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LDH-stabilized ultrasmall iron oxide nanoparticles as a platform for hyaluronidase-promoted MR imaging and chemotherapy of tumors.

ABSTRACT: Development of unique theranostic nanoplatforms for tumor imaging and therapy remains an active topic in current nanomedicine. Here, we designed a novel targeted theranostic nanoplatform for enhanced T₁ -weighted magnetic resonance (MR) imaging-guided chemotherapy by constructing layered double hydroxide (LDH)-stabilized ultrasmall iron oxide (Fe₃O₄) nanoparticles with hyaluronic acid (HA) modified as targeting agents, and anticancer drug doxorubicin (DOX) loaded with a high loading efficiency. Methods: The structure and release property of LDH-Fe₃O₄-HA/DOX nanoplatforms were characterized systematically. B16 melanoma cells with CD44 receptors overexpressed were used as model cells to determine the biocompatibility, targeting capability, and therapeutic efficiency of nanoplatforms. For in vivo experiment, hyaluronidase (HAase) pretreatment was combined with nanoplatform administration to investigate the MR imaging and chemotherapeutic effect. Results: The LDH-Fe₃O₄-HA nanohybrids possess good colloidal stability and cytocompatibility, display an r₁ relaxivity 10-fold higher than the pristine ultrasmall Fe₃O₄ (4.38 mM^-1 s^-1 vs 0.42 mM^-1 s^-1), and could release drug in a pH-responsive manner. In vitro experiments demonstrate that LDH-Fe₃O₄-HA/DOX nanohybrids are able to specifically target B16 cells overexpressing CD44 receptors and effectively release DOX to nucleus. In vivo results show that with the pretreatment of tumor tissue by HAase to degrade the overexpressed HA in extra-cellular matrix, the designed nanoplatforms have a better tumor penetration for significantly enhanced MR imaging of tumors and tumor chemotherapy with low side effects. Conclusion: The designed LDH-Fe₃O₄-HA/DOX nanohybrids may be developed as a novel targeted theranostic nanoplatform for enhanced T₁ -weighted MR imaging-guided chemotherapy of CD44 receptor-overexpressing tumors.

SUBMITTER: Zhang N

PROVIDER: S-EPMC7052882 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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LDH-stabilized ultrasmall iron oxide nanoparticles as a platform for hyaluronidase-promoted MR imaging and chemotherapy of tumors.

Zhang Ni N Wang Yue Y Zhang Changchang C Fan Yu Y Li Du D Cao Xueyan X Xia Jindong J Shi Xiangyang X Guo Rui R

Theranostics 20200203 6

Development of unique theranostic nanoplatforms for tumor imaging and therapy remains an active topic in current nanomedicine. Here, we designed a novel targeted theranostic nanoplatform for enhanced T1 -weighted magnetic resonance (MR) imaging-guided chemotherapy by constructing layered double hydroxide (LDH)-stabilized ultrasmall iron oxide (Fe3O4) nanoparticles with hyaluronic acid (HA) modified as targeting agents, and anticancer drug doxorubicin (DOX) ...[more]

PMID: 32194835

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Project description:PURPOSE: This study was performed to compare the cytotoxicity and magnetic resonance (MR) contrast in diverse cultured cells and xenograft tumors models of two ultra-small superparamagnetic iron oxides (USPIOs), thermally cross-linked superparamagnetic iron oxide nanoparticles (TCL-SPION) and monocrystalline iron oxide nanoparticles (MION-47). MATERIALS AND METHODS: Transmission electron microscopy (TEM) images and R(2) relaxivity values of the TCL-SPION and MION-47 were obtained and the cell viability and cell growth velocity of treated and untreated human fibroblasts and human umbilical vein endothelial cells (HUVEC) were evaluated. The effect of TCL-SPION and MION-47 on the secretion of interlukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-?), the production of nitric oxides and the mitochondrial membrane potentials in murine macrophage cells (RAW264.7) was compared. Human hepatocellular carcinoma cells (HepG2, 5x10(5)) were subcutaneously injected into nude mice (BALB/c) and in vivo MR imaging of tumors before and after injection with TCL-SPION or MION-47 (12.5 mg Fe/kg) was performed on a 1.5 Tesla MRI scanner. RESULTS: On TEM images, the average core diameter of TCL-SPION was 9 nm whereas that of MION-47 was 5 nm. TCL- SPION (345.0 ± 6.2 mM(-1)sec(-1)) had higher relaxivity (R(2)) than MION-47 (130.7 ± 1.1 mM(-1)sec(-1)). Significant changes in cell viability and growth were not found in human fibroblasts and HUVEC exposed to TCL-SPION and MION-47. However, IL-6 and TNF-? secretions increased dose-dependently and significantly in the macrophages treated with MION-47 or TCL-SPION. TCL-SPION had a lower stimulatory effect on IL-6 secretions than did MION-47 (P <0.05) and nitric oxides were produced in the macrophages by MION-47 but not TCL-SPION. A change in the mitochondrial membrane potential of the macrophages was observed 24 hours after the exposure, and MION-47 induced more collapses of the mitochondrial membrane potential than did TCL-SPION. In the in vivo MR imaging, 33.0 ± 1.3% and 7.5 ± 0.4% signal intensity decrease on T(2)*-weighted images was observed in the tumors injected with TCL-SPION and MION-47, respectively. CONCLUSION: Due to the modified surface properties and larger core size of its iron oxide nanoparticles, TCL-SPION achieves lower cytotoxicity and better tumor MR contrast than MION-47. Our study suggests that TCL-SPION may be used as a new platform for tumor imaging and therapy monitoring.

Project description:BackgroundIron oxide nanoparticles have been approved by food and drug administration for clinical application as magnetic resonance imaging (MRI) and are considered to be a biocompatible material. Large iron oxide nanoparticles are usually used as transversal (T2) contrast agents to exhibit dark contrast in MRI. In contrast, ultrasmall iron oxide nanoparticles (USPIONs) (several nanometers) showed remarkable advantage in longitudinal (T1)-weighted MRI due to the brighten effect. The study of the toxicity mainly focuses on particles with size of tens to hundreds of nanometers, while little is known about the toxicity of USPIONs.ResultsWe fabricated Fe3O4 nanoparticles with diameters of 2.3, 4.2, and 9.3 nm and evaluated their toxicity in mice by intravenous injection. The results indicate that ultrasmall iron oxide nanoparticles with small size (2.3 and 4.2 nm) were highly toxic and were lethal at a dosage of 100 mg/kg. In contrast, no obvious toxicity was observed for iron oxide nanoparticles with size of 9.3 nm. The toxicity of small nanoparticles (2.3 and 4.2 nm) could be reduced when the total dose was split into 4 doses with each interval for 5 min. To study the toxicology, we synthesized different-sized SiO2 and gold nanoparticles. No significant toxicity was observed for ultrasmall SiO2 and gold nanoparticles in the mice. Hence, the toxicity of the ultrasmall Fe3O4 nanoparticles should be attributed to both the iron element and size. In the in vitro experiments, all the ultrasmall nanoparticles (< 5 nm) of Fe3O4, SiO2, and gold induced the generation of the reactive oxygen species (ROS) efficiently, while no obvious ROS was observed in larger nanoparticles groups. However, the ·OH was only detected in Fe3O4 group instead of SiO2 and gold groups. After intravenous injection, significantly elevated ·OH level was observed in heart, serum, and multiple organs. Among these organs, heart showed highest ·OH level due to the high distribution of ultrasmall Fe3O4 nanoparticles, leading to the acute cardiac failure and death.ConclusionUltrasmall Fe3O4 nanoparticles (2.3 and 4.2 nm) showed high toxicity in vivo due to the distinctive capability in inducing the generation of ·OH in multiple organs, especially in heart. The toxicity was related to both the iron element and size. These findings provide novel insight into the toxicology of ultrasmall Fe3O4 nanoparticles, and also highlight the need of comprehensive evaluation for their clinic application.

Project description:PurposeTo determine the feasibility of T2-weighted magnetic resonance (MR) imaging in the noninvasive quantification of renal inflammation by using superparamagnetic iron oxide (SPIO) nanoparticles targeted to tissue-bound C3 activation fragments in a mouse model of lupus nephritis.Materials and methodsAll animal procedures were approved by the University of Colorado-Denver animal care and use committee. SPIO nanoparticles were encapsulated by using amine-functionalized phospholipids. A recombinant protein containing the C3d-binding region of complement receptor type 2 (CR2) was then conjugated to the surface of the SPIO nanoparticle. Five MRL/lpr mice (a model of lupus nephritis) and six C57BL/6 wild-type mice were assessed with T2-weighted MR imaging at baseline and after SPIO injection. The same five MRL/lpr mice and three C57BL/6 mice also underwent MR imaging after injection of CR2-targeted SPIO. A series of T2-weighted pulses with 16 echo times was used to enable precise T2 mapping and calculation of T2 relaxation times in the cortex and outer and inner medulla of the kidneys, as well as in the spleen, muscle, and fat. The effects of treatment and animal genotype on T2 relaxation times were analyzed with repeated-measures analysis of variance.ResultsAt baseline, the T2-weighted signal intensity in the kidneys of MRL/lpr mice was higher than that in the kidneys of wild-type mice. Injection of untargeted SPIO did not alter the T2-weighted signal in the kidneys in either strain of mice. Injection of CR2-targeted SPIO in MRL/lpr mice, however, caused a significant accumulation of targeted iron oxide with a subsequent decrease in T2 relaxation times in the cortex and outer and inner medulla of the kidneys. No changes in T2 relaxation time were observed in the wild-type mice after injection of targeted SPIO.ConclusionInjection of CR2-conjugated SPIO caused a significant reduction in T2-weighted MR imaging signal and T2 relaxation time in nephritic kidneys.

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LDH-stabilized ultrasmall iron oxide nanoparticles as a platform for hyaluronidase-promoted MR imaging and chemotherapy of tumors.

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LDH-stabilized ultrasmall iron oxide nanoparticles as a platform for hyaluronidase-promoted MR imaging and chemotherapy of tumors.

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