Active targeted delivery of theranostic thermo/pH dual-responsive magnetic Janus nanoparticles functionalized with folic acid/fluorescein ligands for enhanced DOX combination therapy of rat glioblastoma.

Doxorubicin (DOX), a chemotherapy drug, has demonstrated limited efficacy against glioblastoma, an aggressive brain tumor with resistance attributed to the blood-brain barrier (BBB). This study aims to overcome this challenge by proposing the targeted delivery of magnetic Janus nanoparticles (MJNPs) functionalized with folic acid ligands, fluorescent dye, and doxorubicin (DOX/MJNPs-FLA). The properties of these nanoparticles were comprehensively evaluated using bio-physiochemical techniques such as Fourier transform infrared (FTIR) spectroscopy, dynamic light scattering (DLS), zeta potential analysis, high-resolution transmission electron microscopy (HR-TEM), vibrating sample magnetometry (VSM), fluorescence microscopy, MTT assay, hemolysis assay, and liver enzyme level evaluation. Dual-controlled DOX release was investigated under different pH and temperature conditions. Additionally, the impact of DOX/MJNPs-FLA on apoptosis induction in tumor cells, body weight, and survival time of cancerous animals was assessed. The targeted delivery system was assessed using C6 and OLN-93 cell lines as representatives of cancerous and healthy cell lines, respectively, alongside Wistar rat tumor-bearing models. Results from Prussian blue staining and confocal microscopy tests demonstrated the effective targeted internalization of MJNPs-FLA by glioblastoma cells. Additionally, we investigated the biodistribution of the nanoparticles utilizing fluorescence imaging techniques. This enabled us to track the distribution pattern of MJNPs-FLA in vivo, shedding light on their movement and accumulation within the biological system. Furthermore, the combination of chemotherapy and magnetic hyperthermia exhibited enhanced efficacy in inducing apoptosis, as evidenced by the increase of the pro-apoptotic Bax gene and a decrease in the anti-apoptotic Bcl-2 gene. Remarkably, this combination treatment did not cause any hepatotoxicity. This study highlights the potential of DOX/MJNPs-FLA as carriers for therapeutic and diagnostic agents in the context of theranostic applications for the treatment of brain malignancies. Additionally, it demonstrates the promising performance of DOX/MJNPs-FLA in combination treatment through passive and active targeting.

Experimental and Molecular Docking Studies on Enzyme-Driven Biohybrid-Inspired Micromotors Based on Amylose-b-(PEG-co-PBA) Inclusion Complexes.

Amylose is a linear polysaccharide with a unique ability to form helical inclusion complexes with the appropriate guest components. Numerous studies have been conducted on encapsulation of bioactive compounds for various applications. In the biomedical field, biohybrid micro/nanomotors (MNMs) have emerged as innovative candidates due to their excellent biocompatible and biodegradable properties. This study was inspired by the biohybrid- and enzymatic-propelled MNMs and explored the potential of amylose inclusion complexes (ICs) in creating these MNMs. The study developed a new type of micromotor made from (PEG-co-PBA)-b-amylose. Nanoprecipitation, dimethyl sulfoxide (DMSO), and ultrasound-treated methods were employed to create spherical, thick crystalline, and rod-bacterial-like morphologies, respectively. Candida antarctica lipase B (CALB) was used as the catalytic fuel to induce the motion by the enzymatic degradation of ester linkages in the polymeric segment. Optical microscopy was utilized to observe the motion of the motors following incubation with enzyme concentrations of 5, 10, and 20% (w/w). The results demonstrated that the velocity of the motors increased proportionally with the percentage of added enzyme. Additionally, a comprehensive molecular docking evaluation with PyRx software provided insight into the interaction of the CALB enzyme with polymeric moieties and demonstrated a good affinity between the enzyme and polymer in the binding site. This study provides novel insight into the design and development of enzymatically driven polymeric micromotors and nanomotors.

Dual-drug delivery by thermo-responsive Janus nanogel for improved cellular uptake, sustained release, and combination chemo-thermal therapy.

The goal of this work was to examine the heat-sensitizing effects of Janus-coated magnetic nanoparticles (JMNPs) as a vehicle for 5-fluorouracil (5-Fu) and Quercetin (Qu) in C6 and OLN-93 cell lines. The cellular uptake of nanoparticles was evaluated using Prussian blue staining and ICP-OES after monolayer culturing of C6 (rat brain cancer cell) and OLN-93 (normal rat brain cell) cells. The cells were treated with free 5-Fu, Qu, and MJNPs loaded with Qu/5-Fu for 24 h, followed by magnetic hyperthermia under an alternating magnetic field (AMF) at a temperature of 43 °C. Using the MTT test and Flow cytometry, the C6 and OLN-93 cells were investigated after being subjected to hyperthermia with and without magnetic nanoparticles. The results of Prussian blue staining confirmed the potential of MJNPs as carriers that facilitate the uptake of drugs by cancer cells. The results showed that the combined application of Qu/5-Fu/MJNPs with hyperthermia significantly increased the amount of ROS production compared to interventions without MJNPs. The therapeutic results demonstrated that the combination of Qu/5-Fu/MJNPs with hyperthermia considerably enhanced the rate of apoptotic and necrotic cell death compared to that of interventions without MJNPs. Furthermore, MTT findings indicated that controlled exposure of Qu/5-Fu/MJNPs to AMF caused a synergistic effect. The advanced Janus magnetic nanoparticles in this study can be proposed as a promising dual drug carrier (Qu/5-Fu) and thermosensitizer platform for dual-modal synergistic cancer therapy.

Enhanced anti-tumor activity of transferrin/folate dual-targeting magnetic nanoparticles using chemo-thermo therapy on retinoblastoma cancer cells Y79.

Malignant neoplasms are one of the main causes of death, especially in children, on a global scale, despite strenuous efforts made at advancing both diagnostic and therapeutic modalities. In this regard, a new nanocarrier Vincristine (VCR)-loaded Pluronic f127 polymer-coated magnetic nanoparticles conjugated with folic acid and transferrin (PMNP-VCR-FA-TF) were synthesized and characterized by various methods. The cytotoxicity of these nanoparticles was evaluated in vitro and ex vivo conditions. The in vitro anti-tumor effect of the nanoparticles was evaluated by colony formation assay (CFA) and reactive oxygen species (ROS) in Y79 cell line. The results showed that nanoparticles with two ligands conferred greater toxicity toward Y79 cancer cells than ARPE19 normal cells. Under an alternating magnetic field (AMF), these nanoparticles demonstrated a high specific absorption rate. The CFA and ROS results indicated that the AMF in combination with PMNP-VCR-FA-TF conferred the highest cytotoxicity toward Y79 cells compared with other groups (P < 0.05). PMNP-VCR-FA-TF could play an important role in converting externally applied radiofrequency energy into heat in cancer cells. The present study confirmed that dual targeting chemo-hyperthermia using PMNP-VCR-FA-TF was significantly more effective than hyperthermia or chemotherapy alone, providing a promising platform for precision drug delivery as an essential component in the chemotherapy of retinoblastoma.

Magnetite-based Janus nanoparticles, their synthesis and biomedical applications.

The advent of Janus nanoparticles has been a great breakthrough in the emerging field of nanomaterials. Janus nanoparticles refer to a single structure with two distinct chemical functions on either side. Owing to their asymmetric structures, they can be utilized in a variety of applications where monomorphic particles are insufficient. In the last decade, a wide variety of materials have been employed to fabricate Janus nanoparticles, and due to the great advantages of magnetite (Iron-oxide) NPs, they have been considered as one of the best candidates. With the main benefit of magnetic controlling, magnetite Janus nanoparticles fulfill great promises, especially in biomedical areas such as bioimaging, cancer therapies, theranostics, and biosensing. The intrinsic characteristics of magnetite Janus nanoparticles (MJNPs) even hold great potential in magnetite Janus forms of micro-/nanomotors. Despite the great interest and potential in magnetic Janus NPs, the need for a comprehensive review on MJNPs with a concentration on magnetite NPs has been overlooked. Herein, we present recent advancements in the magnetite-based Janus nanoparticles in the flourishing field of biomedicine. First, the synthesis and fabrication methods of Janus nanoparticles are discussed. Then we will delve into their intriguing biomedical applications, with a separate section for magnetite Janus micro-/nanomotors in biomedicine. And finally, the challenges and future outlook are provided. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Diagnostic Tools > Diagnostic Nanodevices Diagnostic Tools > In Vitro Nanoparticle-Based Sensing.

Synthesis of magnetic electroactive nanomotors based on sodium alginate/chitosan and investigation the influence of the external electric field on the mechanism of locomotion.

In this paper, we report a novel electric-driven Janus nanomotor (JNMs) based on SPIONs nanoparticle decorated with chitosan (Cs) and sodium alginate (Na/Alg) using the Pickering emulsion method. The JNMs dispersed in aqueous media exhibit linear trajectories under DC electric field, and the driving force is attributed to the self-electro-osmotic mechanism and surface modifications. This study offers an approach to remotely control the motion modes of the JNMs, including start, stop, directional and programmable motion, which can be advantageous for various application scenarios. The diffusion coefficient and velocity of the JNMs were investigated through mean square displacement analysis for single particle of JNMs, both in distilled water and in the presence of different di and trivalent metal cations (Fe3+, Al3+, Ba2+, Ca2+ and Mg2+) as crosslinking agents, as well as monovalent salts (LiCl and KCl). The results revealed that the motion of JNMs was fastest in the presence of Fe3+ as crosslinker agent (about 7.2181 µm2/s) due to its higher charge than equimolar Na+ . Moreover, it was demonstrated that increasing the ionic strength led to relatively higher speeds of JNMs, as the solution polarity increased and, as a result, the driving force of electro-osmoesis enhanced.

Dual-Drug Delivery by Anisotropic and Uniform Hybrid Nanostructures: A Comparative Study of the Function and Substrate-Drug Interaction Properties.

By utilizing nanoparticles to upload and interact with several pharmaceuticals in varying methods, the primary obstacles associated with loading two or more medications or cargos with different characteristics may be addressed. Therefore, it is feasible to evaluate the benefits provided by co-delivery systems utilizing nanoparticles by investigating the properties and functions of the commonly used structures, such as multi- or simultaneous-stage controlled release, synergic effect, enhanced targetability, and internalization. However, due to the unique surface or core features of each hybrid design, the eventual drug-carrier interactions, release, and penetration processes may vary. Our review article focused on the drug's loading, binding interactions, release, physiochemical, and surface functionalization features, as well as the varying internalization and cytotoxicity of each structure that may aid in the selection of an appropriate design. This was achieved by comparing the actions of uniform-surfaced hybrid particles (such as core-shell particles) to those of anisotropic, asymmetrical hybrid particles (such as Janus, multicompartment, or patchy particles). Information is provided on the use of homogeneous or heterogeneous particles with specified characteristics for the simultaneous delivery of various cargos, possibly enhancing the efficacy of treatment techniques for illnesses such as cancer.

Exploring Low-Power Single-Pulsed Laser-Triggered Two-Photon Photodynamic/Photothermal Combination Therapy Using a Gold Nanostar/Graphene Quantum Dot Nanohybrid.

Combined photodynamic/photothermal therapy (PDT/PTT) has emerged as a promising cancer treatment modality due to its potential synergistic effects and identical treatment procedures. However, its clinical application is hindered by long treatment times and complicated treatment operations when separate illumination sources are required. Here, we present the development of a new nanohybrid comprising thiolated chitosan-coated gold nanostars (AuNS-TCS) as the photothermal agent and riboflavin-conjugated N,S-doped graphene quantum dot (Rf-N,S-GQD) as the two-photon photosensitizer (TP-PS). The nanohybrid demonstrated combined TP-PDT/PTT when a low-power, single-pulsed laser irradiation was applied, and the localized surface plasmon resonance of AuNS was in resonance with the TP-absorption wavelength of Rf-N,S-GQD. The TCS coating significantly enhanced the colloidal stability of AuNSs while providing a suitable substrate to electrostatically anchor negatively charged Rf-N,S-GQDs. The plasmon-enhanced singlet oxygen (1O2) generation effect led to boosted 1O2 production both extracellularly and intracellularly. Notably, the combined TP-PDT/PTT exhibited significantly improved phototherapeutic outcomes compared to individual strategies against 2D monolayer cells and 3D multicellular tumor spheroids. Overall, this study reveals a successful single-laser-triggered, synergistic combined TP-PDT/PTT based on a plasmonic metal/QD hybrid, with potential for future investigation in clinical settings.

Rumen-protected glucose hastens uterine involution and increases numbers of ovarian follicles in early post-partum dairy cows.

The primary objectives were to investigate the effects of feeding a new rumen-protected glucose (RPG) on uterine involution and ovarian follicular dynamics in recently calved dairy cattle. From 4 to 30 days after calving, 16 Holsteins (first to third lactation, mean parity 1.75) were randomly assigned to be fed either a basal diet top-dressed with either 600 g RPG (RPG group) or 600 g of the coating material and glucose (CONT group). Based on transrectal ultrasonography, conducted every 3 days starting 20 days after calving, the interval from calving to complete uterine involution was shorter in RPG versus CONT (27.1 vs. 30.4 days, p < .01). Furthermore, based on transrectal ultrasonography conducted every 2 days, cattle fed RPG had smaller (3.0-4.9 mm) ovarian follicles (2.96 vs. 0.9, p < .001) and more total follicles (5.26 vs. 2.85, p < .01). Feeding RPG had increased serum insulin concentrations (4.59 ± 0.54 vs. 3.13 ± 0.57, p < .05), but had no significant effects on serum glucose concentrations, dry matter intake or milk yield. In conclusion, we inferred that cattle fed RPG had increased glucose turnover that was responsible for higher insulin concentrations, faster uterine involution, and more ovarian follicles.

Two-photon photodynamic therapy based on FRET using tumor-cell targeted riboflavin conjugated graphene quantum dot.

The photodynamic therapy (PDT) is considered as a noninvasive and photo-controlled treatment for various cancers. However, its potential is not fully developed as current clinically approved photosensitizers (PSs) mainly absorb the light in the UV-visible region (less than 700 nm), where the depth of penetration is inadequate for reaching tumor cells under deeper tissue layers. Furthermore, the lack of specific accumulation capability of the conventional PSs in the tumor cells may cause serious toxicity and low treatment efficiency. To address these problems, riboflavin (Rf) conjugated and amine-functionalized nitrogen-doped graphene quantum dots (am-N-GQD) are herein proposed. Rf functions as both photosensitizer and targeting ligand by indirect excitation through intra-particle fluorescence resonance energy transfer (FRET) via two-photon (TP) excited am-N-GQD, to enhance the treatment depth, and further am-N-GQD-Rf accumulation in cancer cells using Rf transporter family (RFVTs) and Rf carrier proteins (RCPs). The one-photon (OP) and two-photon(TP)-PDT effect and cellular internalization ability of the am-N-GQD-Rf were investigated in vitro in different cancel cell lines. Besides the excellent cellular uptake as well TP-PDT capability, the superior biocompatibility of am-N-GQD-Rf in vitro makes it promising candidate in PDT.

Synthesis of Candida Antarctica Lipase B (CALB) enzyme-powered magnetite nanomotor based on PCL/Chitosan Janus nanostructure.

In this work, we report the design and synthesis of internal energy-driven Janus nanomotors (JNMs), which are composed of certain reactive materials that are capable of converting chemical energy in the backbone of nanomotors into kinetic energy. For this purpose, superparamagnetic iron oxide nanoparticles (SPIONs) with the anisotropic surface were obtained via a Pickering emulsion. Modified chitosan (as hydrophilic polymer) and functionalized polycaprolactone (as hydrophobic domain) were covalently linked to the surface of bi-functional SPIONs to produce Janus nanoparticles (JNPs). Then, the CALB enzyme was loaded in the PCL hemisphere of JNPs to form the Janus nanomotor. When nanomotors are placed in the phosphate-buffered saline solution, the driving force for motion is provided by the decomposition of polyester into monomers and oligomers on one side of the JNMs. The trajectories of the nanomotors were recorded under different circumstances by a video microscope and analyzed by the mean squared displacement. The results show that the velocity of JNMs increases with an increasing percentage of the loaded enzyme. In addition, the diffusion coefficient enhances up to 87.67% in compared with nanoparticles without enzyme. Controlling the motion direction of JNMs by an external magnetic field is also possible, due to the presence of SPIONs.

Sensitization of glioblastoma cancer cells to radiotherapy and magnetic hyperthermia by targeted temozolomide-loaded magnetite tri-block copolymer nanoparticles as a nanotheranostic agent.

AIMS: Recently, the development of new strategies in the treatment and diagnosis of cancer cells such as thermo-radiation-sensitizer and theranostic agents have received a great deal of attention. In this work, folic acid-conjugated temozolomide-loaded SPION@PEG-PBA-PEG nanoparticles (TMZ-MNP-FA NPs) were proposed for use as magnetic resonance imaging (MRI) contrast agents and to enhance the cytotoxic effects of hyperthermia and radiotherapy. MAIN METHODS: Nanoparticles were synthesized by the Nano-precipitation method and their characteristics were determined by dynamic light scattering (DLS), scanning electron microscopy (SEM) and X-ray powder diffraction (XRD). To evaluate the thermo-radio-sensitization effects of NPs, C6 cells were treated with nanoparticles for 24 h and then exposed to 6-MV X-ray radiation. After radiotherapy, the cells were subjected to an alternating magnetic field (AMF) hyperthermia. The therapeutic potential was assessed using clonogenic assay, ROS generation measurement, flow cytometry assay, and qRT-PCR analysis. Also, the diagnostic properties of the nanoparticles were assessed by MRI. KEY FINDINGS: MRI scanning indicated that nanoparticles accumulated in C6 cells could be tracked by T2-weighted MR imaging. Colony formation assay proved that TMZ-MNP-FA NPs enhanced the anti-proliferation effects of AMF by 1.94-fold compared to AMF alone (P < 0.0001). Moreover, these NPs improved the radiation effects with a dose enhancement factor of 1.65. All results showed that the combination of carrier-based chemotherapy with hyperthermia and radiotherapy caused a higher anticancer efficacy than single- or two-modality treatments. SIGNIFICANCE: The nanoparticles advanced in this study can be proposed as the promising theranostic and thermo-radio-sensitizer platform for the diagnosis and tri-modal synergistic cancer therapy.

Self-/Magnetic-Propelled Catalytic Nanomotors Based on a Janus SPION@PEG-Pt/PCL Hybrid Nanoarchitecture: Single-Particle versus Collective Motions.

In this paper, we synthesized superparamagnetic iron oxide nanoparticles (NPs) functionalized with (3-aminopropyl)triethoxysilane (Fe3O4@APTES). The synthesized NPs were coated with succinic anhydride (Fe3O4@COOH) in the next step. Half the surface of the NPs was shielded with wax microparticles via the Pickering emulsion technique, and the unshielded side was covered with poly(ethylene glycol) methyl ether. Platinum nanoparticles (Pt NPs) were deposited between PEG chains by the oxidation-reduction method through an in situ procedure to obtain a metal-polymer composite. These deposited Pt NPs have the potential to catalyze the decomposition of hydrogen peroxide at the surface of Janus nanomotors (JNMs). After de-waxing of the NPs, Irgacure 2959 (as the initiator) was reacted with the bare side of the NPs to provide the opportunity to grow poly(ε-caprolactone) (PCL) chains on the surface of the nanomotors through the "grafting from" method. The diffusion coefficient and velocity of the JNMs (before and after the PCL reaction) in the aqueous solution of 1, 2, 3, 5, and 10% (w/w) hydrogen peroxide and in the presence of different concentrations of NaCl solutions (0, 5, and 10% (w/v)) were investigated by mean square displacement analysis for single-particle or collective motions of JNMs. In addition, the simultaneous effect of an external magnetic field and the NaCl concentration on the movement direction of JNMs was also evaluated in the presence of hydrogen peroxide (10%). Increasing the ionic strength through NaCl addition permits the JNMs to move with relatively lower amounts of fuel [i.e., 2% (w/w)]. The collective motion investigation of the JNMs showed the highest speed in the media with 10% (w/w) hydrogen peroxide and 5% (w/v) NaCl solution (about 1215.78 µm2/s) due to the surfactant effect of the Janus architecture.

Physical and Biological Properties of 5-Fluorouracil Polymer-Coated Magnetite Nanographene Oxide as a New Thermosensitizer for Alternative Magnetic Hyperthermia and a Magnetic Resonance Imaging Contrast Agent: In Vitro and In Vivo Study.

This study reports a new procedure for utilizing 5-fluorouracil (5-Fu)-loaded polycaprolactone (PCL)/chitosan-covered magnetite nanographene oxide (5-Fu/SPION/NGO@PCL-LMWC) as a platform for synergistic thermo-chemotherapy. In fact, superparamagnetic iron oxide nanoparticles/nanographene oxide (SPION/NGO) nanoparticles can be coated with copolymers PCL/chitosan to attain better colloidal stability in the biological environment. Nanoparticles were synthesized and characterized for their size, surface charge, X-ray patterns, polymer content, and in vitro heat-triggered release. In vitro cytotoxic effects of nanoparticles on CT-26 cells were assessed with an MTT assay and real-time polymerase chain reaction. In vivo tumor growth inhibition was evaluated on an allograft mouse model of CT-26 cells. Tumor-bearing mice were injected with 5-Fu-loaded nanoparticles intravenously, and then, the targeted delivery was amplified using a magnetic field and finally exposed to an alternating magnetic field (AMF) (40 A/m, 13.56 MHz), during which the tumor site temperature increased to 43 °C. By using an infrared camera, we managed to heat the nanoparticles up to a constant temperature between 42.5 and 43.5 °C, with a tolerance ±0.03 °C. Finally, in vitro results showed that 5-Fu-loaded nanoparticles combined with AMF hyperthermia significantly reduced the plating efficiency of the cells (P < 0.01) and increased the Bax/Bcl-2 ratio (1.42 times, P < 0.01) compared with those achieved with each one alone. Furthermore, in vivo results demonstrated that the treatment of 5-Fu-loaded nanoparticles combined with the AMF diminished the growth of CT-26 tumor cells and increased the life span of the tumor-bearing mice (P < 0.001) by thermal energy deposition compared to that of the free 5-Fu drug. Also, the high level of accumulation of the nanoparticles within the tumor site was easily monitored with magnetic resonance imaging. It was concluded that the multifunctional magnetic nanoparticles could be used as a promising nanocarrier platform for achieving concurrent goals, drug delivery, magnetic targeting, thermal-sensitizing, cell death induction, and real-time monitoring of response to treatment.

Enhancement of Radio-Thermo-Sensitivity of 5-Iodo-2-Deoxyuridine-Loaded Polymeric-Coated Magnetic Nanoparticles Triggers Apoptosis in U87MG Human Glioblastoma Cancer Cell Line.

INTRODUCTION: With an emphasis on the radioresistant nature of glioblastoma cells, the aim of the present study was to evaluate the radio-thermo-sensitizing effects of PCL-PEG-coated Superparamagnetic iron oxide nanoparticles (SPIONs) as a carrier of 5-iodo-2-deoxyuridine (IUdR) in monolayer culture of U87MG human glioma cell line. METHODS: Following monolayer culture of U87MG cells, nanoparticle uptake was assessed using Prussian blue staining and ICP-OES method. The U87MG cells were treated with an appropriate concentration of free IUdR and PCL-PEG-coated SPIONs (MNPs) loaded with IUdR (IUdR/MNPs) for 24 h, subjected to hyperthermia (water bath and alternating magnetic field (AMF)) at 43 °C, and exposed to X-ray (2 Gy, 6 MV). The combined effects of hyperthermia with or without magnetic nanoparticles on radiosensitivity of the U87MG cells were evaluated using colony formation assay (CFA) and Flowcytometry. RESULTS: Prussian blue staining and ICP-OES showed that the nanoparticles were able to enter the cells. The results also indicated that IUdR/MNPs combined with X-ray radiation and hyperthermia significantly decreased the colony formation ability of monolayer cells (1.11, 1.41 fold) and increased the percentage of apoptotic (2.47, 4.1 fold) and necrotic cells (12.28, 29.34 fold), when compared to IUdR combined with X-ray and hyperthermia or IUdR/MNPs + X-ray. MTT results revealed that the presence of IUdR/MNPs significantly increased the toxicity of AMF hyperthermia compared to the water bath method. CONCLUSIONS: Our study showed that SPIONs/PCL-PEG, as a carrier of IUdR, can enhance the cytotoxic effects of radiotherapy and hyperthermia and act as a radio-thermo-sensitizing agent. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12195-021-00675-y.

Radio-sensitivity enhancement in HT29 cells through magnetic hyperthermia in combination with targeted nano-carrier of 5-Flourouracil.

Normal tissue complication and development of radioresistance in cancer cells are known as the main challenges of ionizing radiation treatment. In the current study, we intended to induce selective radiosensitization in HT29 cancer cells by developing folic acid modified magnetic triblock copolymer nanoparticles as carrier of 5-Flourouracil (5-FU) which was further used in combination with hyperthermia. The aforementioned nanoparticles were synthesized and characterized by differential scanning calorimetric analysis (DSC), UV-visible spectroscopy, dynamic light scattering (DLS), zeta sizer, and transmission electron microscopy (TEM). These nanoparticles were also assessed to determine drug loading capacity (DLC %) and drug release profile. The cytotoxicity of nanoparticles was evaluated on two different cell lines: HUVEC and HT29. Furthermore, radiosensitivity induction of the nanoparticles with and without exposure of alternative magnetic field was investigated. MTT-based cytotoxicity assay demonstrated that the therapeutic ratio was enhanced in response to using 5-FU-loaded nanoparticles as compared to 5-FU. Various characterizations including gene expression study, measurement of reactive oxygen species (ROS) generation, Annexin V/PI staining, and clonogenic assay revealed that ionizing radiation in combination with hyperthermia in the presence of the synthesized nanoparticles led to maximal anti-cancer effects as compared to other single (P < 0.001) and combined treatments (P < 0.01). Our results suggested that combined treatment based on using folic acid modified magnetic copolymer nanoparticle as carrier of 5-FU accompanied with hyperthermia could be proposed as an efficient approach to enhance radiation effects in cancer cells.

Correction: Synergistic effects of magnetic drug targeting using a newly developed nanocapsule and tumor irradiation by ultrasound on CT26 tumors in BALB/c mice.

Correction for 'Synergistic effects of magnetic drug targeting using a newly developed nanocapsule and tumor irradiation by ultrasound on CT26 tumors in BALB/c mice' by Ali Shakeri-Zadeh et al., J. Mater. Chem. B, 2015, 3, 1879-1887, DOI: 10.1039/C4TB01708K.

Evaluation of apoptotic effects of mPEG-b-PLGA coated iron oxide nanoparticles as a eupatorin carrier on DU-145 and LNCaP human prostate cancer cell lines.

Many studies have so far confirmed the efficiency of phytochemicals in the treatment of prostate cancer. Eupatorin, a flavonoid with a wide range of phytomedical activities, suppresses proliferation of and induces apoptosis of multiple cancer cell lines. However, low solubility, poor bioavailability, and rapid degradation limit its efficacy. The aim of our study was to evaluate whether the use of mPEG-b-poly (lactic-co-glycolic) acid (PLGA) coated iron oxide nanoparticles as a carrier could enhance the therapeutic efficacy of eupatorin in DU-145 and LNcaP human prostate cancer cell lines. Nanoparticles were prepared by the co-precipitation method and were fully characterized for morphology, surface charge, particle size, drug loading, encapsulation efficiency and in vitro drug-release profile. The inhibitory effect of nanoparticles on cell viability was evaluated by MTT test. Apoptosis was then determined by Hoechest staining, cell cycle analysis, NO production, annexin/propidium iodide (PI) assay, and Western blotting. The results indicated that eupatorin was successfully entrapped in Fe3O4@mPEG-b-PLGA nanoparticles with an efficacy of (90.99 ± 2.1)%. The nanoparticle's size was around (58.5 ± 4) nm with a negative surface charge [(-34.16 ± 1.3) mV]. In vitro release investigation showed a 30% initial burst release of eupatorin in 24 h, followed by sustained release over 200 h. The MTT assay indicated that eupatorin-loaded Fe3O4@mPEG-b-PLGA nanoparticles exhibited a significant decrease in the growth rate of DU-145 and LNcaP cells and their IC50 concentrations were 100 µM and 75 µM, respectively. Next, apoptosis was confirmed by nuclear condensation, enhancement of cell population in the sub-G1 phase and increased NO level. Annexin/PI analysis demonstrated that eupatorin-loaded Fe3O4@mPEG-b-PLGA nanoparticles could increase apoptosis and decrease necrosis frequency. Finally, Western blotting analysis confirmed these results and showed that Bax/Bcl-2 ratio and the cleaved caspase-3 level were up-regulated by the designing nanoparticles. Encapsulation of eupatorin in Fe3O4@mPEG-b-PLGA nanoparticles increased its anticancer effects in prostate cancer cell lines as compared to free eupatorin. Based on these results, this formulation can provide a sustained eupatorin-delivery system for cancer treatment with the drug remaining active at a significantly lower dose, making it a suitable candidate for pharmacological uses.

The simultaneous role of porphyrins' H- and J- aggregates and host-guest chemistry on the fabrication of reversible Dextran-PMMA polymersome.

Aggregation-induced quenching of porphyrin molecules as photosensitizer significantly reduces the quantum yield of the singlet oxygen generation, and it is able to decrease the efficacy of photodynamic therapy. We utilized amphiphilic copolymers in this work to precisely control porphyrin H-type and J-type aggregations in water. The amphiphilic copolymer bearing azobenzene, ß-cyclodextrin, and porphyrin was successfully synthesized by the atom transfer radical polymerization technique. The azobenzene and ß-cyclodextrin complex, as a host-guest supramolecular interaction, has great potential in the design of light-responsive nanocarriers. The amphiphilic block copolymer can be self-assembled into polymersomes, whose application in the generation of singlet oxygen has been also tested. We further demonstrate that, due to the stable H- and J-aggregates of porphyrin, which act as noncovalent cross-linking points, the structure of polymersomes can be reversible under light-stimulus. This formation method has the advantage of allowing for both the encapsulation of hydrophilic and hydrophobic molecules and release upon external light without any distinguishable changes in the structure. Furthermore, the morphology and particle size distribution of the polymersomes were also investigated by using transition electron microscopy, dynamic light scattering, and field emission scanning electron microscopy.

Improvement of the Solubility Amphotericin B Using Olive Oil Nanoemulsion Coated with Chitosan for More Effective Treatment of Zoonotic Cutaneous Leishmaniasis.

Amphotericin B (AMB) is a macrolide polyene antibiotic presenting potent anti-cutaneous leishmania activity. Nonetheless, its low water solubility, side effects, and toxicity have limited its therapeutic efficiency. The present study aimed to improve the solubility of AmB in oil-in-water using chitosan and determine its cytotoxicity on macrophages, as well as Leishmania major promastigote and amastigote. Olive oil, span 80, tween 80, AmB, and DMSO were employed as excipients, and nanoemulsions (NEs) were prepared by sonicator bath at 37 °C for 1 h at the highest power and stirred overnight with pH 5.5. Thereafter, chitosan was added to the NE and stirred overnight to obtain chitosan nanoemulsion (CNE). The CNE was optimized and investigated for different in-vitro parameters, such as droplet size, zeta potential, morphology, drug content, in-vitro drug release, and in-vitro cytotoxicity. Droplet size and zeta potential for CNE with AmB were obtained at 13.33 ± 1.3 nm, 30.90 ± 1.9 mV, respectively. Encapsulation efficiency and drug loading of the final CNE were reported as 100% and 0.64%, respectively. The results of in-vitro cytotoxicity revealed that CNE did not cause any cytotoxicity in macrophages. The CNE not only reduced drug toxicity for the macrophage but also had a suitable inhibition effect on the parasite. The CNE with AmB exerted an inhibitory effect on L. major promastigote/ amastigote phase. Furthermore, CNE with AmB represented a promising approach for leishmaniasis treatment. Therefore, the obtained outcomes of the IC50 proposed that the application of CNE can cause no toxicity and guarantees better quality drug release.