Biodegradable double-network GelMA-ACNM hydrogel microneedles for transdermal drug delivery.

As a minimally invasive drug delivery platform, microneedles (MNs) overcome many drawbacks of the conventional transdermal drug delivery systems, therefore are favorable in biomedical applications. Microneedles with a combined burst and sustained release profile and maintained therapeutic molecular bioactivity could further broaden its applications as therapeutics. Here, we developed a double-network microneedles (DN MNs) based on gelatin methacrylate and acellular neural matrix (GelMA-ACNM). ACNM could function as an early drug release matrix, whereas the addition of GelMA facilitates sustained drug release. In particular, the double-network microneedles comprising GelMA-ACNM hydrogel has distinctive biological features in maintaining drug activity to meet the needs of application in treating different diseases. In this study, we prepared the double-network microneedles and evaluated its morphology, mechanical properties, drug release properties and biocompatibility, which shows great potential for delivery of therapeutic molecules that needs different release profiles in transdermal treatment.

Enzyme-Responsive Materials as Carriers for Improving Photodynamic Therapy.

Photodynamic therapy (PDT) is a mini-invasive therapy on malignancies via reactive oxygen species (ROS) induced by photosenitizer (PS) upon light irradiation. However, poor target of PS to tumor limits the clinical application of PDT. Compared with normal tissues, tumor tissues have a unique enzymatic environment. The unique enzymatic environment in tumor tissues has been widely used as a target for developing smart materials to improve the targetability of drugs to tumor. Enzyme-responsive materials (ERM) as a smart material can respond to the enzymes in tumor tissues to specifically deliver drugs. In PDT, ERM was designed to react with the enzymes highly expressed in tumor tissues to deliver PS in the target site to prevent therapeutic effects and avoid its side-effects. In the present paper, we will review the application of ERM in PDT and discuss the challenges of ERM as carriers to deliver PS for further boosting the development of PDT in the management of malignancies.

Carbon Quantum Dots: In vitro and in vivo Studies on Biocompatibility and Biointeractions for Optical Imaging.

BACKGROUND: Understanding the biocompatibility and biointeractions of nano-carbon quantum dots (nano-CQDs) in vitro and in vivo is important for assessing their potential risk to human health. In the previous research, the physical properties of CQDs synthesized by the laser ablation in liquid (LAL) method were analyzed in detail; however, possible bioapplications were not considered. MATERIALS AND METHODS: CQDs were prepared by LAL and characterized by atomic force microscopy, fluorescence lifetime, absorption spectrum, Fourier-transform infrared spectroscopy, and dynamic light scattering. Their biocompatibility was evaluated in vitro using assays for cytotoxicity, apoptosis, and biodistribution and in vivo using immunotoxicity and the relative expression of genes. Cells were measured in vitro using fluorescence-lifetime imaging microscopy to analyze the biointeractions between CQDs and intracellular proteins. RESULTS: There were no significant differences in biocompatibility between the CQDs and the negative control. The intracellular interactions had no impact on the optical imaging of CQDs upon intake by cells. Optical imaging of zebrafish showed the green fluorescence was well dispersed. CONCLUSION: We have demonstrated that the CQDs have an excellent biocompatibility and can be used as efficient optical nanoprobes for cell tracking and biomedical labeling except for L929 and PC-3M cells.

In vivo immunotoxicity of Gd2 O3 :Eu3+ nanoparticles and the associated molecular mechanism.

The in vivo toxicity of Gd2 O3 :Eu3+ nanoparticles (NPs) used as dual-modal nanoprobes for molecular imaging has not been studied, and the corresponding molecular mechanism of immunotoxicity remains unknown. In this study, we investigated the cytotoxicity, in vitro apoptosis, and in vivo immunotoxicity of Gd2 O3 :Eu3+ NPs. The NPs showed little immunotoxicity to BALB/c mice. We explored the possible role of the phosphoinositide 3-kinase (PI3K) signaling pathway and found that reactive oxygen species could act as secondary messengers in cellular signaling, inhibiting PI3K expression in the liver. The immune suppression caused by PI3K inhibition helped the mice adapt to stress. The immunotoxicities caused by Gd2 O3 :Eu3+ and gadodiamide, a commonly used contrast agent, were not significantly different, and the mice were able to tolerate the immunotoxicity caused Gd2 O3 :Eu3+ NPs in vitro and in vivo experiments. The results suggest that Gd2 O3 :Eu3+ NPs are sufficiently biocompatible to be used safely in preclinical applications and show promise as bio-imaging agents. Moreover, the in vivo molecular mechanism of immunotoxicity caused by the Gd2 O3 :Eu3+ NPs provides a platform for further research on the immunotoxicity of nano-sized biomaterials.

Role of Exosomes in Photodynamic Anticancer Therapy.

Photodynamic Therapy (PDT) is a promising alternative treatment for malignancies based on photochemical reaction induced by Photosensitizers (PS) under light irradiation. Recent studies show that PDT caused the abundant release of exosomes from tumor tissues. It is well-known that exosomes as carriers play an important role in cell-cell communication through transporting many kinds of bioactive molecules (e.g. lipids, proteins, mRNA, miRNA and lncRNA). Therefore, to explore the role of exosomes in photodynamic anticancer therapy has been attracting significant attention. In the present paper, we will briefly introduce the basic principle of PDT and exosomes, and focus on discussing the role of exosomes in photodynamic anticancer therapy, to further enrich and boost the development of PDT.

Ultrasound-Responsive Materials for Drug/Gene Delivery.

Ultrasound is one of the most commonly used methods in the diagnosis and therapy of diseases due to its safety, deep penetration into tissue, and non-invasive nature. In the drug/gene delivery systems, ultrasound shows many advantages in terms of site-specific delivery and spatial release control of drugs/genes and attracts increasing attention. Microbubbles are the most well-known ultrasound-responsive delivery materials. Recently, nanobubbles, droplets, micelles, and nanoliposomes have been developed as novel carriers in this field. Herein, we review advances of novel ultrasound-responsive materials (nanobubbles, droplets, micelles and nanoliposomes) and discuss the challenges of ultrasound-responsive materials in delivery systems to boost the development of ultrasound-responsive materials as delivery carriers.

A tubular gelatin scaffold capable of the time-dependent controlled release of epidermal growth factor and mitomycin C.

A tubular gelatin scaffold for the time-dependent controlled release of epidermal growth factor (EGF) and mitomycin C (MMC) was fabricated. EGF was incorporated using silk fibroin carriers, and MMC was planted using polylactide (PLA) microspheres. The relationship between scaffold properties and crosslinking degrees was evaluated. As the crosslinking degree was increased from 23.7% to 65.3%, the mechanical properties of the scaffold obviously improved, and the compressive modulus increased to approximately 65kPa. The mass degradation of the scaffold was also controlled from 9 days to approximately 1 month. In vitro release tests indicated that the scaffold mainly released EGF in the early period and MMC in the later period. Urethral epithelial cells (UECs) and urethral scar derived fibroblast cells (UFCs) were coseeded in the scaffold at a ratio of 1:1. After 9 days of coculture, immunostaining results displayed that the proportion of UECs continuously increased to approximately 71%. These changes in cell proportion were confirmed by the results of Western blot analysis. Therefore, the scaffold promoted the growth but inhibited the regeneration of UFCs. This scaffold for time-dependent controlled release of multiple biofactors may be potentially useful in urethral reconstruction and other tissue engineering studies.

In vitro degradation and cell response of calcium carbonate composite ceramic in comparison with other synthetic bone substitute materials.

The robust calcium carbonate composite ceramics (CC/PG) can be acquired by fast sintering calcium carbonate at a low temperature (650 °C) using a biocompatible, degradable phosphate-based glass (PG) as sintering agent. In the present study, the in vitro degradation and cell response of CC/PG were assessed and compared with 4 synthetic bone substitute materials, calcium carbonate ceramic (CC), PG, hydroxyapatite (HA) and ß-tricalcium phosphate (ß-TCP) ceramics. The degradation rates in decreasing order were as follows: PG, CC, CC/PG, ß-TCP, and HA. The proliferation of rat bone mesenchymal stem cells (rMSCs) cultured on the CC/PG was comparable with that on CC and PG, but inferior to HA and ß-TCP. The alkaline phosphatase (ALP) activity of rMSCs on CC/PG was lower than PG, comparable with ß-TCP, but higher than HA. The rMSCs on CC/PG and PG had enhanced gene expression in specific osteogenic markers, respectively. Compared to HA and ß-TCP, the rMSCs on the CC/PG expressed relatively lower level of collagen I and runt-related transcription factor 2, but showed more considerable expression of osteopontin. Although CC, PG, HA, and ß-TCP possessed impressive performances in some specific aspects, they faced extant intrinsic drawbacks in either degradation rate or mechanical strength. Based on considerable compressive strength, moderate degradation rate, good cell response, and being free of obvious shortcoming, the CC/PG is promising as another choice for bone substitute materials.

Toxicity evaluation of Gd2O3@SiO2 nanoparticles prepared by laser ablation in liquid as MRI contrast agents in vivo.

Poor toxicity characterization is one obstacle to the clinical deployment of Gd2O3@ SiO2 core-shell nanoparticles (Gd-NPs) for use as magnetic resonance (MR) imaging contrast agents. To date, there is no systematic toxicity data available for Gd-NPs prepared by laser ablation in liquid. In this article, we systematically studied the Gd-NPs' cytotoxicity, apoptosis in vitro, immunotoxicity, blood circulation half-life, biodistribution and excretion in vivo, as well as pharmacodynamics. The results show the toxicity, and in vivo MR data show that these NPs are a good contrast agent for preclinical applications. No significant differences were found in cell viability, apoptosis, and immunotoxicity between our Gd-NPs and Gd in a DTPA (diethylenetriaminepentaacetic acid) chelator. Biodistribution data reveal a greater accumulation of the Gd-NPs in the liver, spleen, lung, and tumor than in the kidney, heart, and brain. Approximately 50% of the Gd is excreted via the hepatobiliary system within 4 weeks. Furthermore, dynamic contrast-enhanced T1-weighted MR images of xenografted murine tumors were obtained after intravenous administration of the Gd-NPs. Collectively, the single step preparation of Gd-NPs by laser ablation in liquid produces particles with satisfactory cytotoxicity, minimal immunotoxicity, and efficient MR contrast. This may lead to their utility as molecular imaging contrast agents in MR imaging for cancer diagnosis.

In vivo immunotoxicity of SiO2@(Y0.5Gd0.45Eu0.05)2O3 as dual-modality nanoprobes.

We have successfully synthesized SiO2@(Y0.5Gd0.45Eu0.05)2O3 nanocomposites as a potential dual-modality nanoprobe for molecular imaging in vitro. However, their immunotoxicity assessment in vivo remains unknown. In this article, the in vitro biocompatibility of our dual-modality nanoprobes was assayed in terms of cell viability and apoptosis. In vivo immunotoxicity was investigated by monitoring the generation of reactive oxygen species (ROS), cluster of differentiation (CD) markers and cytokines in Balb/c mice. The data show that the in vitro biocompatibility was satisfactory. In addition, the immunotoxicity data revealed there are no significant changes in the expression levels of CD11b and CD71 between the nanoprobe group and the Gd in a diethylenetriaminepentaacetic acid (DTPA) chelator (Gd-DTPA) group 24 h after injection in Balb/c mice (p>0.05). Importantly, there are significant differences in the expression levels of CD206 and CD25 as well as the secretion of IL-4 and the generation of ROS 24 h after injection (p<0.05). Transmission electron microscopy (TEM) images showed that few nanoprobes were localized in the phagosomes of liver and lung. In conclusion, the toxic effects of our nanoprobes may mainly result from the aggregation of particles in phagosomes. This accumulation may damage the microstructure of the cells and generate oxidative stress reactions that further stimulate the immune response. Therefore, it is important to evaluate the in vivo immunotoxicity of these rare earth-based biomaterials at the molecular level before molecular imaging in vivo.