Biocompatible polymer-coated magneto-fluorescent super nanoparticles for the homing of mesenchymal stem cells.

Stem cell plays an important role in the clinical field. However, the effective delivery of stem cells to the targeted site relies on the efficient homing of the cells to the site of injury. In view of that, fluorescent magnetic nanoparticles stick out due to their wide range of enabling functions including cellular homing and tracking. The present study unravels the synthesis of polymer-coated biocompatible and fluorescent magnetic nanoparticles (FMNPs) by a single-step hydrothermal synthesis method. Importantly, the facile method developed the biological super nanoparticles consisting of the magnetic core, which is surrounded by the fluorescent nanodot-decorated polymeric shell. The synthesized particles showed an amorphous nature, and superparamagnetic properties, with efficient fluorescence properties of emission at the blue range (Ì´ 410 nm). The FMNP labeling showed the mesenchymal stem cell (MSC) homing to the desired site in the presence of an external magnetic field. The in-house synthesized nanoparticles showed significant cytocompatibility and hemocompatibility in vitro as well as in vivo conditions owing to their surface coating. This unprecedented work advances the efficient internalization of FMNPs in MSCs and their enhanced migration potential provides a breakthrough in stem cell delivery for therapeutic applications. STATEMENT OF SIGNIFICANCE: The bi-modal fluorescent magnetic nanoparticles hold a promising role in the biomedical field for mesenchymal stem cell homing and tracking. Hence, in this study, for the first time, we have synthesized the fluorescent magnetic nanoparticle with polymer coating via an easy single-step method. The nanoparticle with a polymer coat enhanced the biocompatibility and effortless internalization of the nanoparticle into mesenchymal stem cells without hampering the native stem cell properties. Furthermore, the enhanced migration potential of such magnetized stem cells and their homing at the target site by applying an external magnetic field opened up avenues for the smart delivery of mesenchymal stem cells at complex sites such as retina for the tissue regeneration.

Vitamin k3-Loaded Magnetic Nanoparticle-Mediated Synergistic Magnetothermodynamic Therapy Evokes Massive ROS and Immune Modulation for Augmented Antitumor Potential.

Magnetic nanoparticle (MNP)-mediated magnetic hyperthermia (MHT) under an alternating magnetic field (AMF) causes tumor regression via reactive oxygen species (ROS) generation. However, less therapeutic efficacy has been reported due to the generation of low levels of ROS in a hypoxic tumor microenvironment. Therefore, improved treatments are required to generate relatively high levels of ROS to promote irreversible oxidative damage to the tumor cells. Herein, we report a magnetothermodynamic (MTD) therapy, as a robust and versatile approach for cancer treatment, by combining the magnetothermodynamic-related ROS and heat-related immunological effect in order to overcome the aforementioned obstacle. The synergistic therapy was achieved by the development of vitamin k3 (Vk3)-loaded copper zinc ferrite nanoparticles (Vk3@Si@CuZnIONPs) as an efficient MTD agent. The in vitro results unveiled that enhanced ROS production under the influence of AMF is a predominant aspect in yielding an assertive anticancer response. The in vivo antitumor response was assessed in an ectopic tumor model of A549 lung adenocarcinoma by MTD. The tumor inhibition rate of 69% was achieved within 20 days of MTD treatment, exhibiting complete tumor eradication within 30 days. The validation of antitumor response was marked by severe apoptosis (TUNEL, Caspase-3) in the Vk3@Si@CuZnIONPs + AMF-treated group. The higher expression level of heat shock proteins and proinflammatory cytokines (IL-6, TNF-α, IL-1α, IL-1ß) was speculated to play a role in the activation of immune response for faster tumor regression in the MTD-treated group. Therefore, by implementing a dual ROS and heat-mediated immunogenic effect, the antitumor efficiency of future cancer magnetotherapies will be greatly enhanced.

Transmigration of magnetite nanoparticles across the blood-brain barrier in a rodent model: influence of external and alternating magnetic fields.

Despite advances in neurology, drug delivery to the central nervous system is considered a challenge due to the presence of the blood brain barrier (BBB). In this study, the role of magnetic hyperthermia induced by exposure of magnetic nanoparticles (MNPs) to an alternating magnetic field (AMF) in synergy with an external magnetic field (EMF) was investigated to transiently increase the permeability of the MNPs across the BBB. A dual magnetic targeting approach was employed by first dragging the MNPs by an EMF for an intended enhanced cellular association with the brain endothelial cells and then activating the MNPs by an AMF for the temporary disruption of the tight junctions of BBB. The efficacy of the BBB permeability for the MNPs under the influence of dual magnetic targeting was evaluated in vitro using transwell models developed by co-culturing murine brain endothelial cells with astrocytes, as well as in vivo in mouse models. The in vitro results revealed that the exposure to AMF transiently opened the tight junctions at the BBB, which, after 3 h of treatment, were observed to recover back to their comparable control levels. A biodistribution analysis of nanoparticles confirmed targeted accumulation of MNPs in the brain following dual targeting. This dual targeting approach was observed to open the tight junctions, thus increasing the transport of MNPs into the brain with higher specificity as compared to using EMF targeting alone, suggesting that a dual magnetic targeting-induced transport of MNPs across the BBB is an effective measure for delivery of therapeutics.

Tailoring nanoparticles design for enhanced heating efficiency and improved magneto-chemo therapy for glioblastoma.

Development of multifunctional magnetic nanomaterials (MNPs) with improved heat-generating capabilities and effective combination with localized chemotherapy has emerged as a promising therapeutic regime for solid tumors like glioblastoma. In this regard, the shape-dependent hyperthermic and chemo-therapeutic potential of nanomaterials, has not been extensively explored. Here we present, development of various morphological designs of MNPs including spherical, clusters, rods and cubic; to compare the effect of shape on tuning the properties of MNPs that are relevant to many potential biomedical applications like drug delivery, cellular uptake and heat generation. The study includes extensive comparison of morpho-structural characteristics, size distributions, chemical composition, surface area measurements and magnetic properties of the variable shaped MNPs. Further the heating efficiencies in aqueous and cellular environments and heat triggered drug release profiles for successful magneto-chemotherapy were compared among all in-house synthesized MNPs. Under biosafety limit considerations given by Hergt's limit (H*f value <5 × 109 Am-1 s-1), cuboidal shaped MNPs demonstrated highest heating efficiency owing to magnetosome-like chain formation along with sustained drug release profile as compared to other synthesized MNPs. The mechanism of cancer cell death mediated via magneto-chemotherapy was elucidated to be the oxidative stress-mediated apoptotic cell death pathway. In vivo studies further demonstrated complete tumor regression only in the magneto-chemotherapy treated group. These findings suggest the potential of combinatorial therapy to overcome the clinical limitations of the independent therapies for advanced thermotherapy of glioblastoma.

In vitro and in silico anticancer potential analysis of Streptomyces sp. extract against human lung cancer cell line, A549.

During our previous investigation, bioactive compounds present in the extract of Streptomyces sp. strain 196 were characterized using LC-MS/MS and 1H NMR studies. These compounds were K-252-C aglycone indolocarbazole alkaloid, decoyinine, and cycloheximide; the study of these natural drugs against lung carcinoma is still limited. Focus of the current investigation was to study the anticancer effect of strain 196 extract on lung cancer cells (A549). During in vitro studies, anti-proliferative effect of extract was studied using MTT assay in A549 cells. Effect of extract on cell survival was further evaluated using colony assay. Cell death was qualitatively assessed using apoptosis assay. The aftereffect of extract treatment on metastatic potential of cancerous cells was studied using wound closure assay. Effect of extract on the morphology and cytoskeletal arrangement of A549 cells was studied using phalloidin staining. The extract demonstrated concentration and time-dependent cytotoxicity with IC50 value at 0.5 mg/ml (6 h) and 0.15 mg/ml (24 h). The proliferation and metastatic potential of cells, as characterized by MTT and migration assay, decreased over time in a concentration-dependent manner. Discrete changes in cellular morphology were noted as a result of the induced cytotoxicity. Apoptosis assay demonstrated 98.7% cell death at highest concentration of extract (1 mg/ml). During in silico studies, molecular docking revealed that strain 196 compounds are efficiently binding to mutant EGFR form (T790M/L858R) with release of binding energy (∆G) between - 5 and - 6.9 kcal/Mol. In conclusion, strain 196 extract could be a source of therapeutic drugs to treat lung carcinoma.

Rapid tumor inhibition via magnetic hyperthermia regulated by caspase 3 with time-dependent clearance of iron oxide nanoparticles.

Among conventional cancer therapies, radio-frequency magnetic hyperthermia (MHT) has widely been investigated for use with magnetic nanoparticles (MNPs). However, the majority of in vivo biodistribution studies have tested very low MNP dosages (equivalent to magnetic resonance imaging (MRI) applications) to check for clearance rate; which is far below the clinical dose of MHT. Due to this poor validation in preclinical scenarios, quite a few MNPs already in clinical use were later discontinued, on grounds of unexpected clinical outcomes in terms of inflammation, and prolonged clearance in vivo. By exploiting an economical method of synthesis, we have developed chitosan-coated Fe3O4 nanoparticles with high heating efficiency performance. Their anti-tumor response was evaluated in an ectopic tumor model of C6 glioblastoma by MHT. The intratumoral injection of MNPs on days 1 and 7 resulted in rapid tumor inhibition rate of 69.4% within 8 days, with complete inhibition within 32 days, and no recurrence recorded over a 5-month follow-up. Notably, the MNP-mediated MHT therapy achieved the highest degree of therapeutic efficacy required for complete tumor ablation by combining controlled temperature range (<44 °C), reduced MNP dosage; much lower than in most reported studies, and AMF parameters (time of exposure and frequency) within the clinical safety limit. Periodic body weight measurements confirmed negligible adverse side effects in rats. The anti-tumor activity was validated by severe apoptosis (TUNEL, cleaved Caspase-3), reduced proliferation (Ki 67) and disrupted vasculature (CD 31) in the Fe3O4-MHT-treated group. Real-time gene expression of pro-inflammatory cytokines (IL-6, TNF-α, IL-1α, IL-1ß) confirmed the intratumoral activation of IL-6, suggesting the role of immunomodulation in triggering the adaptive immune response for faster tumor regression in the treated group. In addition, the biodistribution and clearance rate of MNPs monitored using ICP-OES confirmed their time-dependent biodegradation via excretion (urine, feces), phagocytosis (liver) and circulatory system (blood), with negligible deposition in other major organs (kidney, heart, lungs). Although we could not show complete clearance of our MNPs within the time frame tested, future studies should focus on combining MHT with immunotherapy, and target tumors at a much-reduced iron dose, consequently improving in vivo clearance rate, and hence overcoming the limitations of MHT in clinical therapy.

Draft genome and secondary metabolite biosynthetic gene clusters of Streptomyces sp. strain 196.

Emergence of MDR 'superbugs' inflamed a severe sense of urgency amongst scientists aiming at the discovery of novel potential drug molecules. Bacteria of the genus Streptomyces are really worth investigating for their immense potential to produce natural compounds of pharmaceutical importance. In the present study, the genome of Streptomyces sp. strain 196 was sequenced, studied and secondary metabolite biosynthetic gene clusters (smBGCs) were detected. FAME analysis was used for taxonomic validation of strain 196. Genome of strain 196 was sequenced using the Illumina NextSeq system which has resulted in a draft genome of 7.4 Mb. Rapid annotation using subsystem technology (RAST) results revealed the presence of 6682 CDS, 64 tRNA genes and 7 rRNA genes. Comparative studies revealed that strain 196 have 93.5% nucleotide and 96% protein level similarities with Streptomyces rhizosphaericola 1AS2c. Genome mining using antiSMASH predicted the presence of BGCs responsible for diverse bioactive compound production. The detected gene clusters were two PKS-III, one PKS-I, five NRPS, two hybrid PKS-I/NRPS, one thiopeptide/LAP, and one bacteriocin types. Furthermore, many other types BGCs such as three ectoine, two siderophore, one arylpolyene, two butyrolactone, one lassopeptide, one lanthipeptide and one melanin were also found. The results of this study provides information about genome and BGCs of strain 196, this information is valuable for researchers who are interested in isolation of bioactive compounds and working on heterologous expression of cryptic BGCs for novel bioactive compounds production.

Tailoring the Design of a Lanthanide Complex/Magnetic Ferrite Nanocomposite for Efficient Photoluminescence and Magnetic Hyperthermia Performance.

In this work, we have designed a magnetoluminescent nanocomposite as a single platform for optical imaging and safe magnetic hyperthermia therapy by optimizing the composition of magnetic nanoparticles and controlling the conjugation strategy of the luminescent lanthanide complex. We have synthesized CoxMn1-xFe2O4 nanoferrites, with x = 0 to 1 in 0.25 steps, from soft (MnFe2O4) to hard (CoFe2O4) ferrites of size (∼20 nm) following a one-pot oxidative hydrolysis method. We have performed the induction heating study with an aqueous dispersion of nanoferrites using an alternating magnetic field (AMF) of 12 kAm-1, 335 kHz. This shows an enhancement of heating efficiency with the increment of manganese content and attains the highest intrinsic loss power (ILP) of 6.47 nHm2 kg-1 for MnFe2O4 nanoparticles. We have then fabricated a magnetoluminescent nanocomposite employing MnFe2O4 nanoparticles as it shows outstanding heating performance within the threshold limit of AMF (≤5 × 109 Am-1 s-1). A layer-by-layer coating strategy is followed, where a pure silica coating of thickness ∼10 nm on MnFe2O4 nanoparticles is achieved before encapsulation of the luminescent complex of europium(III), 2-thenoyltrifluoroacetone, and 1,10-phenanthroline in the second layer of silica. This is to ensure the optimal distance between the magnetic core and Eu(III)-complex to pertain significant luminescence in the composite (Eu-MnFe2O4). The photoluminescence spectra of an aqueous dispersion of Eu-MnFe2O4 by excitation in the UV region show a narrow and strong emission at 612 nm, which is stable even after 72 h. The induction heating study of an aqueous dispersion of Eu-MnFe2O4 in 12 kAm-1, 335 kHz AMF shows an ILP as 4.02 nHm2 kg-1, which is remarkably higher than the hyperthermia efficiency of reported magnetoluminescent nanoparticles.

Investigation of room temperature ferromagnetism in transition metal doped BiFeO3.

Spintronic functionality in ferromagnetic materials is a next-generation technique, to be used in data storage, high-frequency communications, and logic devices with minimum energy consumption. Ultra-low energy consumption in high-speed logic devices can be envisioned by inducing ferromagnetic behavior into room temperature multiferroic materials. However, there is a scarcity of room temperature multiferroic materials which have a definite spin degree of freedom. To fully exploit these technological challenges, we introduce the induced ferromagnetism in bismuth ferrite (BiFeO3, BFO) by doping transition metal (Cr, Ni, Co) elements. Our investigation initiates with the experimental study on chemically synthesized BiFe(1-x)M x O3 samples where x = 0.0625 (6.25%) and M = Cr, Ni and Co. Experimental findings are verified by theoretical simulation using density functional theory (DFT + U) and gauge including projector augmented wave (GIPAW) based calculation. All the experimental studies are done at room temperature while the theoretical verification using DFT is carried to understand the underlying mechanism behind the magnetic behavior of doped BiFeO3. It is done by optimizing the structural parameters comparable to the room temperature values. Microstructural and magnetic properties are studied using x-ray diffraction (XRD), transmission electron microscopy (TEM) and Vibrating sample magnetometer (VSM). All these experimental studies confirm the structural changes and induced ferromagnetism with doping. X-ray photoelectron spectroscopy (XPS) verified the reason behind this ferromagnetic property on the basis of oxygen vacancy content. Electron paramagnetic resonance (EPR) spectroscopy shows the tuning of Δg values due to enhanced magnetization. The density of states (DOS) calculations were performed on BFO (band-gap 1.89 eV) after structural optimization using DFT + U method, confirm our experimental findings. Magnetic moment values change drastically with doping elements (M), i.e. almost negligible for BFO (antiferromagnetic) to maximum (2.85 µ B/f.u.) for Ni-doped sample. We also compute the EPR g-tensor using GIPAW method to confirm the tuning of Δg values due to enhanced magnetization. These results can highlight the impact and importance of suitable transition element doping to induce the room temperature ferromagnetism in BiFeO3.