The microneedles carrying cisplatin and IR820 to perform synergistic chemo-photodynamic therapy against breast cancer.

BACKGROUNDS: Surgical resection and adjunct chemotherapy or radio-therapy has been applied for the therapy of superficial malignant tumor in clinics. Whereas, there are still some problems limit its clinical use, such as severe pains and side effect. Thus, it is urgent need to develop effective, minimally invasive and low toxicity therapy stagey for superficial malignant tumor. Topical drug administration such as microneedle patches shows the advantages of reduced systemic toxicity and nimble application and, as a result, a great potential to treat superficial tumors. METHODS: In this study, microneedle (MN) patches were fabricated to deliver photosensitizer IR820 and chemotherapy agent cisplatin (CDDP) for synergistic chemo-photodynamic therapy against breast cancer. RESULTS: The MN could be completely inserted into the skin and the compounds carrying tips could be embedded within the target issue for locoregional cancer treatment. The photodynamic therapeutic effects can be precisely controlled and switched on and off on demand simply by adjusting laser. The used base material vinylpyrrolidone-vinyl acetate copolymer (PVPVA) is soluble in both ethanol and water, facilitating the load of both water-soluble and water-insoluble drugs. CONCLUSIONS: Thus, the developed MN patch offers an effective, user-friendly, controllable and low-toxicity option for patients requiring long-term and repeated cancer treatments.

Bismuth chelate as a contrast agent for X-ray computed tomography.

BACKGROUNDS: Due to the unexpected side effects of the iodinated contrast agents, novel contrast agents for X-ray computed tomography (CT) imaging are urgently needed. Nanoparticles made by heavy metal elements are often employed, such as gold and bismuth. These nanoparticles have the advantages of long in vivo circulation time and tumor targeted ability. However, due to the long residence time in vivo, these nanoparticles may bring unexpected toxicity and, the preparation methods of these nanoparticles are complicated and time-consuming. METHODS: In this investigation, a small molecular bismuth chelate using diethylenetriaminepentaacetic acid (DPTA) as the chelating agent was proposed to be an ideal CT contrast agent. RESULTS: The preparation method is easy and cost-effective. Moreover, the bismuth agent show better CT imaging for kidney than iohexol in the aspect of improved CT values. Up to 500 µM, the bismuth agent show negligible toxicity to L02 cells and negligible hemolysis. And, the bismuth agent did not induce detectable morphology changes to the main organs of the mice after intravenously repeated administration at a high dose of 250 mg/kg. The pharmacokinetics of the bismuth agent follows the first-order elimination kinetics and, it has a short half-life time of 0.602 h. The rapid clearance from the body promised its excellent biocompatibility. CONCLUSIONS: This bismuth agent may serve as a potential candidate for developing novel contrast agent for CT imaging in clinical applications.

The use of amphiphilic copolymer in the solid dispersion formulation of nimodipine to inhibit drug crystallization in the release media: Combining nano-drug delivery system with solid preparations.

Solid dispersion is a widely used method to improve the dissolution and oral bioavailability of water-insoluble drugs. However, due to the strong hydrophobicity, the drug crystallization in the release media after drug dissolution and the resulted decreased drug absorption retards the use of solid dispersions. It is widely known that the amphiphilic copolymer can encapsulate the hydrophobic compounds and help form stable nano-dispersions in water. Inspired by this, we tried to formulate the solid dispersion of nimodipine by using amphipathic copolymer as one of the carriers. Concerning the solid dispersions, there are many important points involved in these formulations, such as the miscibility between the drug and the carriers, the storage stability of solid dispersions, the dissolution enhancement and so on. In this study, a systemic method is proposed. In details, the supersaturation test and the glass transition temperature (Tg) measurement to predict the crystallization inhibition, the ratios of different components and the storage stability, the interactions among the components were investigated in detail by nuclear magnetic resonance (1H NMR) and isothermal titration calorimetry (ITC) and, the final dissolution and oral bioavailability enhancement. It was found that the amphiphilic copolymer used in the solid dispersion encouraged the formation the drug loading micelles in the release media and, finally, the problem of drug crystallization in the dissolution process was successfully solved.

Preparation, characterization and in vitro-in vivo evaluation of bortezomib supermolecular aggregation nanovehicles.

BACKGROUNDS: Intolerable toxicity and unsatisfactory therapeutic effects are still big problems retarding the use of chemotherapy against cancer. Nano-drug delivery system promised a lot in increasing the patients' compliance and therapeutic efficacy. As a unique nano-carrier, supermolecular aggregation nanovehicle has attracted increasing interests due to the following advantages: announcing drug loading efficacy, pronouncing in vivo performance and simplified production process. METHODS: In this study, the supermolecular aggregation nanovehicle of bortezomib (BTZ) was prepared to treat breast cancer. RESULTS: Although many supermolecular nanovehicles are inclined to disintegrate due to the weak intermolecular interactions among the components, the BTZ supermolecules are satisfying stable. To shed light on the reasons behind this, the forces driving the formation of the nanovehicles were detailed investigated. In other words, the interactions among BTZ and other two components were studied to characterize the nanovehicles and ensure its stability. CONCLUSIONS: Due to the promising tumor targeting ability of the BTZ nanovehicles, the supermolecule displayed promising tumor curing effects and negligible systemic toxicity.

Exploration and validation of downregulated microRNA-199a-3p, downstream messenger RNA targets and transcriptional regulation in osteosarcoma.

Osteosarcoma (OS) is a primary bone tumor with a high incidence and mortality in children and adolescents. Emerging evidence shows that microRNAs (miRNAs) participate in biological tumor mechanisms by targeting downstream messenger RNAs (mRNAs). This article aimed to investigate the potential regulatory targets of microRNA-199a-3p (miR-199a-3p) in OS and to contribute to the understanding of miR-199a-3p-related OS regulatory mechanisms. MicroRNA-related Gene Expression Omnibus (GEO) chips, ArrayExpress chips and literature data were used to determine the expression of miR-199a-3p in OS and pooled to explore its potential clinical value. To investigate the target genes of miR-199a-3p further, we integrated the results from the following three-part gene study: Twelve online prediction tools were used to predict the target genes of miR-199a-3p; the GEO GSE89370 chip transfected with miRSelect pEP-miR-199a-3p was used to analyze the downregulated differentially expressed genes (DEGs) in OS cells; and highly expressed DEGs were derived from an in-house microarray generated from three pairs of clinical OS and normal tissue samples acquired through our department. Then, we analyzed the target genes using the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases and the protein-protein interaction (PPI) network to further identify the primary target genes. In addition, we constructed transcription factor (TF)-miRNA-joint gene feed-forward regulatory loops (FFLs) with Circuits DB using miR-199a-3p as the core. A comprehensive meta-analysis of a hub of miR-199a-3p targeted genes was performed to integrate expression level, summary ROC (sROC) curves and survival analysis results from the GEO data for verification and exploration. Finally, the expression levels of the hub genes were verified in OS tissues and U2OS cells by immunohistochemistry (IHC) and immunocytochemistry (ICC). Data on miR-199a-3p expression were obtained from three data sets (GSE65071, GSE69524, and PMID 21666078), which showed low miR-199a-3p expression levels in OS tissues. The combined data indicated the same tendency, with the SMD of the random effect model, as shown in forest plots, being -2.8 (95% CI: -4.49, -1.11). In addition, we determined that miR-199a-3p may serve as a molecular marker useful for distinguishing OS tissues from normal tissues with high sensitivity and specificity, with the measured outcomes being 0.94 (95% CI: 0.80, 0.99) and 0.96 (95% CI: 0.78, 1.00), respectively. In addition, 391 genes were considered targets of miR-199a-3p in OS, and the enrichment analysis indicated that these targets were mainly enriched in proteoglycans in cancer and in spliceosomes. Four genes, CDKI, CCNB1, AURKA and NEK2, were regarded as hub targets based on the PPI data. Subsequently, TF-miRNA-joint genes FFLs were constructed in Circuits DB and included 17 TFs and 82 joint targets. These joint targets were mainly enriched in spliceosomes. UBE2D1 and RBM25 were regarded as hub joint targets based on the enrichment analysis. All selected target genes were further verified to ensure that they were upregulated in OS and to determine their prognostic significance. At the experimental verification level, the CDK1 protein was confirmed to be positively expressed in the cytoplasm of OS tissues and the U2OS cell line. Our study verified that miR-199a-3p was obviously downregulated in OS. CDK1, CCNB1, NEK2, AURKA, UBE2D1 and RBM25 were identified as potential target genes of miR-199a-3p in OS.

Injectable hydrogel encapsulating Cu2MnS2 nanoplates for photothermal therapy against breast cancer.

BACKGROUND: In order to explore the possibility of treating breast cancer by local photo-therapy, a photothermal agents loaded in situ hydrogel was established. In detail, The Cu2MnS2 nanoplates were prepared by one-pot synthesis and, the thermosensitive Pluronic F127 was used as the hydrogel matrix. The Cu2MnS2 nanoplates and the hydrogel were characterized by morphous, particle size, serum stability, photothermal performance upon repeated 808 nm laser irradiation as well as the rheology features. The therapeutic effects of the Cu2MnS2 nanoplates and the hydrogel were evaluated qualitatively and quantitatively in 4T1 mouse breast cancer cells. The retention, photothermal efficacy, therapeutic effects and systemic toxicity of the hydrogel were assessed in tumor bearing mouse model. RESULTS: The Cu2MnS2 nanoplates with a diameter of about 35 nm exhibited satisfying serum stability, photo-heat conversion ability and repeated laser exposure stability. The hydrogel encapsulation did not negatively influence the above features of the photothermal agent. The nanoplates loaded in situ hydrogel shows a phase transition at body temperature and, as a result, a long retention in vivo. CONCLUSIONS: The photothermal agent embedded hydrogel played a promising photothermal therapeutic effects in tumor bearing mouse model with low systemic toxicity after peritumoral administration.