Multicomponent, peptide-targeted glycol chitosan nanoparticles containing ferrimagnetic iron oxide nanocubes for bladder cancer multimodal imaging.
ABSTRACT: While current imaging modalities, such as magnetic resonance imaging (MRI), computed tomography, and positron emission tomography, play an important role in detecting tumors in the body, no single-modality imaging possesses all the functions needed for a complete diagnostic imaging, such as spatial resolution, signal sensitivity, and tissue penetration depth. For this reason, multimodal imaging strategies have become promising tools for advanced biomedical research and cancer diagnostics and therapeutics. In designing multimodal nanoparticles, the physicochemical properties of the nanoparticles should be engineered so that they successfully accumulate at the tumor site and minimize nonspecific uptake by other organs. Finely altering the nano-scale properties can dramatically change the biodistribution and tumor accumulation of nanoparticles in the body. In this study, we engineered multimodal nanoparticles for both MRI, by using ferrimagnetic nanocubes (NCs), and near infrared fluorescence imaging, by using cyanine 5.5 fluorescence molecules. We changed the physicochemical properties of glycol chitosan nanoparticles by conjugating bladder cancer-targeting peptides and loading many ferrimagnetic iron oxide NCs per glycol chitosan nanoparticle to improve MRI contrast. The 22 nm ferrimagnetic NCs were stabilized in physiological conditions by encapsulating them within modified chitosan nanoparticles. The multimodal nanoparticles were compared with in vivo MRI and near infrared fluorescent systems. We demonstrated significant and important changes in the biodistribution and tumor accumulation of nanoparticles with different physicochemical properties. Finally, we demonstrated that multimodal nanoparticles specifically visualize small tumors and show minimal accumulation in other organs. This work reveals the importance of finely modulating physicochemical properties in designing multimodal nanoparticles for bladder cancer imaging.
Project description:This study is to demonstrate the nanoscale size effect of ferrimagnetic H-ferritin (M-HFn) nanoparticles on magnetic properties, relaxivity, enzyme mimetic activities, and application in magnetic resonance imaging (MRI) and immunohistochemical staining of cancer cells.M-HFn nanoparticles with different sizes of magnetite cores in the range of 2.7-5.3 nm were synthesized through loading different amounts of iron into recombinant human H chain ferritin (HFn) shells. Core size, crystallinity, and magnetic properties of those M-HFn nanoparticles were analyzed by transmission electron microscope and low-temperature magnetic measurements. The MDA-MB-231 cancer cells were incubated with synthesized M-HFn nanoparticles for 24 hours in Dulbecco's Modified Eagle's Medium. In vitro MRI of cell pellets after M-HFn labeling was performed at 7 T. Iron uptake of cells was analyzed by Prussian blue staining and inductively coupled plasma mass spectrometry. Immunohistochemical staining by using the peroxidase-like activity of M-HFn nanoparticles was carried out on MDA-MB-231 tumor tissue paraffin sections.The saturation magnetization (M(s)), relaxivity, and peroxidase-like activity of synthesized M-HFn nanoparticles were monotonously increased with the size of ferrimagnetic cores. The M-HFn nanoparticles with the largest core size of 5.3 nm exhibit the strongest saturation magnetization, the highest peroxidase activity in immunohistochemical staining, and the highest r2 of 321 mM(-1) s(-1), allowing to detect MDA-MB-231 breast cancer cells as low as 10(4) cells mL(-1).The magnetic properties, relaxivity, and peroxidase-like activity of M-HFn nanoparticles are size dependent, which indicates that M-HFn nanoparticles with larger magnetite core can significantly enhance performance in MRI and staining of cancer cells.
Project description:Diagnostic approaches based on multimodal imaging of clinical noninvasive imaging (eg. MRI/CT scanner) are highly developed in recent years for accurate selection of the therapeutic regimens in critical diseases. Therefore, it is highly demanded in the development of appropriate all-in-one multimodal contrast agents (MCAs) for the MRI/CT multimodal imaging. Here a novel ideal MCAs (F-AuNC@Fe3O4) were engineered by assemble Au nanocages (Au NC) and ultra-small iron oxide nanoparticles (Fe3O4) for simultaneous T1-T2dual MRI and CT contrast imaging. In this system, the Au nanocages offer facile thiol modification and strong X-ray attenuation property for CT imaging. The ultra-small Fe3O4 nanoparticles, as excellent contrast agent, is able to provide great enhanced signal of T1- and T2-weighted MRI (r1?=?6.263?mM(-1) s(-1), r2?=?28.117?mM(-1) s(-1)) due to their ultra-refined size. After functionalization, the present MCAs nanoparticles exhibited small average size, low aggregation and excellent biocompatible. In vitro and In vivo studies revealed that the MCAs show long-term circulation time, renal clearance properties and outstanding capability of selective accumulation in tumor tissues for simultaneous CT imaging and T1- and T2-weighted MRI. Taken together, these results show that as-prepared MCAs are excellent candidates as MRI/CT multimodal imaging contrast agents.
Project description:Iron oxide nanoparticles (IOs) are intrinsically theranostic agents that could be used for magnetic resonance imaging (MRI) and local hyperthermia or tissue thermal ablation. Yet, effective hyperthermia and high MR contrast have not been demonstrated within the same nanoparticle configuration. Here, magnetic nanoconstructs are obtained by confining multiple, ? 20 nm nanocubes (NCs) within a deoxy-chitosan core. The resulting nanoconstructs-magnetic nanoflakes (MNFs)-exhibit a hydrodynamic diameter of 156 ± 3.6 nm, with a polydispersity index of ?0.2, and are stable in PBS up to 7 days. Upon exposure to an alternating magnetic field of 512 kHz and 10 kA m(-1), MNFs provide a specific absorption rate (SAR) of ?75 W gFe(-1), which is 4-15 times larger than that measured for conventional IOs. Moreover, the same nanoconstructs provide a remarkably high transverse relaxivity of ?500 (mM s)(-1), at 1.41T. MNFs represent a first step toward the realization of nanoconstructs with superior relaxometric and ablation properties for more effective theranostics.
Project description:Bromelain, a set of proteolytic enzymes potential pharmaceutical applications, was encapsulated in chitosan nanoparticles to enhance enzyme stability, and the effect of different chitosan sources was evaluated. Chitosan types (i.e., low molecular weight chitosan, chitosan oligosaccharide lactate, and chitosan from shrimp shells) produced nanoparticles with different physicochemical properties, however in all cases, particle size and zeta potential decreased, and polydispersity index increased after bromelain addition. Bromelain encapsulation was higher than 84% and 79% for protein content and enzymatic activity, respectively, with low molecular weight chitosan presenting the highest encapsulation efficiency. Nanoparticle suspension was also tested for accelerated stability and rheological behavior. For the chitosan-bromelain nanoparticles, an instability index below 0.3 was recorded and, in general, the loading of bromelain in chitosan nanoparticles decreased the cohesiveness of the final suspension.
Project description:Multifunctional nanoparticles are synthesized for both pH-triggered drug release and imaging with radioluminescence, upconversion luminescent, and magnetic resonance imaging (MRI). The particles have a yolk-in-shell morphology, with a radioluminescent core, an upconverting shell, and a hollow region between the core and shell for loading drugs. They are synthesized by controlled encapsulation of a radioluminescent nanophosphor yolk in a silica shell, partial etching of the yolk in acid, and encapsulation of the silica with an upconverting luminescent shell. Metroxantrone, a chemotherapy drug, was loaded into the hollow space between X-ray phosphor yolk and up-conversion phosphor shell through pores in the shell. To encapsulate the drug and control the release rate, the nanoparticles are coated with pH-responsive biocompatible polyelectrolyte layers of charged hyaluronic acid sodium salt and chitosan. The nanophosphors display bright luminescence under X-ray, blue light (480 nm), and near infrared light (980 nm). They also served as T1 and T2 MRI contrast agents with relaxivities of 3.5 mM(-1) s(-1) (r1 ) and 64 mM(-1) s(-1) (r2 ). These multifunctional nanocapsules have applications in controlled drug delivery and multimodal imaging.
Project description:Multimodal imaging using novel multifunctional nanoparticles provides new approach to biomedical field. Thiol-organosilica nanoparticles containing iron oxide magnetic nanoparticles (MNPs) and rhodamine B (thiol OS-MNP/Rho) were applied to multimodal imaging of hepatic tumor of Long-Evans Cinnamon (LEC) rat. The magnetic resonance imaging (MRI) of LEC rats revealed tumors in the liver clearly and semi-quantitatively due to a labeling of macrophages in liver. The fluorescent imaging (FI) showed abnormal fluorescent patterns of the liver at the mesoscopic level that was between macroscopic and microscopic level. We performed correlation analysis between optical imaging including FI and MRI. We found that the labeled macrophages located specific area in the tumor tissue and influenced the tumor size on MRI. In addition histological observation showed the labeled macrophages related specific tissue in the pathological region. We demonstrated a new approach to evaluate tumor tissue at the macroscopic and microscopic level as well as mesoscopic level using multimodal imaging.
Project description:Multimodal imaging probes can provide diagnostic information combining different imaging modalities. Nanoparticles (NPs) can contain two or more imaging tracers that allow several diagnostic techniques to be used simultaneously. In this work, a complex coacervation process to produce core-shell completely biocompatible polymeric nanoparticles (HyCoS) for multimodal imaging applications is described. Innovations on the traditional coacervation process are found in the control of the reaction temperature, allowing a speeding up of the reaction itself, and the production of a double-crosslinked system to improve the stability of the nanostructures in the presence of a clinically relevant contrast agent for MRI (Gd-DTPA). Through the control of the crosslinking behavior, an increase up to 6 times of the relaxometric properties of the Gd-DTPA is achieved. Furthermore, HyCoS can be loaded with a high amount of dye such as ATTO 633 or conjugated with a model dye such as FITC for in vivo optical imaging. The results show stable core-shell polymeric nanoparticles that can be used both for MRI and for optical applications allowing detection free from harmful radiation. Additionally, preliminary results about the possibility to trigger the release of a drug through a pH effect are reported.
Project description:Objective:Titanium dioxide nanoparticles (TiO2) nanoparticles have been widely explored in the prevention of cancer risk. Due to the difficult solubility of TiO2 nanoparticles, it is essential to synthesize new surfactants to increase its bioavailability and anti-tumor activity and reduce its cytotoxicity. Furthermore, oxidative and inflammation are closely associated with the osteosarcoma risk. Chitosan has biocompatibility, antioxidant and anti-inflammatory properties. The effects of chitosan-coated TiO2-embedded paclitaxel nanoparticles on an osteosarcoma model were explored. Methods:An osteosarcoma model was established and chitosan-coated TiO2-embedded paclitaxel nanoparticles were prepared using a freeze-drying strategy. The morphological characteristics of nanoparticles were observed using scanning electron microscopy (SEM). The physicochemical properties of nanoparticle were evaluated by X-ray diffraction (XRD) and Fourier transform infrared (FTIR) spectroscopy. The cytotoxicity was tested by using human osteoblast cells hFob1.19 and osteosarcoma cells 143B. Osteosarcoma mice were treated with PBS buffer, paclitaxel, TiO2-embedded paclitaxel and chitosan-coated TiO2-embedded paclitaxel nanoparticles. The biomarkers of oxidative-inflammatory status, anti-tumor activities and survival rates of the model were measured. Results:XRD analysis showed that the peaks of chitosan/TiO2 (anatase) were consistent with those of crystalline TiO2 and broad phase of chitosan. The FTIR spectrum indicated the relevant functional groups in TiO2. Chitosan-coated TiO2-embedded paclitaxel nanoparticles had good biocompatibility and improve antioxidant and anti-inflammatory properties in the osteosarcoma model. Chitosan-coated TiO2-embedded paclitaxel nanoparticles was less toxic to the cells hFob1.19 and more toxic to the cells 143B than TiO2-embedded paclitaxel nanoparticles. Chitosan-coated TiO2-embedded paclitaxel nanoparticles showed significant antitumor activity and increased the survival rate of the osteosarcoma model (P < 0.05). Conclusions:Chitosan improved anti-tumor potential of TiO2-embedded paclitaxel nanoparticles in the prevention of osteosarcoma.
Project description:Conventional X-ray mammography has low diagnostic sensitivity for women with dense breasts. As a result, alternative contrast-enhanced screening tools such as dual energy mammography (DEM), computed tomography (CT), magnetic resonance imaging (MRI), and near-infrared fluorescence (NIRF) imaging are being used or investigated for these women. However, currently available contrast agents are non-ideal, have safety issues, and each imaging technique requires a different contrast agent. We therefore sought to develop a multimodal contrast agent that is functional for each breast imaging modality to simplify the diagnosis process and address the issues of existing contrast agents. Herein, we present a novel "all-in-one" nanoparticle (AION) multimodal imaging probe that has potent DEM, CT, MRI, and NIRF contrast properties and improved biocompatibility. AION were formed by co-encapsulation of a near-infrared fluorophore (DiR), silver sulfide nanoparticles (Ag2S-NP), and iron oxide nanoparticles (IO-NP) in PEGylated micelles. AION showed negligible cytotoxicity, which was in agreement with its minimal silver ion release profiles. AION generated strong contrast with all imaging modalities as demonstrated in phantom imaging. AION allowed in vivo tumor imaging as evidenced by the increase in contrast after injection. This study indicates the potential of AION as an effective multimodal contrast agent for breast cancer diagnosis with a range of imaging methods.
Project description:Gold nanoparticles (AuNPs) are interesting for the design of new cancer theranostic tools, mainly due to their biocompatibility, easy molecular vectorization, and good biological half-life. Herein, we report a gold nanoparticle platform as a bimodal imaging probe, capable of coordinating Gd3+ for Magnetic Resonance Imaging (MRI) and 67Ga3+ for Single Photon Emission Computed Tomography (SPECT) imaging. Our AuNPs carry a bombesin analogue with affinity towards the gastrin releasing peptide receptor (GRPr), overexpressed in a variety of human cancer cells, namely PC3 prostate cancer cells. The potential of these multimodal imaging nanoconstructs was thoroughly investigated by the assessment of their magnetic properties, in vitro cellular uptake, biodistribution, and radiosensitisation assays. The relaxometric properties predict a potential T1- and T2- MRI application. The promising in vitro cellular uptake of 67Ga/Gd-based bombesin containing particles was confirmed through biodistribution studies in tumor bearing mice, indicating their integrity and ability to target the GRPr. Radiosensitization studies revealed the therapeutic potential of the nanoparticles. Moreover, the DOTA chelating unit moiety versatility gives a high theranostic potential through the coordination of other therapeutically interesting radiometals. Altogether, our nanoparticles are interesting nanomaterial for theranostic application and as bimodal T1- and T2- MRI / SPECT imaging probes.