Kexin Qiu

Effect of pH-Responsive Alginate/Chitosan Multilayers Coating on Delivery Efficiency, Cellular Uptake and Biodistribution of Mesoporous Silica Nanoparticles Based Nanocarriers

Surface fuctionalization plays a crucial role in developing efficient nanoparticulate drug-delivery systems by improving their therapeutic efficacy and minimizing adverse effects. Here we propose a simple layer-by-layer self-assembly technique capable of constructing mesoporous silica nanoparticles (MSNs) into a pH-responsive drug delivery system with enhanced efficacy and biocompatibility. In this system, biocompatible polyelectrolyte multilayers of alginate/chitosan were assembled on MSNs surface to achieve pH-responsive nanocarriers. The functionalized MSNs exhibited improved blood compatibility over the bare MSNs in terms of low hemolytic and cytotoxic activity against human red blood cells. As a proof-of-concept, the anticancer drug doxorubicin (DOX) was loaded into nanocarriers to evaluate their use for the pH-responsive drug release both in vitro and in vivo. The DOX release from nanocarriers was pH dependent, and the release rate was much faster at lower pH than that of at higher pH. The in vitro evaluation on HeLa cells showed that the DOX-loaded nanocarriers provided a sustained intracellular DOX release and a prolonged DOX accumulation in the nucleus, thus resulting in a prolonged therapeutic efficacy. In addition, the pharmacokinetic and biodistribution studies in healthy rats showed that DOX-loaded nanocarriers had longer systemic circulation time and slower plasma elimination rate than free DOX. The histological results also revealed that the nanocarriers had good tissue compatibility. Thus, the biocompatible multilayers functionalized MSNs hold the substantial potential to be further developed as effective and safe drug-delivery carriers.

Doxorubicin-loaded electrospun poly(L-lactic acid)/mesoporous silica nanoparticles composite nanofibers for potential postsurgical cancer treatment

A drug-loaded implantable scaffold is a promising alternative for the treatment of a tissue defect after tumor resection. In this study, mesoporous silica nanoparticles (MSNs) were used as carriers to load an anticancer drug - doxorubicin hydrochloride (DOX), and the DOX-loaded MSNs (DOX@MSNs) were subsequently incorporated into poly(l-lactic acid) (PLLA) nanofibers via electrospinning, resulting in a new drug-loaded nanofibrous scaffold (PLLA/DOX@MSNs). The as-prepared composite nanofibrous scaffold was characterized by various techniques. In vitro release profiles of DOX from PLLA/DOX@MSNs composite nanofibers were examined and the in vitro antitumor efficacy against HeLa cells was also evaluated. The results showed that DOX-loaded MSNs were successfully incorporated into composite nanofibers with different MSN (or DOX) contents. Among them, the PLLA/1.0% DOX@10% MSN nanofibers exhibited good particle distribution and improved thermal stability. More importantly, they possessed high DOX-loading capacities due to which the drug can be released in a sustained and prolonged manner, and therefore higher in vitro antitumor efficacy than their MSNs-free counterparts. Thus, the prepared PLLA/MSNs composite nanofibrous mats are highly promising as local implantable scaffolds for potential postsurgical cancer treatment.

Polyelectrolyte multilayer functionalized mesoporous silica nanoparticles for pH-responsive drug delivery: layer thickness-dependent release profiles and biocompatibility

Surface functionalization of mesoporous silica nanoparticles (MSNs) has been proposed as an efficient approach to enhance the biocompatibility and efficiency of MSN-based carrier systems. Herein, polyelectrolyte multilayers (PEMs) composed of poly(allylamine hydrochloride) (PAH) and poly(styrene sulfonate) (PSS) were coated onto the MSN surface via a layer-by-layer (LbL) technique, and doxorubicin hydrochloride (DOX) was loaded into the prepared PEM-MSNs, thus constructing potential pH-responsive carrier systems. Extensive studies were performed to evaluate their biocompatibility and efficiency, emphasizing the influences of the layer numbers on the release profiles, cytotoxicity and hemocompatibility. It is demonstrated that PEM layer thickness has an exponential relationship with the number of coated layers, and release profiles of nanoparticles were both pH- and layer thickness-dependent. PEM-MSNs exhibited a very low and layer thickness-dependent cytotoxicity against macrophage cells. They did not induce obvious hemolysis or cause significant platelet aggregation, but also did not activate any coagulation pathways. The cellular uptake of DOX-loaded PEM-MSNs in HeLa cells was remarkably larger than that in L929 cells, thus resulting in a desirable growth-inhibiting effect on cancer cells. DOX-loaded PEM-MSNs exhibited a slower and prolonged DOX accumulation in the nucleus than free DOX. In vivo biodistribution indicated that they induced a sustained drug concentration in blood plasma but lower drug accumulation in the major organs, especially in the heart, compared to free DOX. The histological results also revealed that DOX-loaded PEM-MSNs had lower systemic toxicity than free DOX. Therefore, LbL functionalization of MSNs provides the practical possibility for creating MSN-based carrier systems with low systemic toxicity and high efficiency.

Au/polypyrrole@Fe3O4 nanocomposites for MR/CT dual-modal imaging guided-photothermal therapy: an in vitro study.

Construction of multifunctional nanocomposites as theranostic platforms has received considerable biomedical attention. In this study, a triple-functional theranostic agent based on the cointegration of gold nanorods (Au NRs) and superparamagnetic iron oxide (Fe3O4) into polypyrrole was developed. Such a theranostic agent (referred to as Au/PPY@Fe3O4) not only exhibits strong magnetic property and high near-infrared (NIR) optical absorbance but also produces high contrast for magnetic resonance (MR) and X-ray computed tomography (CT) imaging. Importantly, under the irradiation of the NIR 808 nm laser at the power density of 2 W/cm(2) for 10 min, the temperature of the solution containing Au/PPY@Fe3O4 (1.4 mg/mL) increased by about 35 °C. Cell viability assay showed that these nanocomposites had low cytotoxicity. Furthermore, an in vitro photothermal treatment test demonstrates that the cancer cells can be efficiently killed by the photothermal effects of the Au/PPY@Fe3O4 nanocomposites. In summary, this study demonstrates that the highly versatile multifunctional Au/PPY@Fe3O4 nanocomposites have great potential in simultaneous multimodal imaging-guided cancer theranostic applications.

Flower-like PEGylated MoS2 nanoflakes for near-infrared photothermal cancer therapy.

Photothermal cancer therapy has attracted considerable interest for cancer treatment in recent years, but the effective photothermal agents remain to be explored before this strategy can be applied clinically. In this study, we therefore develop flower-like molybdenum disulfide (MoS2) nanoflakes and investigate their potential for photothermal ablation of cancer cells. MoS2 nanoflakes are synthesized via a facile hydrothermal method and then modified with lipoic acid-terminated polyethylene glycol (LA-PEG), endowing the obtained nanoflakes with high colloidal stability and very low cytotoxicity. Upon irradiation with near infrared (NIR) laser at 808 nm, the nanoflakes showed powerful ability of inducing higher temperature, good photothermal stability and high photothermal conversion efficiency. The in vitro photothermal effects of MoS2-PEG nanoflakes with different concentrations were also evaluated under various power densities of NIR 808-nm laser irradiation, and the results indicated that an effective photothermal killing of cancer cells could be achieved by a low concentration of nanoflakes under a low power NIR 808-nm laser irradiation. Furthermore, cancer cell in vivo could be efficiently destroyed via the photothermal effect of MoS2-PEG nanoflakes under the irradiation. These results thus suggest that the MoS2-PEG nanoflakes would be as promising photothermal agents for future photothermal cancer therapy.

The aligned core–sheath nanofibers with electrical conductivity for neural tissue engineering

Currently, electroactive biomaterials have often been fabricated as tissue engineering scaffolds to provide electrical stimulation for neural tissue engineering. The goal of this work was to study the synergistic effect of electrical stimulation and nerve growth factor (NGF) on neuron growth. The composite meshes of polyaniline (PANi) and well-blended poly(l-lactic acid-co-ε-caprolactone)/silk fibroin (PS) incorporated with nerve growth factor (NGF) were prepared by coaxial electrospinning. The results showed that the increased concentration of PANi had a large effect on the fiber diameter, which was significantly reduced from 683 ± 138 nm to 411 ± 98 nm and then increased to 498 ± 100 nm. The contact angles and Youngs modulus decreased to 28.3°± 5.4° and 7.2 ± 1.2 MPa, respectively, and the conductance increased to 30.5 ± 3.1 mS cm-1. The results of the viability and morphology of mouse Schwann cells on the nanofibrous meshes showed that PS-PANi-1 loaded with NGF exhibited the highest cell number after 5 days culture and the aligned nanofibers could guide cell orientation. The synergistic effects of electrical stimulation and NGF were also investigated via the growth and differentiation of rat pheochromocytoma 12 (PC12) cells. The scaffolds loaded with NGF under electrical stimulation could effectively support PC12 neurite outgrowth and increase the percentage of neurite-bearing cells as well as the median neurite length. More importantly, the NGF release from the conductive core-shell structure nanofiber could be increased by electrical stimulation. These promising results demonstrated that there was a potential use of this functional scaffold for nerve tissue regeneration.

BMP-2 Derived Peptide and Dexamethasone Incorporated Mesoporous Silica Nanoparticles for Enhanced Osteogenic Differentiation of Bone Mesenchymal Stem Cells

Bone morphogenetic protein-2 (BMP-2), a growth factor that induces osteoblast differentiation and promotes bone regeneration, has been extensively investigated in bone tissue engineering. The peptides of bioactive domains, corresponding to residues 73-92 of BMP-2 become an alternative to reduce adverse side effects caused by the use of high doses of BMP-2 protein. In this study, BMP-2 peptide functionalized mesoporous silica nanoparticles (MSNs-pep) were synthesized by covalently grafting BMP-2 peptide on the surface of nanoparticles via an aminosilane linker, and dexamethasone (DEX) was then loaded into the channel of MSNs to construct nanoparticulate osteogenic delivery systems (DEX@MSNs-pep). The in vitro cell viability of MSNs-pep was tested with bone mesenchymal stem cells (BMSCs) exposure to different particle concentrations, revealing that the functionalized MSNs had better cytocompatibility than their bare counterparts, and the cellular uptake efficiency of MSNs-pep was remarkably larger than that of bare MSNs. The in vitro results also show that the MSNs-pep promoted osteogenic differentiation of BMSCs in terms of the levels of alkaline phosphatase (ALP) activity, calcium deposition, and expression of bone-related protein. Moreover, the osteogenic differentiation of BMSCs can be further enhanced by incorporating of DEX into MSNs-pep. After intramuscular implantation in rats for 3 weeks, the computed tomography (CT) images and histological examination indicate that this nanoparticulate osteogenic delivery system induces effective osteoblast differentiation and bone regeneration in vivo. Collectively, the BMP-2 peptide and DEX incorporated MSNs can act synergistically to enhance osteogenic differentiation of BMSCs, which have potential applications in bone tissue engineering.

In vitro and in vivo toxicity studies of copper sulfide nanoplates for potential photothermal applications

UNLABELLED Copper sulfide (CuS) has emerged as a promising photothermal agent. However, its potential toxic effects still remained poorly understood. Herein, CuS nanoplates were synthesized for toxicity assessment. The in vitro study indicated that the cell viability decreased when CuS nanoplate concentration was higher than 100 μg/mL. CuS nanoplates caused apparent toxicity to HUVEC and RAW 264.7 cells. For acute toxicity, maximum tolerated dose and lethal dose 50 were 8.66 and 54.5 mg/kg, respectively. Furthermore, the sub-chronic toxicity test results indicated that there was no obvious effect at tested doses during the test period. The biodistribution study showed that intravenously administrated CuS nanoplates were mainly present in the spleen, liver and lung. Taken together, our results shed light on the rational design of CuS nanomaterials to minimize toxicity, thus providing a useful guideline in selecting CuS as the photothermal agent for cancer therapy. FROM THE CLINICAL EDITOR Photothermal ablation therapy is a promising new treatment modality for cancer. One of the potential photothermal agents is copper sulfide (CuS). In this article, the potential toxic effects of CuS nanoplates were studied. The authors showed that further modification on the design of CuS nanomaterials was needed to minimize toxicity.

Rapid mineralization of porous gelatin scaffolds by electrodeposition for bone tissue engineering

In bone tissue engineering, rapid mineralization of polymeric scaffolds is of particular importance in protecting the encapsulated therapeutic drugs or growth factors from loss and degradation. Here, we present a simple and rapid approach to the fabrication of mineralized porous scaffolds for bone tissue engineering. In this approach, three-dimensional (3-D) porous gelatin scaffolds were firstly fabricated by freeze-drying followed by an electrodeposition process for mineralization. We show that a high-quality apatite coating on the gelatin scaffold could be achieved within a couple of hours by electrodeposition. Increasing the deposition voltage or electrolyte temperature favored to the formation of large amounts of apatite coatings with compositions dominated by the hydroxyapatite crystals, whereas the presence of ultrasonic field facilitated the production of homogeneous apatite coatings. Moreover, biological assays indicated that the mineralized scaffolds exhibited better support for the proliferation and osteoblastic differentiation of MC3T3-E1 cells over a neat gelatin scaffold, especially for the case of mineralized scaffolds by electrodeposition at 60 °C. Therefore, the method developed would be highly desired for the rapid mineralization of polymer scaffolds in which biological molecules were loaded for functional bone tissue engineering applications.

Electrophoretic Deposition of Dexamethasone-Loaded Mesoporous Silica Nanoparticles onto Poly(l-Lactic Acid)/Poly(ε-Caprolactone) Composite Scaffold for Bone Tissue Engineering

The incorporation of microcarriers as drug delivery vehicles into polymeric scaffold for bone regeneration has aroused increasing interest. In this study, the aminated mesoporous silica nanoparticles (MSNs-NH2) were prepared and used as microcarriers for dexamethasone (DEX) loading. Poly(l-lactic acid)/poly(ε-caprolactone) (PLLA/PCL) nanofibrous scaffold was fabricated via thermally induced phase separation (TIPS) and served as template, onto which the drug-loaded MSNs-NH2 nanoparticles were deposited by electrophoretic deposition (EPD). The physicochemical and release properties of the prepared scaffolds (DEX@MSNs-NH2/PLLA/PCL) were examined, and their osteogenic activities were also evaluated through in vitro and in vivo studies. The release of DEX from the scaffolds revealed an initial rapid release followed by a slower and sustained one. The in vitro results indicated that the DEX@MSNs-NH2/PLLA/PCL scaffold exhibited good biocompatibility to rat bone marrow-derived mesenchymal stem cells (BMSCs). Also, BMSCs cultured on the DEX@MSNs-NH2/PLLA/PCL scaffold exhibited a higher degree of osteogenic differentiation than those cultured on PLLA/PCL and MSNs-NH2/PLLA/PCL scaffolds, in terms of alkaline phosphatase (ALP) activity, mineralized matrix formation, and osteocalcin (OCN) expression. Furthermore, the in vivo results in a calvarial defect model of Sprague-Dawley (SD) rats demonstrated that the DEX@MSNs-NH2/PLLA/PCL scaffold could significantly promote calvarial defect healing compared with the PLLA/PCL scaffold. Thus, the EPD technique provides a convenient way to incorporate osteogenic agents-containing microcarriers to polymer scaffold, and thus, prepared composite scaffold could be a potential candidate for bone tissue engineering application due to its capacity for delivery of osteogenic agents.