Lina Song

Controlled Drug Release and Hydrolysis Mechanism of Polymer–Magnetic Nanoparticle Composite

Uniform and multifunctional poly(lactic acid) (PLA)-nanoparticle composite has enormous potential for applications in biomedical and materials science. A detailed understanding of the surface and interface chemistry of these composites is essential to design such materials with optimized function. Herein, we designed and investigated a simple PLA-magnetic nanoparticle composite system to elucidate the impact of nanoparticles on the degradation of polymer-nanoparticle composites. In order to have an in-depth understanding of the mechanisms of hydrolysis in PLA-nanoparticle composites, degradation processes were monitored by several surface sensitive techniques, including scanning electron microscopy, contact angle goniometry, atomic force microscopy, and sum frequency generation spectroscopy. As a second-order nonlinear optical technique, SFG spectroscopy was introduced to directly probe in situ chemical nature at the PLA-magnetic nanoparticle composite/aqueous interface, which allowed for the delineation of molecular mechanisms of various hydrolysis processes for degradation at the molecular level. The best PLA-NP material, with a concentration of 20% MNP in the composite, was found to enhance the drug release rate greater than 200 times while maintaining excellent controlled drug release characteristics. It was also found that during hydrolysis, various crystalline-like PLA domains on the surfaces of PLA-nanoparticle composites influenced various hydrolysis behaviors of PLA. Results from this study provide new insight into the design of nanomaterials with controlled degradation and drug release properties, and the underlined molecular mechanisms. The methodology developed in this study to characterize the polymer-nanoparticle composites is general and widely applicable.

Magnetic assembly-mediated enhancement of differentiation of mouse bone marrow cells cultured on magnetic colloidal assemblies.

Here we reported an interesting phenomenon that the field-induced assemblies of magnetic nanoparticles can promote the differentiation of primary mouse bone marrow cells into osteoblasts. The reason was thought to lie in the remnant magnetic interaction inside the assemblies which resulted from the magnetic field-directed assembly. Influence of the assemblies on the cells was realized by means of interface effect rather than the internalization effect. We fabricated a stripe-like assemblies array on the glass plate and cultured cells on this surface. We characterized the morphology of assemblies and measured the mechanic property as well as the magnetic property. The cellular differentiation was measured by staining and quantitative PCR. Finally, Fe uptake was excluded as the reason to cause the phenomenon.

Cardioprotective activity of iron oxide nanoparticles

Iron oxide nanoparticles (IONPs) are chemically inert materials and have been mainly used for imaging applications and drug deliveries. However, the possibility whether they can be used as therapeutic drugs themselves has not yet been explored. We reported here that Fe2O3 nanoparticles (NPs) can protect hearts from ischemic damage at the animal, tissue and cell level. The cardioprotective activity of Fe2O3 NPs requires the integrity of nanoparticles and is not dependent upon their surface charges and molecules that were integrated into nanoparticles. Also, Fe2O3 NPs showed no significant toxicity towards normal cardiomyocytes, indicative of their potential to treat cardiovascular diseases.

Magnetic field activated drug release system based on magnetic PLGA microspheres for chemo-thermal therapy

Controlled drug delivery systems have been extensively investigated for cancer therapy in order to obtain better specific targeting and therapeutic efficiency. Herein, we developed doxorubicin-loaded magnetic PLGA microspheres (DOX-MMS), in which DOX was encapsulated in the core and high contents (28.3 wt%) of γ-Fe2O3 nanoparticles (IOs) were electrostatically assembled on the surface of microsphere to ensure the high sensitivity to response of an external alternating current magnetic field (ACMF). The IOs in PLGA shell can both induce the heat effect and trigger shell permeability enhancement to release drugs when DOX-MMs was activated by ACMF. Results show that the cumulative drug release from DOX-MMs exposed to ACMF for 30 min (21.6%) was significantly higher (approximately 7 times higher) than that not exposed to ACMF (2.8%). The combination of hyperthermia and enhanced DOX release from DOX-MMS is beneficial for in vitro 4T1 breast cancer cell apoptosis as well as effective inhibition of tumor growth in 4T1 tumor xenografts. Therefore, the DOX-MMS can be optimized as powerful delivery system for efficient magnetic responsive drug release and chemo-thermal therapy.

Fabrication of Hydrogel with Cell Adhesive Micropatterns for Mimicking the Oriented Tumor-Associated Extracellular Matrix

For mimicking the fibrous extracellular matrix (ECM), a facile method for patterning anticell adhesive substrate was novelly applied on agarose hydrogel. Without using masks or templates for etching, we applied the magnetic field-induced colloidal assembly of magnetic nanoparticles on the flat agarose hydrogel to form cell-adhesive micropatterns. Meanwhile, tuning the hydrogel substrates modulus to fit real tissue was experimentally demonstrated. Magnetic nanobeads were also assembled on this hydrogel surface and formed more complete and regular patterns. The patterned hydrogel substrate could actually influence behaviors of different cancer cells, including adhesion, growth, and migration.

Altering the response of intracellular reactive oxygen to magnetic nanoparticles using ultrasound and microbubbles

Engineered iron oxide magnetic nanoparticles (MNPs) are one of the most promising tools in nanomedicine-based diagnostics and therapy. However, increasing evidence suggests that their specific delivery efficiency and potential long-term cytotoxicity remain a great concern. In this study, using 12 nm γ-Fe2O3 MNPs, we investigated three types of uptake pathways for MNPs into HepG2 cells: (1) a conventional incubation endocytic pathway; (2) MNPs co-administrated with microbubbles under ultrasound exposure; and (3) ultrasound delivery of MNPs covalently coated on the surface of microbubbles. The delivery efficiency and intracellular distribution of MNPs were evaluated, and the cytotoxicity induced by reactive oxygen species (ROS) was studied in detail. The results show that MNPs can be delivered into the lysosomes via classical incubation endocytic internalization; however, microbubbles and ultrasound allow the MNPs to pass through the cell membrane and enter the cytosol via a non-internalizing uptake route much more evenly and efficiently. Further, these different delivery routes result in different ROS levels and antioxidant capacities, as well as intracellular glutathione peroxidase activity for HepG2 cells. Our data indicate that the microbubble–ultrasound treatment method can serve as an efficient cytosolic delivery strategy to minimize long-term cytotoxicity of MNPs.中文摘要磁性纳米颗粒在纳米生物医学诊断和治疗研究领域是极具潜力的一种纳米材料. 如何实现纳米颗粒在特定细胞或靶器官的高效率传输以及如何降低细胞毒性是目前纳米材料研究的重点内容. 本文首先研究了12 nm的γ-Fe2O3磁性纳米颗粒进入细胞的三种不同途径: (1) 纳米颗粒与肿瘤细胞共孵育后的内吞途径; (2) 纳米颗粒与微气泡共混合后超声辐照传输途径; (3) 纳米颗粒化学偶联到微气泡膜壳表面后超声辐照传输途径. 其次, 基于上述三种不同的纳米颗粒传输途径, 对纳米颗粒引起的细胞氧化应激毒性进行了深入研究. 结果表明, 纳米颗粒与肿瘤细胞共孵育后的内吞途径使纳米颗粒通过溶酶体包裹进入细胞; 通过超声微气泡辐照, 纳米颗粒能够以更高效率通过非内吞途径直接传输进入细胞质而不被溶酶体包裹. 不同传输途径导致纳米颗粒分别进入溶酶体和细胞质, 造成对细胞内氧化应激水平、总抗氧化能力以及谷胱甘肽过氧化物酶活性的响应不同. 综上研究表明, 超声微气泡介导的磁性纳米颗粒传输能够成为一种高效无损的细胞纳米颗粒输运新方法, 同时通过控制纳米颗粒进入细胞质降低了纳米颗粒的毒性, 从而能够更广泛应用于纳米生物医学的应用研究.

A Functional Iron Oxide Nanoparticles Modified with PLA-PEG-DG as Tumor-Targeted MRI Contrast Agent

PurposeTumor targeting could greatly promote the performance of magnetic nanomaterials as MRI (Magnetic Resonance Imaging) agent for tumor diagnosis. Herein, we reported a novel magnetic nanoparticle modified with PLA (poly lactic acid)-PEG (polyethylene glycol)-DG (D-glucosamine) as Tumor-targeted MRI Contrast Agent.MethodsIn this work, we took use of the D-glucose passive targeting on tumor cells, combining it on PLA-PEG through amide reaction, and then wrapped the PLA-PEG-DG up to the Fe3O4@OA NPs. The stability and anti phagocytosis of Fe3O4@OA@PLA-PEG-DG was tested in vitro; the MRI efficiency and toxicity was also detected in vivo.ResultsThese functional magnetic nanoparticles demonstrated good biocompatibility and stability both in vitro and in vivo. Cell experiments showed that Fe3O4@OA@PLA-PEG-DG nanoparticles exist good anti phagocytosis and high targetability. In vivo MRI images showed that the contrast effect of Fe3O4@OA@PLA-PEG-DG nanoparticles prevailed over the commercial non tumor-targeting magnetic nanomaterials MRI agent at a relatively low dose.ConclusionsThe DG can validly enhance the tumor-targetting effect of Fe3O4@OA@PLA-PEG nanoparticle. Maybe MRI agents with DG can hold promise as tumor-targetting development in the future.

Superparamagnetic anisotropic nano-assemblies with longer blood circulation in vivo: a highly efficient drug delivery carrier for leukemia therapy.

Leukemia, unlike solid tumors, has no definite shape and spreads throughout the whole circulatory system, therefore the therapy of leukemia requires medication to stay longer in the circulatory system. Anisotropic nanoparticles, showing longer blood circulating life than that of isotropic nanoparticles reported in previous research, meet the demands of leukemia therapy. Based on this strategy, superparamagnetic anisotropic nano-assemblies (SANs) were fabricated and loaded with vincristine (VCR) to form VCR-SANs. When compared to the same dose of VCR-loaded isotropic nano-assemblies (SINs), the decrease in the leukocytes count and the positive expression ratio of CD13 in the VCR-SANs group were 19.38% and 16.4%, respectively, which indicated the improved anti-leukemia activity of the VCR-SANs. From the results of the pharmacokinetics study, the VCR-SANs remarkably held the amount of drug removed from the whole body per unit time half of the isotropic group and the concentration of drug in blood plasma against time was 2.1 times the isotropic group, demonstrating the rapid and sustained release behavior and longer blood circulation when combined with the results of in vivo tissue distribution studies. In summary, anisotropic nano-assemblies were found to be more promising than isotropic nano-assemblies via our in vivo and in vitro examinations.

In vitro cytotoxicity evaluation of graphene oxide from the peroxidase-like activity perspective

In this study, PEGylated graphene oxide (PEG-GO)-hemin composite structure was constructed. Hemin in the form of nanoscaled aggregates were immobilized on PEG-GO sheets by the π-π stacking super-molecular interaction. Via catalyzing the oxidation of chromogenic substrates, we elicited the obtained PEG-GO-Hemin composite sheets have much higher peroxidase-like activity compared to hemin or PEG-GO alone, which is due to the introduction of enzyme active center of hemin with high dispersity, the excellent affinity to organic substrate through π-π stacking and/or electrostatic adsorption and the rapid electron transfer capability of PEG-GO. Similarly, PEG-GO-Hemin was found to be able to catalyze the oxidation of low density lipoprotein (LDL) by H2O2, resulting in toxicity to porcine iliac endothelial cells (PIECs) in vitro. Furthermore, we also demonstrated that PEG-GO sheets showed enhanced peroxidase activity when met hemin containing proteins including hemoglobin and cytochrome c. High glucose level (HG) in human umbilical vein endothelial cells (HUVECs) can induce cytochrome c to release from the respiratory chain, thus applying PEG-GO under HG condition could cause a much higher peroxidase-like activity, resulting in the production of hydroxyl radical (OH) and cytochrome c radical (cytochrome c), which eventually enhance the apoptosis. These results suggest GO has potential hazard for biomedical applications in some pathophysiological conditions.

Downregulation of MIM protein inhibits the cellular endocytosis process of magnetic nanoparticles in macrophages

Magnetic nanoparticles (MNPs) are widely used in biomedical applications in vivo. However, the endocytosis of mononuclear phagocyte system (MPS) is still a major challenge for MNPs delivery in vivo. MIM (MTSS1) is a multifunctional scaffold protein to regulate both actin dynamics and membrane dynamics, which may decide the readily particles clear ability of MPS and be implicated in the cellular endocytosis. To find out the exact role of MIM plays in the nanoparticle uptake process of macrophages, we established a MIM knock-down cell line RAW 264.7MIM-. The endocytosis rate and efficiency were detected to find out the differences between the normal RAW 264.7 and RAW 264.7MIM- cell after 24 h of exposure to the Fe2O3@DMSA MNPs (70 nm hydrodynamic size). The results indicated that the clathrin-mediated endocytosis of RAW 264.7MIM- cell involves fewer particles than normal RAW 264.7 cells with significant differences in the concentration ranging from 100 to 200 μg mL−1. Therefore, knock-down the MIM expression in macrophage would affect the endocytosis process to iron oxide nanoparticles mainly in clathrin-mediated pathway. As a whole, our results presented here illustrated that MIM plays a positive role in the cellular endocytosis process of MNPs, which is a meaningful molecular basis for biomedical applications of nanomaterials.