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Here, we fabricated nanoparticles made solely from the membrane of cells found in the pancreatic tumour's microenvironment (TME), like the human MiaPaCa-2 cells and M2-polarized macrophages. The cell membrane-derived nanoparticles (CMNPs) deriving from the MiaPaCa-2 cells (MPC2-CMNPs) were loaded with the chemotherapeutic drug paclitaxel (PTX), and the CMNPs deriving from M2-polarized macrophages (M2-CMNPs) were loaded with the colony-stimulating factor 1 receptor inhibitor, pexidartinib (PXDB). The CMNPs' thorough morphological and physicochemical characterisation was followed by an in-depth study of their targeting ability and the endocytosis pathway involved during their internalisation. An in vitro model of the desmoplastic stroma comprising cancer-associated fibroblast-mimicking cells and M2-polarized macrophages was also developed. The model was characterised by collagen and α-smooth muscle actin (α-SMA) expression (overexpressed in desmoplasia) and was used to assess the CMNPs' ability to cross the stroma and target the tumour cells. Moreover, we assessed the effect of PXDB-loaded M2-CMNPs on the expression of M1 (CD80/CD86) and M2 (CD206/CD209) polarisation markers on activated macrophages. Finally, we evaluated the PTX and PXDB-loaded CMNPs' effect on the viability of all the used TME cell lines alone or in combination. Overall, this pilot study showed the potential of the CMNPs to cross an in vitro stroma model and act synergistically to treat PDAC., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Stem cell-based therapies have shown promising results for the regeneration of the nervous system. However, the survival and integration of the stem cells in the neural circuitry is suboptimal and might compromise the therapeutic outcomes of this approach. The development of functional scaffolds capable of actively interacting with stem cells may overcome the current limitations of stem cell-based therapies. In this study, three-dimensional hydrogels based on graphene derivatives and cerium oxide (CeO 2 ) nanoparticles are presented as prospective supports allowing neural stem cell adhesion, migration and differentiation. The morphological, mechanical and electrical properties of the resulting hydrogels can be finely tuned by controlling several parameters of the self-assembly of graphene oxide sheets, namely the amount of incorporated reducing agent (ascorbic acid) and CeO 2 nanoparticles. The intrinsic properties of the hydrogels, as well as the presence of CeO 2 nanoparticles, clearly influence the cell fate. Thus, stiffer adhesion substrates promote differentiation to glial cell lineages, while softer substrates enhance mature neuronal differentiation. Remarkably, CeO 2 nanoparticle-containing hydrogels support the differentiation of neural stem cells to neuronal, astroglial and oligodendroglial lineage cells, promoting the in vitro generation of nerve tissue grafts that might be employed in neuroregenerative cell therapies.

Remarkable progress in phototherapy has been made in recent decades, due to its non-invasiveness and instant therapeutic efficacy. In addition, with the rapid development of nanoscience and nanotechnology, phototherapy systems based on nanoparticles or nanocomposites also evolved as an emerging hotspot in nanomedicine research, especially in cancer. In this review, first we briefly introduce the history of phototherapy, and the mechanisms of phototherapy in cancer treatment. Then, we summarize the representative development over the past three to five years in nanoparticle-based phototherapy and highlight the design of the innovative nanoparticles thereof. Finally, we discuss the feasibility and the potential of the nanoparticle-based phototherapy systems in clinical anticancer therapeutic applications, aiming to predict future research directions in this field. Our review is a tutorial work, aiming at providing useful insights to researchers in the field of nanotechnology, nanoscience and cancer., Competing Interests: The authors declare no conflict of interest., (© 2022 The Authors.)

Upon coming into contact with the biological environment, nanostructures are immediately covered by biomolecules, particularly by proteins forming the so-called "protein corona" (PC). The phenomenon of PC formation has gained great attention in recent years due to its implication in the use of nanostructures in biomedicine. In fact, it has been shown that the formation of the PC can impact the performance of nanostructures by reducing their stability, causing aggregation, increasing their toxicity, and providing unexpected and undesired nanostructure-cell interactions. In this work, we decided to study for the first time the formation and the evolution of PC on the surface of nanostructured lipid carriers loaded with superparamagnetic iron oxide nanoparticles, before and after the crossing of an in vitro model of the blood-brain barrier (BBB). Combining confocal microscopy, direct STochastic Optical Reconstruction Microscopy (dSTORM), and proteomic analysis, we were able to carry out a complete analysis of the PC formation and evolution. In particular, we highlighted that PC formation is a fast process, being formed around particles even after just 1 min of exposure to fetal bovine serum. Moreover, PC formed around particles is extremely heterogeneous: while some particles have no associated PC at all, others are completely covered by proteins. Lastly, the interaction with an in vitro BBB model strongly affects the PC composition: in particular, a large amount of the proteins forming the initial PC is lost after the BBB passage and they are partially replaced by new proteins derived from both the brain endothelial cells and the cell culture medium. Altogether, the obtained data could potentially provide new insights into the design and fabrication of lipid nanostructures for the treatment of central nervous system disorders.

Cardiovascular and cerebrovascular diseases (CCVDs) describe abnormal vascular system conditions affecting the brain and heart. Among these, ischemic heart disease and ischemic stroke are the leading causes of death worldwide, resulting in 16% and 11% of deaths globally. Although several therapeutic approaches are presented over the years, the continuously increasing mortality rates suggest the need for more advanced strategies for their treatment. One of these strategies lies in the use of stimuli-responsive biomaterials. These "smart" biomaterials can specifically target the diseased tissue, and after "reading" the altered environmental cues, they can respond by altering their physicochemical properties and/or their morphology. In this review, the progress in the field of stimuli-responsive biomaterials for CCVDs in the last five years, aiming at highlighting their potential as early-stage therapeutics in the preclinical scenery, is described., (© 2022 The Authors. Small published by Wiley-VCH GmbH.)

The combined approach of ex situ normothermic machine perfusion (NMP) and nanotechnology represents a strategy to mitigate ischemia/reperfusion injury in liver transplantation (LT). We evaluated the uptake, distribution, and efficacy of antioxidant cerium oxide nanoparticles (nanoceria) during normothermic perfusion of discarded human livers. A total of 9 discarded human liver grafts were randomized in 2 groups and underwent 4 h of NMP: 5 grafts were treated with nanoceria conjugated with albumin (Alb-NC; 50 µg/ml) and compared with 4 untreated grafts. The intracellular uptake of nanoceria was analyzed by electron microscopy (EM) and inductively coupled plasma-mass spectrometry (ICP-MS). The antioxidant activity of Alb-NC was assayed in liver biopsies by glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) assay, telomere length, and 4977-bp common mitochondrial DNA deletion (mtDNA 4977 deletion). The cytokine profile was evaluated in perfusate samples. EM and ICP-MS confirmed Alb-NC internalization, rescue of mitochondrial phenotype, decrease of lipid droplet peroxidation, and lipofuscin granules in the treated grafts. Alb-NC exerted an antioxidant activity by increasing GSH levels (percentage change: +94% ± 25%; p = 0.01), SOD (+17% ± 4%; p = 0.02), and CAT activity (51% ± 23%; p = 0.03), reducing the occurrence of mtDNA 4977 deletion (-67.2% ± 11%; p = 0.03), but did not affect cytokine release. Alb-NC during ex situ perfusion decreased oxidative stress, upregulating graft antioxidant defense. They could be a tool to improve quality grafts during NMP and represent an antioxidant strategy aimed at protecting the graft against reperfusion injury during LT., (© 2022 American Association for the Study of Liver Diseases.)

Ribonucleic acid interference (RNAi) is an innovative treatment strategy for a myriad of indications. Non-viral synthetic nanoparticles (NPs) have drawn extensive attention as vectors for RNAi due to their potential advantages, including improved safety, high delivery efficiency and economic feasibility. However, the complex natural process of RNAi and the susceptible nature of oligonucleotides render the NPs subject to particular design principles and requirements for practical fabrication. Here, we summarize the requirements and obstacles for fabricating non-viral nano-vectors for efficient RNAi. To address the delivery challenges, we discuss practical guidelines for materials selection and NP synthesis in order to maximize RNA encapsulation efficiency and protection against degradation, and to facilitate the cytosolic release of oligonucleotides. The current status of clinical translation of RNAi-based therapies and further perspectives for reducing the potential side effects are also reviewed., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Oxidative stress represents a common issue in most neurological diseases, causing severe impairments of neuronal cell physiological activity that ultimately lead to neuron loss of function and cellular death. In this work, lipid-coated polydopamine nanoparticles (L-PDNPs) are proposed both as antioxidant and neuroprotective agents, and as a photothermal conversion platform able to stimulate neuronal activity. L-PDNPs showed the ability to counteract reactive oxygen species (ROS) accumulation in differentiated SH-SY5Y, prevented mitochondrial ROS-induced dysfunctions and stimulated neurite outgrowth. Moreover, for the first time in the literature, the photothermal conversion capacity of L-PDNPs was used to increase the intracellular temperature of neuron-like cells through near-infrared (NIR) laser stimulation, and this phenomenon was thoroughly investigated using a fluorescent temperature-sensitive dye and modeled from a mathematical point of view. It was also demonstrated that the increment in temperature caused by the NIR stimulation of L-PDNPs was able to produce a Ca 2+ influx in differentiated SH-SY5Y, being, to the best of our knowledge, the first example of organic nanostructures used in such an approach. This work could pave the way to new and exciting applications of polydopamine-based and of other NIR-responsive antioxidant nanomaterials in neuronal research.

Cerebral ischemia (or ischemic stroke) is undeniably one of the most important life-threatening cerebral disorders. It occurs due to a clot formation in one of the blood arteries supplying the brain, causing a reduction or interruption of the blood flow. To date, the use of thrombolytics like the recombinant tissue plasminogen activator or the use of mechanical thrombectomy are the only two food and drug administration-approved treatments. However, these cannot be applied without first evaluating the beneficial or adverse effects on the patient. Thus, imaging is decisive for identifying the appropriateness of each stroke patient, leading potentially to improved therapeutic outcomes. In this review, we will present a variety of diagnostic nano-agents, and a few theranostic ones, for the assessment of ischemic stroke, highlighting their strengths and weaknesses.

Glioblastoma multiforme (GBM) is one of the most aggressive types of brain cancer, characterized by rapid progression, resistance to treatments, and low survival rates; the development of a targeted treatment for this disease is still today an unattained objective. Among the different strategies developed in the latest few years for the targeted delivery of nanotherapeutics, homotypic membrane-membrane recognition is one of the most promising and efficient. In this work, we present an innovative drug-loaded nanocarrier with improved targeting properties based on the homotypic recognition of GBM cells. The developed nanoplatform consists of boron nitride nanotubes (BNNTs) loaded with doxorubicin (Dox) and coated with cell membranes (CM) extracted from GBM cells (Dox-CM-BNNTs). We demonstrated as Dox-CM-BNNTs are able to specifically target and kill GBM cells in vitro , leaving unaffected healthy brain cells, upon successful crossing an in vitro blood-brain barrier model. The excellent targeting performances of the nanoplatform can be ascribed to the protein component of the membrane coating, and proteomic analysis of differently expressed membrane proteins present on the CM of GBM cells and of healthy astrocytes allowed the identification of potential candidates involved in the process of homotypic cancer cell recognition., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Competing Interests: Conflict of Interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Aiming at finding new solutions for fighting glioblastoma multiforme, one of the most aggressive and lethal human cancer, here an in vitro validation of multifunctional nanovectors for drug delivery and hyperthermia therapy is proposed. Hybrid magnetic lipid nanoparticles have been fully characterized and tested on a multi-cellular complex model resembling the tumor microenvironment. Investigations of cancer therapy based on a physical approach (namely hyperthermia) and on a pharmaceutical approach (by exploiting the chemotherapeutic drug temozolomide) have been extensively carried out, by evaluating its antiproliferative and pro-apoptotic effects on 3D models of glioblastoma multiforme. A systematic study of transcytosis and endocytosis mechanisms has been moreover performed with multiple complimentary investigations, besides a detailed description of local temperature increments following hyperthermia application. Finally, an in-depth proteomic analysis corroborated the obtained findings, which can be summarized in the preparation of a versatile, multifunctional, and effective nanoplatform able to overcome the blood-brain barrier and to induce powerful anti-cancer effects on in vitro complex models.

In this study, hybrid nanocubes composed of magnetite (Fe 3 O 4 ) and manganese dioxide (MnO 2 ), coated with U-251 MG cell-derived membranes (CM-NCubes) are synthesized. The CM-NCubes demonstrate a concentration-dependent oxygen generation (up to 15%), and, for the first time in the literature, an intracellular increase of temperature (6 °C) due to the exothermic scavenging reaction of hydrogen peroxide (H 2 O 2 ) is showed. Internalization studies demonstrate that the CM-NCubes are internalized much faster and at a higher extent by the homotypic U-251 MG cell line compared to other cerebral cell lines. The ability of the CM-NCubes to cross an in vitro model of the blood-brain barrier is also assessed. The CM-NCubes show the ability to respond to a static magnet and to accumulate in cells even under flowing conditions. Moreover, it is demonstrated that 500 µg mL -1 of sorafenib-loaded or unloaded CM-NCubes are able to induce cell death by apoptosis in U-251 MG spheroids that are used as a tumor model, after their exposure to an alternating magnetic field (AMF). Finally, it is shown that the combination of sorafenib and AMF induces a higher enzymatic activity of caspase 3 and caspase 9, probably due to an increment in reactive oxygen species by means of hyperthermia., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Major obstacles to the successful treatment of gliolastoma multiforme are mostly related to the acquired resistance to chemotherapy drugs and, after surgery, to the cancer recurrence in correspondence of residual microscopic foci. As innovative anticancer approach, low-intensity electric stimulation represents a physical treatment able to reduce multidrug resistance of cancer and to induce remarkable anti-proliferative effects by interfering with Ca 2+ and K + homeostasis and by affecting the organization of the mitotic spindles. However, to preserve healthy cells, it is utterly important to direct the electric stimuli only to malignant cells. In this work, we propose a nanotechnological approach based on ultrasound-sensitive piezoelectric nanoparticles to remotely deliver electric stimulations to glioblastoma cells. Barium titanate nanoparticles (BTNPs) have been functionalized with an antibody against the transferrin receptor (TfR) in order to obtain the dual targeting of blood-brain barrier and of glioblastoma cells. The remote ultrasound-mediated piezo-stimulation allowed to significantly reduce in vitro the proliferation of glioblastoma cells and, when combined with a sub-toxic concentration of temozolomide, induced an increased sensitivity to the chemotherapy treatment and remarkable anti-proliferative and pro-apoptotic effects., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Neurodegenerative diseases comprise a large group of disorders characterized by a dramatic synaptic connections loss, occurring as a result of neurodegeneration, which is closely related to the overproduction of reactive oxygen and nitrogen species. Currently, the treatment of neurodegenerative diseases has been limited mainly because of the inability of the synthesized delivery systems to cross the blood-brain barrier and to successfully deliver their therapeutic cargo to the diseased tissue. Taking into consideration the aforementioned limitations, we designed a lipid-based nanotherapeutic vector composed of biomimetic lipids and CeO 2 nanoparticles (nanoceria, NC). NC have shown to be a promising tool for the treatment of several pathological conditions ranging from cancer to neurological diseases, mainly because of their antioxidant properties, while lipid-based structures have been shown to have an inherent ability to cross the blood-brain barrier. The lipid-based nanotherapeutics were successfully fabricated using a combination of ultrasonication and high-pressure homogenization techniques, and they were fully characterized morphologically and physicochemically. Their antioxidant ability was demonstrated using electron paramagnetic resonance spectroscopy and antioxidant assays. These innovative nanotherapeutics demonstrated a higher colloidal stability with respect to free NC, preserving at the same time their antioxidant properties. Finally, the ability of the lipid carriers to cross a model of the blood-brain barrier and to be internalized by neurons, acting both as neuroprotective and pro-neurogenic agents, was demonstrated using single- and triple-culture systems.

In this study, taking into consideration the limitations of current treatments of glioblastoma multiforme, we fabricated a biomimetic lipid-based magnetic nanovector with a good loading capacity and a sustained release profile of the encapsulated chemotherapeutic drug, temozolomide. These nanostructures demonstrated an enhanced release after exposure to an alternating magnetic field, and a complete release of the encapsulated drug after the synergic effect of low pH (4.5), increased concentration of hydrogen peroxide (50 μM), and increased temperature due to the applied magnetic field. In addition, these nanovectors presented excellent specific absorption rate values (up to 1345 W g-1) considering the size of the magnetic component, rendering them suitable as potential hyperthermia agents. The presented nanovectors were progressively internalized in U-87 MG cells and in their acidic compartments (i.e., lysosomes and late endosomes) without affecting the viability of the cells, and their ability to cross the blood-brain barrier was preliminarily investigated using an in vitro brain endothelial cell-model. When stimulated with alternating magnetic fields (20 mT, 750 kHz), the nanovectors demonstrated their ability to induce mild hyperthermia (43 °C) and strong anticancer effects against U-87 MG cells (scarce survival of cells characterized by low proliferation rates and high apoptosis levels). The optimal anticancer effects resulted from the synergic combination of hyperthermia chronic stimulation and the controlled temozolomide release, highlighting the potential of the proposed drug-loaded lipid magnetic nanovectors for treatment of glioblastoma multiforme.

Excess reactive oxygen species (ROS) has been implicated in numerous diseases including cancer, cardiovascular and neurodegenerative diseases. Overexpression of ROS can lead to oxidative stress and subsequently to H 2 O 2 -mediated cell apoptosis. In this study, it was demonstrated that biodegradable PLGA microspheres coated with collagen type I and decorated with MnO 2 nanoparticles acted as ROS scavengers controlling the H 2 O 2 -mediated apoptosis of cells undergoing oxidative stress. The results showed that the functionalized collagen spheres can protect cells even under very harsh conditions of oxidative stress., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Osteosarcoma is an aggressive form of bone cancer mostly affecting young people. To date, the most effective strategy for the treatment of osteosarcoma is the surgical removal of the tumor with or without combinational chemotherapy. In this study, we present the development of a pH-sensitive drug-delivery system in the form of microparticles, with increased chemotherapeutic action against the osteosarcoma cell line SAOS-2, and with reduced toxicity against the heart myoblastic cell line H9C2. The delivery system is composed of calcium carbonate and collagen type I, and is loaded with cerium dioxide (CeO 2 ) nanoparticles (<25 nm) and the anticancer drug doxorubicin. The fabricated microparticles were fully characterized morphologically and physicochemically, and their ability to induce or inhibit apoptosis/necrosis was assessed using in vitro functional assays and flow cytometry. The results presented in this study show that the highest concentration (250 μg/mL) of the therapeutic microparticles (CaCO 3 -based therapeutic modulators (C-TherMods)), which corresponds to 6.4 μg/mL of encapsulated doxorubicin, can protect the H9C2 cells even after 120 h, since the percentage of viable cells at this time point is 65%. On the contrary, when H9C2 cells are treated with 0.5 μg/mL of free doxorubicin, 75% of the cells are dead only after 24 h. When SAOS-2 cells are treated with the same concentration of C-TherMods (250 μg/mL), the viability of SAOS-2 cells is 80% after 24 h, while it reduces to 50% after 120 h. At pH 6.0, the synergic effect of the pro-oxidant CeO 2 nanoparticles and of the encapsulated doxorubicin leads to almost 100% of cell death, even at the lowest concentration of C-TherMods (50 μg/mL)., Competing Interests: The authors declare no competing financial interest.

With the increasing advances in the fabrication and in monitoring approaches of nanotechnology devices, novel materials are being synthesized and tested for the interaction with biological environments. Among them, smart materials in particular provide versatile and dynamically tunable platforms for the investigation and manipulation of several biological activities with very low invasiveness in hardly accessible anatomical districts. In the following, we will briefly recall recent examples of nanotechnology-based materials that can be remotely activated and controlled through different sources of energy, such as electromagnetic fields or ultrasounds, for their relevance to both basic science investigations and translational nanomedicine. Moreover, we will introduce some examples of hybrid materials showing mutually beneficial components for the development of multifunctional devices, able to simultaneously perform duties like imaging, tissue targeting, drug delivery, and redox state control. Finally, we will highlight challenging perspectives for the development of theranostic agents (merging diagnostic and therapeutic functionalities), underlining open questions for these smart nanotechnology-based devices to be made readily available to the patients in need.

Atherosclerosis is a chronic inflammatory disease of the arterial wall that leads to cardiovascular diseases which are the major cause of deaths worldwide. There is currently no treatment that can stop or reverse the disease. However, the use of microparticles with anti-inflammatory properties could represent a promising treatment. Herein, spherical microparticles with a core-shell structure and an average diameter of 1μm were synthesized. The microparticles were comprised of a MnCO 3 and MnO 2 core and a 4-arm PEG-amine cross-linked shell of hyaluronic acid. The HA-Mn-SM microparticles were loaded with D-α-tocopherol (vitamin-E) (TOC), to fabricate a targeted biocompatible delivery platform for the treatment of atherosclerotic inflamed cells. Loading and release studies of TOC demonstrated a lactic acid concentration dependant controlled release profile of the HA-Mn-SM mimicking the atherosclerotic environment where lactic acid is over-produced. The microparticles exhibited a high scavenging ability towards H 2 O 2 in addition to the controlled generation of O 2 . The optimal results were obtained for 250μg/mL microparticles which in the presence of 1000μM H 2 O 2 resulted in the scavenging of almost all the H 2 O 2 . Our results demonstrate that 50μg/mL of microparticles scavenged continuously produced H 2 O 2 up to a concentration of 1000μM, a characteristic that demonstrates the sustained therapeutic effect of the HA-Mn-SM microparticles in an environment that mimics that of inflamed tissues. Our results indicate the potential use of HA-Mn-SM as a novel platform for the treatment of atherosclerosis. In vitro studies confirmed that the microparticles are not cytotoxic at concentrations up to 250μg/mL and for 72h. These preliminary results indicate the potential use of HA-Mn-SM as a novel drug delivery system for atherosclerotic tissues., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) comprise a category of versatile drug delivery systems that have been used in the biomedical field for >25years. SLNs and NLCs have been used for the treatment of various diseases including cardiovascular and cerebrovascular, and are considered a standard treatment for the latter, due to their inherent ability to cross the blood brain barrier (BBB). In this review, a presentation of the most important brain diseases (brain cancer, ischemic stroke, Alzheimer's disease, Parkinson's disease and multiple sclerosis) is approached, followed by the basic fabrication techniques of SLNs and NLCs. A detailed description of the reported studies of the last seven years, of active and passive targeting SLNs and NLCs for the treatment of glioblastoma multiforme and of other brain cancers, as well as for the treatment of neurodegenerative diseases is also carried out. Finally, a brief description of the advantages, the disadvantages, and the future perspectives in the use of these nanocarriers is reported, aiming at giving an insight of the limitations that have to be overcome in order to result in a delivery system with high therapeutic efficacy and without the limitations of the existing nano-systems., (Copyright © 2017 Elsevier B.V. All rights reserved.)

A versatile drug delivery carrier that responds to external stimuli was synthesized via the emulsion polymerization process. This simple two-step process was carried out by using Poly (Methyl Methacrylate) as a soft template and a series of monomers, with desired properties, as coating monomers. It is noteworthy that during shell fabrication (2nd step) an inner cavity is created inside the nanocontainers that can be used as a host for small drug molecules. The thermo-, pH- and redox sensitive monomers used in the coating procedure were Dimethyl Amino Ethyl Methacrylate (DMAEMA), Acrylic Acid (AA) and N,N'-(disulfanediylbis(ethane-2,1-diyl))bis(2-methylacrylamide) (Disulfide or DS), respectively. It has to be noted that DMAEMA is also pH- sensitive and acts synergistically with AA. The surface of the multi-stimuli nanocontainers was functionalized with magnetite nanoparticles in order to induce an alternating magnetic field (AMF) sensitivity. By using AMF in various strenghts and frequencies, the temperature of the final multi-stimuli nanocontainers (Q-NCs) can be increased in a controlled manner resulting in the Hyperthermia phenomenon. Loading and release studies were carried out using the anthracycline drug, Doxorubicin, aiming at the confirmation of the release mechanism., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Reactive oxygen species (ROS) (H2 O2 , OCl(-) , (•) OH, O2 (-) ) are a family of reactive molecules that are generated intracellularly and are engaged in many biological processes. In physiological concentrations, ROS act as signaling molecules to a number of metabolic pathways; however, in excess they can be harmful to living organisms. Overproduction of ROS has been related to many pathophysiological conditions and a number of studies have been reported in elucidating their mechanism in these conditions. With the aim of harnessing this role, a number of imaging tools and therapeutic compounds have been developed. Here these imaging and therapeutic tools are reviewed and particularly those structures with ROS-sensitivity based on their biomedical applications and their functional groups. There is also a brief discussion about the method of preparation as well as the mechanism of action., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

On page 5553, C. Tapeinos and A. Pandit review the properties of reactive oxygen species (ROS)-sensitive moieties which can respond to oxidative conditions inside cells. ROS-sensitive chemical structures, shown in the background of the image, are currently used in the biomedical field as drug-delivery systems, imaging probes, prochelators, and prodrugs for imaging and treatment of various diseases., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Polymeric pH- and thermo-sensitive microcontainers (MCs) were developed as a potential drug delivery system for cancer therapy. It is well known that cancer cells exhibit notable characteristics such as acidic pH due to glycolytic cycle and higher temperature due to their higher proliferation rate. Based on these characteristics, we constructed a dual pH- and thermo-sensitive material for specific drug release on the pathological tissue. The MC's fabrication is based on a two-step procedure, in which, the first step involves the core synthesis and the second one is related to the shell formation. The core consists of poly(methyl methacrylate (PMMA), while the shell consists of PMMA, poly(isopropylacrylamide), poly(acrylic acid) and poly(divinylbenzene). Three different types of MCs were synthesized based on the seed polymerization method. The synthesized MCs were characterized structurally by Fourier transform infrared and morphologically by scanning electron microscopy. Dynamic light scattering was also used to study their behavior in aqueous solution under different pH and temperature conditions. For the loading and release study, the anthracycline drug daunorubicin (DNR) was used as a model drug, and its release properties were evaluated under different pH and thermo-conditions. Cytotoxicity studies were also carried out against MCF-7 breast cancer and 3T3 mouse embryonic fibroblast cells. According to our results, the synthesized microcontainers present desired pH and thermo behavior and can be applied in drug delivery systems. It is worth mentioning that the synthesized microcontainers which incorporated the drug DNR exhibit higher toxicity than the free drug., (Copyright © 2014 Elsevier B.V. All rights reserved.)

This paper deals with the synthesis, characterization and property evaluation of drug-loaded magnetic microspheres with pH-responsive cross-linked polymer shell. The synthetic procedure consists of 3 steps, of which the first two comprise the synthesis of a poly methyl methacrylate (PMMA) template and the synthesis of a shell by using acrylic acid (AA) and methyl methacrylate (MMA) as monomers, and divinyl benzene (DVB) as cross-linker. The third step of the procedure refers to the formation of magnetic nanoparticles on the microsphere's surface. AA that attaches pH-sensitivity in the microspheres and magnetic nanoparticles in the inner and the outer surface of the microspheres, enhance the efficacy of this intelligent drug delivery system (DDS), which constitutes a promising approach toward cancer therapy. A number of experimental techniques were used to characterize the resulting microspheres. In order to investigate the in vitro controlled release behavior of the synthesized microspheres, we studied the Dox release percentage under different pH conditions and under external magnetic field. Hyperthermia caused by an alternating magnetic field (AFM) is used in order to study the doxorubicin (Dox) release behavior from microspheres with pH functionality. The in vivo fate of these hybrid-microspheres was tracked by labeling them with the γ-emitting radioisotope (99m)Tc after being intravenously injected in normal mice. According to our results, microsphere present a pH depending and a magnetic heating, release behavior. As expected, labeled microspheres were mainly found in the mononuclear phagocyte system (MPS). The highlights of the current research are: (i) to illustrate the advantages of controlled release by combining hyperthermia and pH-sensitivity and (ii) to provide noninvasive, in vivo information on the spatiotemporal biodistribution of these microsphere by dynamic γ-imaging., (Copyright © 2013 Elsevier B.V. All rights reserved.)