faceted nanoparticles, and with fine control of structural/magnetic properties to achieve point-of-reference magnetic hyperthermia performance. This straightforward method comprises simple steps: (i) making a homogeneous alcoholic solution of a surfactant and an alkyl amine; (ii) adding an organometallic metal precursor together with an aldehyde molecule, which acts as the key shape directing agent; and (iii) reacting the mixture in an autoclave for solvothermal crystallization. The shape of the ferrite nanoparticles can be controlled by the structure of the aldehyde ligand. Benzaldehyde and its aromatic derivatives favor the formation of cubic ferrite nanoparticles while aliphatic aldehydes result in spherical nanoparticles. The replacement of the primary amine, used in the nanocubes synthesis, with a secondary/tertiary amine results in nanoparticles with star-like shape. The well-defined control in terms of shape, narrow size distribution (below 5%), compositional tuning and crystallinity guarantees the preparation, at the gram scale, of nanocubes/star-like nanoparticles that possess, under magnetic field conditions of clinical use, specific adsorption rates comparable to or even superior to those obtained through thermal decomposition methods, which are typically prepared at the milligram scale. Here, gram-scale nanoparticle products with benchmark features for magnetic hyperthermia applications can be prepared in ~10 h with an average level of expertise in chemistry.

Clickable Polymer Ligand-Functionalized Iron Oxide Nanocubes: A Promising Nanoplatform for 'Local Hot Spots' Magnetically Triggered Drug Release.

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.

Fe3 O4 @Au@Cu2-x S Heterostructures Designed for Tri-Modal Therapy: Photo- Magnetic Hyperthermia and 64 Cu Radio-Insertion.

Here, the synthesis and proof of exploitation of three-material inorganic heterostructures made of iron oxide-gold-copper sulfide (Fe3 O4 @Au@Cu2-x S) are reported. Starting with Fe3 O4 -Au dumbbell heterostructure as seeds, a third Cu2-x S domain is selectively grown on the Au domain. The as-synthesized trimers are transferred to water by a two-step ligand exchange procedure exploiting thiol-polyethylene glycol to coordinate Au and Cu2-x S surfaces and polycatechol-polyethylene glycol to bind the Fe3 O4 surface. The saline stable trimers possess multi-functional properties: the Fe3 O4 domain, of appropriate size and crystallinity, guarantees optimal heating losses in magnetic hyperthermia (MHT) under magnetic field conditions of clinical use. These trimers have indeed record values of specific adsorption rate among the inorganic-heterostructures so far reported. The presence of Au and Cu2-x S domains ensures a large adsorption which falls in the first near-infrared (NIR) biological window and is here exploited, under laser excitation at 808 nm, to produce photo-thermal heat alone or in combination with MHT obtained from the Fe3 O4 domain. Finally, an intercalation protocol with radioactive 64 Cu ions is developed on the Cu2-x S domain, reaching high radiochemical yield and specific activity making the Fe3 O4 @Au@Cu2-x S trimers suitable as carriers for 64 Cu in internal radiotherapy (iRT) and traceable by positron emission tomography (PET).

Magnetic nanoparticles and clusters for magnetic hyperthermia: optimizing their heat performance and developing combinatorial therapies to tackle cancer.

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.

Switchable Anion Exchange in Polymer-Encapsulated APbX3 Nanocrystals Delivers Stable All-Perovskite White Emitters.

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.

Magnetic Nanoparticle-Based Hyperthermia Mediates Drug Delivery and Impairs the Tumorigenic Capacity of Quiescent Colorectal Cancer Stem Cells.

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.

Transparent Bioplastic Derived from CO2-Based Polymer Functionalized with Oregano Waste Extract toward Active Food Packaging.

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.

Thermoresponsive Iron Oxide Nanocubes for an Effective Clinical Translation of Magnetic Hyperthermia and Heat-Mediated Chemotherapy.

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 copper-mediated 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).

Fe2+ Deficiencies, FeO Subdomains, and Structural Defects Favor Magnetic Hyperthermia Performance of Iron Oxide Nanocubes into Intracellular Environment.

Herein, by studying a stepwise phase transformation of 23 nm FeO-Fe3O4 core-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-Fe3O4 nanocubes from having stoichiometric phase compositions into Fe2+-deficient Fe3O4 phases. 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 Fe3O4 structure on the heating performance into intracellular environment.

Nanosystems Based on Magnetic Nanoparticles and Thermo- or pH-Responsive Polymers: An Update and Future Perspectives.

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 and vice versa at 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.