Cuimiao Zhang

Hybrid Mesoporous Silica-Based Drug Carrier Nanostructures with Improved Degradability by Hydroxyapatite

Potential bioaccumulation is one of the biggest limitations for silica nanodrug delivery systems in cancer therapy. In this study, a mesoporous silica nanoparticles/hydroxyapatite (MSNs/HAP) hybrid drug carrier, which enhanced the biodegradability of silica, was developed by a one-step method. The morphology and structure of the nanoparticles were characterized by TEM, DLS, FT-IR, XRD, N2 adsorption-desorption isotherms, and XPS, and the drug loading and release behaviors were tested. TEM and ICP-OES results indicate that the degradability of the nanoparticles has been significantly improved by Ca(2+) escape from the skeleton in an acid environment. The MSNs/HAP sample exhibits a higher drug loading content of about 5 times that of MSNs. The biological experiment results show that the MSNs/HAP not only exhibits good biocompatibility and antitumor effect but also greatly reduces the side effects of free DOX. The as-synthesized hybrid nanoparticles may act as a promising drug delivery system due to their good biocompatibility, high drug loading efficiency, pH sensitivity, and excellent biodegradability.

Size-dependent cytotoxicity of europium doped NaYF4 nanoparticles in endothelial cells

Lanthanide-doped sodium yttrium fluoride (NaYF4) nanoparticles exhibit novel optical properties which make them be widely used in various fields. The extensive applications increase the chance of human exposure to these nanoparticles and thus raise deep concerns regarding their riskiness. In the present study, we have synthesized europium doped NaYF4 (NaYF4:Eu(3+)) nanoparticles with three diameters and used endothelial cells (ECs) as a cell model to explore the potential toxic effect. The cell viability, cytomembrane integrity, cellular uptake, intracellular localization, intracellular reactive oxygen species (ROS), mitochondrial membrane potential (MMP), apoptosis detection, caspase-3 activity and expression of inflammatory gene were studied. The results indicated that these nanoparticles could be uptaken into ECs and decrease the cell viability, induce the intracellular lactate dehydrogenase (LDH) release, increase the ROS level, and decrease the cell MMP in a size-dependent manner. Besides that, the cells were suffered to apoptosis with the caspase-3 activation, and the inflammation specific gene expressions (ICAM1 and VCAM1) were also increased. Our results suggest that the damage pathway may be related to the ROS generation and mitochondrial damage. The results provide novel evidence to elucidate their toxicity mechanisms and may be helpful for more rational applications of these compounds in the future.

Defect-Related Luminescent Mesoporous Silica Nanoparticles Employed for Novel Detectable Nanocarrier

Uniform and well-dispersed walnut kernel-like mesoporous silica nanoparticles (MSNs) with diameters about 100 nm have been synthesized by a templating sol-gel route. After an annealing process, the as-obtained sample (DLMSNs) inherits the well-defined morphology and good dispersion of MSNs, and exhibits bright white-blue luminescence, higher specific surface area and pore volume, and better biocompatibility. The drug loading and release profiles show that DLMSNs have high drug loading capacity, and exhibit an initial burst release followed by a slow sustained release process. Interestingly, the luminescence intensity of the DLMSNs-DOX system increases gradually with the increase of cumulative released DOX, which can be verified by the confocal laser scanning images. The drug carrier DLMSNs can potentially be applied as a luminescent probe for monitoring the drug release process. Moreover, the DLMSNs-DOX system exhibits potent anticancer effect against three kinds of cancer cells (HeLa, MCF-7, and A549 cells).

Up-Conversion Y2O3:Yb3+,Er3+ Hollow Spherical Drug Carrier with Improved Degradability for Cancer Treatment

The rare earth hollow spheres with up-conversion luminescence properties have shown potential applications in drug delivery and bioimaging fields. However, there have been few reports for the degradation properties of rare earth oxide drug carriers. Herein, uniform and well-dispersed Y2O3:Yb(3+),Er(3+) hollow spheres (YOHSs) have been fabricated by a general Pechini sol-gel process with melamine formaldehyde colloidal spheres as template. The novel YOHSs with up-conversion luminescence has good drug loading amount and drug-release efficiency; moreover, it exhibits pH-responsive release patterns. In particular, the YOHSs sample exhibits low cytotoxicity and excellent degradable properties in acid buffer. After the sample was loaded with anticancer drug doxorubicin (DOX), the antitumor result in vitro indicates that YOHS-DOX might be effective in cancer treatment. The animal imaging test also reveals that the YOHSs drug carrier can be used as an outstanding luminescent probe for bioimaging in vivo application prospects. The results suggest that the degradable drug carrier with up-conversion luminescence may enhance the delivery efficiency of drugs and improve the cancer therapy in clinical applications.

Defect-Related Luminescent Hydroxyapatite-Enhanced Osteogenic Differentiation of Bone Mesenchymal Stem Cells Via an ATP-Induced cAMP/PKA Pathway

Novel defect-related hydroxyapatite (DHAP), which combines the advantages of HAP and defect-related luminescence, has the potential application in tissue engineering and biomedical area, because of its excellent capability of monitoring the osteogenic differentiation and material biodegradation. Although the extracellular mechanism of DHAP minerals and PO4(3-) functioning in osteogenic differentiation has been widely studied, the intracellular molecular mechanism through which PO4(3-) mediates osteogenesis of bone mesenchymal stem cells (BMSCs) is not clear. We examined a previously unknown molecular mechanism through which PO4(3-) promoted osteogenesis of BMSCs with an emphasis on adenosine-triphosphate (ATP)-induced cAMP/PKA pathway. Our studies showed that DHAP could be uptaken into lysosome, in which PO4(3-) was released from DHAP, because of the acid environment of lysosome. The released PO4(3-) interacted with ADP to form ATP, and then degraded into adenosine, an ATP metabolite, which interacted with A2b adenosine receptor to activate the cAMP/PKA pathway, resulting in the high expression of osteogenesis-related genes, such as Runx2, BMP-2, and OCN. These findings first revealed the function of ATP-metabolism in bone physiological homeostasis, which may be developed to cure bone metabolic diseases.

Oxidative stress-induced apoptosis of osteoblastic MC3T3-E1 cells by hydroxyapatite nanoparticles through lysosomal and mitochondrial pathways

Hydroxyapatite nanoparticles (HAPs) are increasingly utilized in biomedical fields including dental composites, bone tissue engineering and orthopedic implants due to its similar properties to bone minerals. With their widespread use, toxicological effects of HAPs have aroused peoples close attention. However, the potential toxic effects of HAPs on bone cells are poorly understood. In our present work, the HAPs with aspect ratios of 4 were synthesized by a hydrothermal method and characterized by transmission electron microscopy (TEM), X-ray diffractometry (XRD), dynamic light scattering (DLS) and photoluminescence (PL). The cytotoxicity of HAPs on MC3T3-E1 cells and the relevant mechanisms were further studied. The results proved that HAPs could be uptaken into MC3T3-E1 cells via macropinocytosis-mediated endocytosis pathway, and mainly localized in lysosome. HAPs inhibited the cells proliferation in dose- and time-dependent manners. Results from annexin V-FITC/PI apoptosis assay showed that HAPs induced cell apoptosis significantly, and the mechanism of apoptosis was related to oxidative stress. HAPs induced ROS generation and antioxidant enzymes superoxide dismutase (SOD) and glutathion peroxidase (GSH-Px) decrease, which not only induced a lysosome-dependent damage pathway via lysosomal membrane permeabilization (LMP) and increased the release of cathepsins B, but also a mitochondria-dependent damage pathway via counter regulating expressions of bax and bcl-2, decrease of mitochondrial membrane potential (MMP), activation of caspase3. In addition, the ROS also caused DNA damage. In summary, HAPs induces apoptosis through oxidative stress-induced lysosomal and mitochondrial pathways. Our study will provide some valuable data for biomedical applications of HAPs in the future.

Europium-doped NaYF4 nanoparticles cause the necrosis of primary mouse bone marrow stromal cells through lysosome damage

Applications of europium-doped NaYF4 (NaYF4:Eu3+) nanoparticles in biomedical fields will inevitably increase their exposure to humans, therefore, the assessment of toxicities must be taken into consideration. It was reported that NaYF4:Eu3+ nanoparticles could accumulate in the bone. However, the potential effect of NaYF4:Eu3+ nanoparticles on bone marrow stromal cells (BMSCs) has not been reported. In this study, NaYF4:Eu3+ particles with diameters of 50 and 200 nm (NY50 and NY200) were prepared and characterized by scanning electron microscopy, transmission electron microscopy, powder X-ray diffraction, photoluminescence excitation and emission spectra, and dynamic light scattering. The cytotoxicity of NaYF4:Eu3+ particles on BMSCs and the associated mechanisms were further studied. The results indicated that NaYF4:Eu3+ particles could be uptaken into BMSCs and primarily localized in the lysosome. NaYF4:Eu3+ particles effectively inhibited the viability of BMSCs in a size-dependent manner at 24 and 48 h. After cells were treated with 20 μg mL−1 of NY50 and NY200 for 24 h, NaYF4:Eu3+ particles could trigger cell necrosis in a size-dependent manner. The percentage of necrotic BMSCs (PI+/Annexin V−) increased to 15.93 and 14.73%. Necrosis was further verified by increased lactate dehydrogenase leakage. Meanwhile, both NY50 and NY200 induced an increased cell population in the S and G2/M phases. The following mechanism is involved in NaYF4:Eu3+ particle-induced BMSCs necrosis: the NaYF4:Eu3+ particles lead to lysosomal rupture by lysosomal swelling, permeabilization of lysosomal membranes, and increased cathepsins B and D. In addition, NaYF4:Eu3+ particle-induced BMSCs necrosis is also directly caused by the overproduction of ROS through injury to the mitochondria. This study provides novel evidence to elucidate the toxicity mechanisms for bone metabolism and may be beneficial to more rational applications of these nanomaterials in the future.

A traceable and bone-targeted nanoassembly based on defect-related luminescent mesoporous silica for enhanced osteogenic differentiation

Osteoporosis is a degenerative bone disorder that affects millions of people worldwide. Despite many novel drugs or therapy strategies that have been developed, the curative effect of current treatments is far from satisfying. Development of effective treatments toward osteoporosis is imminent. Bone mesenchymal stem cells (BMSCs) are one kind of pluripotent stem cells, which are not only easy to separate and purify but also can self-renew and differentiate into osteogenic cells. In this work, a traceable drug delivery system based on gadolinium-labeled defect-related luminescent mesoporous silica nanoparticles (MSNs) was developed for bone marrow homing and enhanced osteogenic differentiation. The results showed that dexamethasone (DEX) could be loaded into nanocarriers and gave a sustained release behaviour. A unique defect-related luminescent property could be utilized to monitor the drug release effectively. In addition, the nanocarriers showed good biocompatibility and were uptaken mainly via an energy-dependent endocytosis process which was mediated by the macropinocytosis pathway. Furthermore, the nanocarriers can be simultaneously used as predominant contrast agents for magnetic resonance imaging. More importantly, DEX-loaded nanocarriers can significantly enhance the alkaline phosphatase activity and promote formation of matrix nodules of the BMSCs.

Recent Advances of Mesoporous Silica Based Multifunctional Nano Drug Delivery Systems

Mesoporous silica materials have attracted much attention for their potential biomedical applications due to their tailored mesoporous structure, large surface area, good biocompatibility, and the ease of surface functionalization. In the past few years, the mesoporous silica based drug nanocarriers have become the research focus of many researchers. This article reviews the recent research advances of mesoporous silica based multifunctional drug delivery systems with targeting modification and bioimaging, and details the design, surface modification, and applications in drug delivery field of mesoporous silica based drug delivery systems with diverse morphologies(such as hollow/rattle-type, nanotubes, etc.). Finally, we analyze the existing problems in practical applications and outlook the future development trends of mesoporous silica based drug delivery systems(including the specific morphological, multifunctional hybrid, and biodegradable mesoporous silica drug delivery systems).