Computed tomography (CT) contrast and radiosensitization usually increase with particle sizes of gold nanoparticles (AuNPs), but there is a huge challenge to improve both by adjusting sizes under the requirements of in vivo application. Here, we report that AuNPs have great size-dependent enhancements on CT imaging as well as radiotherapy (RT) in the size range of 3-50 nm. It is demonstrated that AuNPs with a size of ∼13 nm could simultaneously possess superior CT contrast ability and significant radioactive disruption. The Monte Carlo method is further used to evaluate this phenomenon and indicates that the inhomogeneity of gold atom distributions caused by sizes may influence secondary ionization in whole X-ray interactions. In vivo studies further indicate that this optimally sized AuNP improves real-time CT imaging and radiotherapeutic inhibition of tumors in living mice by effective accumulation at tumors with prolonged in vivo circulation times compared to clinically used small-molecule agents. These results suggest that ∼13 nm AuNPs may serve as multifunctional adjuvants for clinical X-ray theranostic application.

BackgroundThe communication between carcinoma associated fibroblasts (CAFs) and cancer cells facilitate tumor metastasis. In this study, we further underlying the epigenetic mechanisms of CAFs feed the cancer cells and the molecular mediators involved in these processes.MethodsMCF-7 and MDA-MB-231 cells were treated with CAFs culture conditioned medium, respectively. Cytokine antibody array, enzyme-linked immunosorbent assay, western blotting and immunofluorescence were used to identify the key chemokines. Chromatin immunoprecipitation and luciferase reporter assay were performed to explore the transactivation of target LncRNA by CAFs. A series of in vitro assays was performed with RNAi-mediated knockdown to elucidate the function of LncRNA. An orthotopic mouse model of MDA-MB-231 was conducted to confirm the mechanism in vivo.ResultsHere we reported that TGF-β1 was top one highest level of cytokine secreted by CAFs as revealed by cytokine antibody array. Paracrine TGF-β1 was essential for CAFs induced EMT and metastasis in breast cancer cells, which is a crucial mediator of the interaction between stromal and cancer cells. CAF-CM significantly enhanced the HOTAIR expression to promote EMT, whereas treatment with small-molecule inhibitors of TGF-β1 attenuated the activation of HOTAIR. Most importantly, SMAD2/3/4 directly bound the promoter site of HOTAIR, located between nucleotides -386 and -398, -440 and -452, suggesting that HOTAIR was a directly transcriptional target of SMAD2/3/4. Additionally, CAFs mediated EMT by targeting CDK5 signaling through H3K27 tri-methylation. Depletion of HOTAIR inhibited CAFs-induced tumor growth and lung metastasis in MDA-MB-231 orthotopic animal model.ConclusionsOur findings demonstrated that CAFs promoted the metastatic activity of breast cancer cells by activating the transcription of HOTAIR via TGF-β1 secretion, supporting the pursuit of the TGF-β1/HOTAIR axis as a target in breast cancer treatment.Electronic supplementary materialThe online version of this article (10.1186/s12943-018-0758-4) contains supplementary material, which is available to authorized users.

No abstract

To integrate multiple diagnostic and therapeutic strategies on a single particle through simple and effective methods is still challenging for nanotheranostics. Herein, we develop multifunctional nanotheranostic PB@Au core-satellite nanoparticles (CSNPs) based on Prussian blue nanoparticles (PBNPs) and gold nanoparticles (AuNPs), which are two kinds of intrinsic theranostic nanomaterials, for magnetic resonance (MR)-computed tomography (CT) imaging and synergistic photothermal and radiosensitive therapy (PTT-RT). PBNPs as cores enable T- and T-weighted MR contrast and strong photothermal effect, while AuNPs as satellites offer CT enhancement and radiosensitization. As revealed by both MR and CT imaging, CSNPs realized efficient tumor localization by passively targeted accumulation after intravenous injection. In vivo studies showed that CSNPs resulted in synergistic PTT-RT action to achieve almost entirely suppression of tumor growth without observable recurrence. Moreover, no obvious systemic toxicity of mice confirmed good biocompatibility of CSNPs. These results raise new possibilities for clinical nanotheranostics with multimodal diagnostic and therapeutic coalescent design.

Realizing precise control of the therapeutic process is crucial for maximizing efficacy and minimizing side effects, especially for strategies involving gene therapy (GT). Herein, a multifunctional Prussian blue (PB) nanotheranostic platform is first designed and then loaded with therapeutic plasmid DNA (HSP70-p53-GFP) for near-infrared (NIR) light-triggered thermo-controlled synergistic GT/photothermal therapy (PTT). Due to the unique structure of the PB nanocubes, the resulting PB@PEI/HSP70-p53-GFP nanoparticles (NPs) exhibit excellent photothermal properties and pronounced tumor-contrast performance in T 1 /T 2weighted magnetic resonance imaging. Both in vitro and in vivo studies demonstrate that mild NIR-laser irradiation (≈41 °C) activates the HSP70 promoter for tumor suppressor p53-dependent apoptosis, while strong NIR-laser irradiation (≈50 °C) induces photothermal ablation for cellular dysregulation and necrosis. Significant synergistic efficacy can be achieved by adjusting the NIR-laser irradiation (from ≈41 to ≈50 °C), compared to using GT or PTT alone. In addition, in vitro and in vivo toxicity studies demonstrate that PB@PEI/HSP70-p53-GFP NPs have good biocompatibility. Therefore, this work provides a promising theranostic approach for controlling combined GT and PTT via the heat-shock response.

Hypoxia-induced radioresistance is the primary reason for failure of tumor radiotherapy (RT). Changes within the irradiated tumor microenvironment (TME) including oxygen, reactive oxygen species (ROS) and nitric oxide (NO) are closely related to radioresistance. Therefore, there is an urgent need to develop new approaches for overcoming hypoxic radioresistance by incorporating TME regulation into current radiotherapeutic strategies.Methods: Herein, we explored a radiation-responsive nanotheranostic system to enhance RT effects on hypoxic tumors by multi-way therapeutic effects. This system was developed by loading S-nitrosothiol groups (SNO, a NO donor) and indocyanine green (ICG, a photosensitizer) onto mesoporous silica shells of Eu3+-doped NaGdF4 scintillating nanocrystals (NSC).Results: Under X-ray radiation, this system can increase the local dosage by high-Z elements, promote ROS generation by X-ray-induced photodynamic therapy, and produce high levels of NO to enhance tumor-killing effects and improve hypoxia via NO-induced vasodilation. In vitro and in vivo studies revealed that this combined strategy can greatly reinforce DNA damage and apoptosis of hypoxic tumor cells, while significantly suppressing tumor growth, improving tumor hypoxia and promoting p53 up-regulation and HIF1α down-regulation. In addition, this system showed pronounced tumor contrast performance in T1-weighted magnetic resonance imaging and computed tomography.Conclusion: This work demonstrates the great potential of scintillating nanotheranostics for multimodal imaging-guided X-ray radiation-triggered tumor combined therapy to overcome radioresistance.

No abstract

Background Hyperinsulinemia is independently associated with increased risk and mortality of pancreatic cancer. We recently reported that genetically reduced insulin production resulted in ~ 50% suppression of pancreatic intraepithelial neoplasia (PanIN) precancerous lesions in mice. However, only female mice remained normoglycemic, and only the gene dosage of the rodent-specific Ins1 alleles was tested in our previous model. Moreover, we did not delve into the molecular and cellular mechanisms associated with modulating hyperinsulinemia. Methods We studied how reduced Ins2 gene dosage affects PanIN lesion development in both male and female Ptf1aCreER;KrasLSL-G12D mice lacking the rodent-specific Ins1 gene (Ins1-/-). We generated control mice having two alleles of the wild-type Ins2 gene (Ptf1aCreER;KrasLSL-G12D;Ins1-/-;Ins2+/+) and experimental mice having one allele of Ins2 gene (Ptf1aCreER;KrasLSL-G12D;Ins1-/-;Ins2+/-). We then performed thorough histopathological analyses and single-cell transcriptomics for both genotypes and sexes. Results High-fat diet–induced hyperinsulinemia was transiently or modestly reduced in female and male mice, respectively, with only one allele of Ins2. This occurred without dramatically affecting glucose tolerance. Genetic reduction of insulin production resulted in mice with a tendency for less PanIN and acinar-to-ductal metaplasia (ADM) lesions. Using single-cell transcriptomics, we found hyperinsulinemia affected multiple cell types in the pancreas, with the most statistically significant effects on local immune cell types that were highly represented in our sampled cell population. Specifically, hyperinsulinemia modulated pathways associated with protein translation, MAPK-ERK signaling, and PI3K-AKT signaling, which were changed in epithelial cells and subsets of immune cells. Conclusions These data suggest a potential role for the immune microenvironment in hyperinsulinemia-driven PanIN development. Together with our previous work, we propose that mild suppression of insulin levels may be useful in preventing pancreatic cancer by acting on multiple cell types.