A Lysosome-Targeting Self-Condensation Prodrug-Nanoplatform System for Addressing Drug Resistance of Cancer.

Lysosome-targeting self-assembling prodrugs had emerged as an attractive approach to overcome the acquisition of resistance to chemotherapeutics by inhibiting lysosomal sequestration. Taking advantage of lysosomal acidification induced intracellular hydrolytic condensation, we developed a lysosomal-targeting self-condensation prodrug-nanoplatform (LTSPN) system for overcoming lysosome-mediated drug resistance. Briefly, the designed hydroxycamptothecine (HCPT)-silane conjugates self-assembled into silane-based nanoparticles, which were taken up into lysosomes by tumor cells. Subsequently, the integrity of the lysosomal membrane was destructed because of the acid-triggered release of alcohol, wherein the nanoparticles self-condensed into silicon particles outside the lysosome through intracellular hydrolytic condensation. Significantly, the LTSPN system reduced the half-maximal inhibitory concentration (IC50) of HCPT by approximately 4 times. Furthermore, the LTSPN system realized improved control of large established tumors and reduced regrowth of residual tumors in several drug-resistant tumor models. Our findings suggested that target destructing the integrity of the lysosomal membrane may improve the therapeutic effects of chemotherapeutics, providing a potent treatment strategy for malignancies.

In Situ Constructed Nano-Drug Depots through Intracellular Hydrolytic Condensation for Chemotherapy of Bladder Cancer.

Intravesical administration of first-line drugs has shown failure in the treatment of bladder cancer owing to the poor tumor retention time of chemotherapeutics. Herein, we report an intracellular hydrolytic condensation (IHC) system to construct long-term retentive nano-drug depots in situ, wherein sustained drug release results in highly efficient suppression of bladder cancer. Briefly, the designed doxorubicin (Dox)-silane conjugates self-assemble into silane-based prodrug nanoparticles, which condense into silicon particle-based nano-drug depots inside tumor cells. Significantly, we demonstrate that the IHC system possesses highly potent antitumor efficacy, which leads to the regression and eradication of large established tumors and simultaneously extends the overall survival of air pouch bladder cancer mice compared with that of mice treated with Dox. The concept of intracellular hydrolytic condensation can be extended via conjugating other chemotherapeutic drugs, which may facilitate rational design of novel nanomedicines for augmentation of chemotherapy.

Molybdenum derived from nanomaterials incorporates into molybdenum enzymes and affects their activities in vivo.

Many nanoscale biomaterials fail to reach the clinical trial stage due to a poor understanding of the fundamental principles of their in vivo behaviour. Here we describe the transport, transformation and bioavailability of MoS2 nanomaterials through a combination of in vivo experiments and molecular dynamics simulations. We show that after intravenous injection molybdenum is significantly enriched in liver sinusoid and splenic red pulp. This biodistribution is mediated by protein coronas that spontaneously form in the blood, principally with apolipoprotein E. The biotransformation of MoS2 leads to incorporation of molybdenum into molybdenum enzymes, which increases their specific activities in the liver, affecting its metabolism. Our findings reveal that nanomaterials undergo a protein corona-bridged transport-transformation-bioavailability chain in vivo, and suggest that nanomaterials consisting of essential trace elements may be converted into active biological molecules that organisms can exploit. Our results also indicate that the long-term biotransformation of nanomaterials may have an impact on liver metabolism.

New power of self-assembling carbonic anhydrase inhibitor: Short peptide-constructed nanofibers inspire hypoxic cancer therapy.

Carbonic anhydrase (CA) IX overexpresses exclusively on cell membranes of hypoxic tumors, regulating the acidic tumor microenvironment. Small molecules of CA inhibitor modified with short peptide successfully achieve CA IX-targeted self-assembly that localizes CA inhibitors on hypoxic cancer cell surfaces and enhances their inhibition efficacy and selectivity. CA IX-related endocytosis also promotes selective intracellular uptake of these nanofibers under hypoxia, in which nanofiber structures increase in size with decreasing pH. This effect subsequently causes intracellular acid vesicle damage and blocks protective autophagy. The versatility of tunable nanostructures responding to cell milieu impressively provokes selective toxicities and provides strategic therapy for hypoxic tumors. Moreover, in vivo tests demonstrate considerable antimetastatic and antiangiogenesis effects in breast tumors, and particularly remarkable enhancement of antitumor efficacy in doxorubicin administration. With its biocompatible components and distinctive hypoxia therapies, this nanomaterial advances current chemotherapy, providing a new direction for hypoxic cancer therapy.

A potential involvement of plant systemic response in initiating genotoxicity of Ag-nanoparticles in Arabidopsis thaliana.

The extensive availability of engineered nanomaterials in global markets has led to the release of substantial amounts of nanoparticles (NP) into atmosphere, water body and soil, yielding both beneficial and harmful effects in plant systems. The NP are mainly aggregated onto the surface of plant roots and leaves exposed and only slightly transported into other tissues with a low rate of internalization. This raises a question of whether plant systemic response is involved in the induction of biological effects of NP. To address this, model plant Arabidopsis thaliana were root exposed to low concentrations of Ag-NP of two particle sizes (10-nm and 60-nm), and expressions of homologous recombination (HR)-related genes and the alleviation of transcriptional gene silencing (TGS) in aerial leafy tissues were examined as genotoxic endpoints. Results showed that exposure of roots to two sizes of Ag-NP up-regulated expressions of HR genes, and reactivated TGS-silenced repetitive elements in aerial tissues. These effects were blocked by the impairment in the salicylic acid signal pathway, indicating a potential involvement of plant systemic response in the induction of Ag-NP genotoxicity. This is further supported by ICP-MS analysis, in which the Ag content in aerial tissues was not significantly changed by root exposure to 10-nm Ag-NP. Although a significant increase in the Ag content in aerial tissues was observed after root exposure to 60-nm Ag-NP, its genotoxic effects had no obvious difference from that by 10-nm Ag-NP exposure, also suggesting that the genotoxicity might be mainly induced via plant systemic response, at least in the experiments of root exposure to Ag-NP.

A pivotal role of the jasmonic acid signal pathway in mediating radiation-induced bystander effects in Arabidopsis thaliana.

Although radiation-induced bystander effects (RIBE) in Arabidopsis thaliana have been well demonstrated in vivo, little is known about their underlying mechanisms, particularly with regard to the participating signaling molecules and signaling pathways. In higher plants, jasmonic acid (JA) and its bioactive derivatives are well accepted as systemic signal transducers that are produced in response to various environmental stresses. It is therefore speculated that the JA signal pathway might play a potential role in mediating radiation-induced bystander signaling of root-to-shoot. In the present study, pretreatment of seedlings with Salicylhydroxamic acid, an inhibitor of lipoxigenase (LOX) in JA biosynthesis, significantly suppressed RIBE-mediated expression of the AtRAD54 gene. After root irradiation, the aerial parts of A. thaliana mutants deficient in JA biosynthesis (aos) and signaling cascades (jar1-1) showed suppressed induction of the AtRAD54 and AtRAD51 genes and TSI and 180-bp repeats, which have been extensively used as endpoints of bystander genetic and epigenetic effects in plants. These results suggest an involvement of the JA signal pathway in the RIBE of plants. Using the root micro-grafting technique, the JA signal pathway was shown to participate in both the generation of bystander signals in irradiated root cells and radiation responses in the bystander aerial parts of plants. The over-accumulation of endogenous JA in mutant fatty acid oxygenation up-regulated 2 (fou2), in which mutation of the Two Pore Channel 1 (TPC1) gene up-regulates expression of the LOX and allene oxide synthase (AOS) genes, inhibited RIBE-mediated expression of the AtRAD54 gene, but up-regulated expression of the AtKU70 and AtLIG4 genes in the non-homologous end joining (NHEJ) pathway. Considering that NHEJ is employed by plants with increased DNA damage, the switch from HR to NHEJ suggests that over-accumulation of endogenous JA might enhance the radiosensitivity of plants in terms of RIBE.

UV-C-Induced alleviation of transcriptional gene silencing through plant-plant communication: Key roles of jasmonic acid and salicylic acid pathways.

Plant stress responses at the epigenetic level are expected to allow more permanent changes of gene expression and potentially long-term adaptation. While it has been reported that plants subjected to adverse environments initiate various stress responses in their neighboring plants, little is known regarding epigenetic responses to external stresses mediated by plant-plant communication. In this study, we show that DNA repetitive elements of Arabidopsis thaliana, whose expression is inhibited epigenetically by transcriptional gene silencing (TGS) mechanism, are activated by UV-C irradiation through airborne plant-plant and plant-plant-plant communications, accompanied by DNA demethylation at CHH sites. Moreover, the TGS is alleviated by direct treatments with exogenous methyl jasmonate (MeJA) and methyl salicylate (MeSA). Further, the plant-plant and plant-plant-plant communications are blocked by mutations in the biosynthesis or signaling of jasmonic acid (JA) or salicylic acid (SA), indicating that JA and SA pathways are involved in the interplant communication for epigenetic responses. For the plant-plant-plant communication, stress cues are relayed to the last set of receiver plants by promoting the production of JA and SA signals in relaying plants, which exhibit upregulated expression of genes for JA and SA biosynthesis and enhanced emanation of MeJA and MeSA.

Radiation-induced epigenetic bystander effects demonstrated in Arabidopsis thaliana.

Radiation-induced bystander effects (RIBE) in vivo in the higher plant Arabidopsis thaliana ( A. thaliana ) have been well demonstrated in terms of effects on development and genetics. However, there is not yet robust evidence regarding RIBE-mediated epigenetic changes in plants. To address this, in the current work the roots of A. thaliana seedlings were locally irradiated with 10 Gy of α particles, after which DNA methylation in bystander aerial plants were detected using the methylation-sensitive amplification polymorphism (MSAP) and bisulfite sequencing PCR (BSP). Results showed that irradiation of the roots led to long-distance changes in DNA methylation patterns at some CCGG sites over the whole genome, specifically from hemi-methylation to non-methylation, and the methylation ratios, mainly at CG sites, strongly indicating the existence of RIBE-mediated epigenetic changes in higher plants. Root irradiation also influenced expressions of DNA methylation-related MET1, DRM2 and SUVH4 genes and demethylation-related DML3 gene in bystander aerial plants, suggesting a modulation of RIBE to the methylation machinery in plants. In addition, the multicopy P35S:GUS in A. thaliana line L5-1, which is silenced epigenetically by DNA methylation and histone modification, was transcriptionally activated through the RIBE. The transcriptional activation could be significantly inhibited by the treatment with reactive oxygen species (ROS) scavenger dimethyl sulfoxide (DMSO), indicative of a pivotal role of ROS in RIBE-mediated epigenetic changes. Time course analyses showed that the bystander signaling molecule(s) for transcriptional activation of multicopy P35S:GUS, although of unknown chemical nature, were generated in the root cells within 24 h postirradiation.