Temporal clinical, proteomic, histological and cellular immune responses of dextran sulfate sodium-induced acute colitis

AIM To investigate the temporal clinical, proteomic, histological and cellular immune profiles of dextran sulfate sodium(DSS)-induced acute colitis.METHODS Acute colitis was induced in C57 BL/6 female mice by administration of 1%, 2% or 3% DSS in drinking water for 7 d. Animals were monitored daily for weight loss, stool consistency and blood in the stool, while spleens and colons were harvested on day 8. A time course analysis was performed in mice ingesting 3% DSS, which included colon proteomics through multiplex assay, colon histological scoring by a blinded investigator, and immune response through flow cytometry or immunohistochemistry of the spleen, mesenteric lymph node and colon.RESULTS Progressive worsening of clinical colitis was observed with increasing DSS from 1% to 3%. In mice ingesting 3% DSS, colon shortening and increase in proinflammatory factors starting at day 3 was observed, with increased spleen weights at day 6 and day 8. This coincided with cellular infiltration in the colon from day 2 to day 8, with progressive accumulation of macrophages F4/80^+, T helper CD4^+(Th), T cytotoxic CD8^+(Tcyt) and T regulatory CD25^+(Treg) cells, and progressive changes in colonic pathology including destruction of crypts, loss of goblet cells and depletion of the epithelial barrier. Starting on day 4, mesenteric lymph node and/or spleen presented with lower levels of Treg, Th and Tcyt cells, suggesting an immune cell tropism to the gut. CONCLUSION These results demonstrate that the severity of experimental colitis is dependent on DSS concentration, correlated with clinical, proteomic, histological and cellular immune response on 3% DSS.

Synergy between molecular biology and imaging science toward mechanism-based biomarkers associated with prostate cancer

Prostate cancer is a heterogeneous disease with subtypes that are characterized by different molecular profiles as a result of chromosomal rearrangements, epigenetic modifications, and activation of various signaling pathways. The subtype heterogeneity contributes to the challenges with a definitive diagnosis and biomarkers for disease progression. The current diagnostic test based on the detection of prostate specific antigen lacks sensitivity and specificity. Imaging plays an important role in characterizing biomarkers and elucidating the underlying molecular mechanisms. For example, 18F-fluoro-2-deoxy glucose is commonly used to assess cancer cell metabolism. More recently, magnetic resonance spectroscopic observations of the in vivo dynamic conversion of hyperpolarized 13C- pyruvate to lactate demonstrate that imaging enables the visualization of molecular processes. Biomarkers have also been developed that reveal aberrant cell growth and proliferation, both hallmarks of cancer. Androgen dependent and independent signaling path- ways underpin prostate cancer pathogenesis as they lead to downstream effect in cell growth, proliferation, survival, and suppression of apoptosis. Molecular imaging with radiolabeled ligands and positron emission tomography/computed tomography has provided quantitative characterization of the interactions between receptors and testosterone or growth factors. These observations, along with data on genetic alterations of the receptor genes, shed light on signal transduction involved in prostate cancer. This review article highlights advances in the understanding of the molecular mechanisms of prostate cancer and the synergy of this knowledge with imaging in characterizing potential biomarkers of the disease.

Activatable nanoscale metal-organic framework for ratiometric photoacoustic imaging of hydrogen sulfide and orthotopic colorectal cancer in vivo

Nanoscale metal-organic frameworks(nano MOFs)have emerged as a promising biomedical nanoplatform because of their unique properties.However,the exploration of nano MOFs in photoacoustic(PA)imaging is still limited.Here,a novel hydrogen sulfide(H2 S)-activated nano copper-based MOF(Cu-MOF)was developed as a near-infrared(NIR)ratiometric PA probe for in vivo monitoring of endogenous H2 S level and orthotopic colorectal cancer imaging via in situ reaction of nano Cu-MOFs with endogenous H2 S that is closely associated with tumor growth and proliferation in colon cancer.The synthesized nano Cu-MOFs displayed excellent PA responsiveness towards tumor H2 S level with high selectivity and rapid kinetics.The result suggests the developed probe may provide a unique opportunity to investigate the malignant behaviors of H2 S-associated events in vivo.

Hollow iron oxide nanoparticles as multidrug resistant drug delivery and imaging vehicles

Magnetic nanopartides have been used as drug delivery vehicles against a number of cancer cells. Most of these theranostic formulations have used solid iron oxide nanoparticles （SIONPs） loaded with chemotherapeutics as nano-carrier formulation for both magnetic resonance imaging （MRI） and cancer therapy. In this study, we applied the dopamine-plus-human serum albumin （HSA） method to modify hollow iron oxide nanoparticles （HIONPs） and encapsuated doxorubicin （DOX） within the hollow porous structure of the nano-carrier. The new delivery system can load more drug than solid iron oxide nanoparticles of the same core size using the same coating strategy. The HIONPs-DOX formulation also has a pH-dependent drug release behaviour. Compared with free DOX, the HIONPs-DOX were more effectively uptaken by the multidrug resistant OVCAR8- ADR cells and consequently more potent in killing drug resistant cancer cells. MRI phantom and cell studies also showed that the HIONPs-DOX can decrease the T2 MRI signal intensity and can be used as a MR/contrast agent while acting as a drug delivery vehicle. For the first time, the dual application of chemo drug transport and MR imaging using the HIONPs-DOX formulation was achieved against both DOX-sensitive and DOX-resistant cancer cells.

Exosomes derived from tumor adjacent fibroblasts efficiently target pancreatic tumors

The application of extracellular vesicles,particularly exosomes(EXs),is rapidly expanding in the field of medicine,owing to their remarkable properties as natural carriers of biological cargo.This study investigates utilization of exosomes derived from stromal cells of tumor adjacent normal tissues(NAF-EXs)for personalized medicine,which can be derived at the time of diagnosis by endoscopic ultrasound.Herein,we show that exosomes(EXs)derived from NAFs demonstrate differential bio-physical characteristics,efficient cellular internalization,drug loading efficiency,pancreatic tumor targeting and delivery of payloads.NAF-derived EXs(NAF-EXs)were used for loading ormeloxifene(ORM),a potent anti-cancer and desmoplasia inhibitor as a model drug.We found that ORM maintains normal fibroblast cell phenotype and renders them incompatible to be triggered for a CAF-like phenotype,which may be due to regulation of Ca^(2+) influx in fibroblast cells.NAF-EXs-ORM effectively blocked oncogenic signaling pathways involved in desmoplasia and epithelial mesenchymal transition(EMT)and repressed tumor growth in xenograft mouse model.In conclusion,our data suggests preferential tropism of NAF-EXs for PDAC tumors,thus imply feasibility of developing a novel personalized medicine for PDAC patients using autologous NAF-EXs for improved therapeutic outcome of anti-cancer drugs.Additionally,it provides the opportunity of utilizing this biological scaffold for effective therapeutics in combination with standard therapeutic regimen.

Self-assembled multifunctional DNA nanoflowers for the circumvention of multidrug resistance in targeted anticancer drug delivery

Cancer chemotherapy has been limited by its side effects and multidrug resistance （MDR）, the latter of which is partially caused by drug efflux from cancer cells. Thus, targeted drug delivery systems that can circumvent MDR are needed. Here, we report multifunctional DNA nanoflowers （NFs） for targeted drug delivery to both chemosensitive and MDR cancer cells that circumvented MDR in both leukemia and breast cancer cell models. NFs are self-assembled via potential co-precipitation of DNA and magnesium pyrophosphate generated by rolling circle replication, during which NFs are incorporated using aptamers for specific cancer cell recognition, fluorophores for bioimaging, and doxorubicin （Dox）- binding DNA for drug delivery. NF sizes are tunable （down to N200 nm in diameter）, and the densely packed drug-binding motifs and porous intrastructures endow NFs with a high drug-loading capacity （71.4%, wt/wt）. Although the Dox- loaded NFs （NF-Dox） are stable at physiological pH, drug release is facilitated under acidic or basic conditions. NFs deliver Dox into target chemosensitive and MDR cancer cells, preventing drug efflux and enhancing drug retention in MDR cells. NF-Dox induces potent cytotoxicity in both target chemosensitive cells and MDR cells, but not in nontarget cells, thus concurrently circumventing MDR and reducing side effects. Overall, these NFs are promising tools for circumventing MDR in targeted cancer therapy.

Metal-organic frameworks nanoswitch:Toward photo-controllable endo/lysosomal rupture and release for enhanced cancer RNA interference

Endo/lysosomal escape and gene release are two critical bottlenecks in gene delivery.Herein,a novel photo-controllable metal-organic frameworks(MOFs)nanoswitch is rationally designed for enhancing small interfering RNA(siRNA)delivery.One single laser triggers the“off-to-on”switching of MOFs nanocomplexes,inducing significant siRNA release accompanied by rapid MOFs dissociation into protonatable 2-methylimidazalo and osmotic rupturing Zn2+ions,which cooperatively contribute to remarkable endo/lysosomal rupture(∼90%).The simultaneous endo/lysosomal rupture and release enable a high spatio-temporal control on RNA interference for effective cancer therapy.Notably,the“off-to-on”switching also activates fluorescence recovery for real-time monitoring siRNA delivery.The nanoswitch could easily be extended to deliver other therapeutic agents(e.g.,DNA,protein,anticancer drug)for overcoming endo/lysosomal entrapment.

Precise nanomedicine for intelligent therapy of cancer

Precise nanomedicine has been extensively explored for efficient cancer imaging and targeted cancer therapy, as evidenced by a few breakthroughs in their preclinical and clinical explorations. Here, we demonstrate the recent advances of intelligent cancer nanomedicine, and discuss the comprehensive understanding of their structure-function relationship for smart and efficient cancer nanomedicine including various imaging and therapeutic applications, as well as nanotoxicity. In particular, a few emerging strategies that have advanced cancer nanomedicine are also highlighted as the emerging focus such as tumor imprisonment, supramolecular chemotherapy, and DNA nanorobot. The challenge and outlook of some scientific and engineering issues are also discussed in future development. We wish to highlight these new progress of precise nanomedicine with the ultimate goal to inspire more successful explorations of intelligent nanoparticles for future clinical translations.

A pillar[5]arene-based molecular grapple of hexafluorophosphate

A symmetric pillararene-based receptor containing ten triazole units was synthesized.Interestingly,it formed 1:1 complexes instead of 1:2 with different halide anions.This was caused by the cooperative multivalent hydrogen-bond interactions between the triazole protons on one side of the receptor and the halide anion,which changed its structure from pillar to conical.However,by the regulation of the effector F-,it can work like an excavator grapple selectively grasps a PF6-anion.

Environmentally responsive dual-targeting nanotheranostics for overcoming cancer multidrug resistance

The development of multiple drug resistance(MDR) to chemotherapy and subsequent treatment failures are major obstacles in cancer therapy. An attractive option for combating MDR is inhibiting the expression of P-glycoprotein(P-gp) in tumor cells. Here, we report a novel chemosensitizing agent, XMD8-92,which can down-regulate P-gp. To enhance the specificity of MDR chemotherapy, a promising nanotheranostic micelle system based on poly(ethylene glycol)-blocked-poly(L-leucine)(PEG-b-Leu) was developed to simultaneously carry the anticancer drug doxorubicin, chemosensitizing agent XMD8-92, and superparamagnetic iron oxide nanoparticles(SPIOs). Featured with MDR environmentally responsive dual-targeting capability, controllable drug delivery, and efficient magnetic resonance(MR) imaging characteristics, the prepared nanotheranostics(DXS@NPs) showed outstanding in vitro cytotoxicity on MDR cells(SCG 7901/VCR) with only 53% of cells surviving compared to 90% of DOX-treated cells.Furthermore, efficient tumor inhibition and highly reduced systemic toxicity were exhibited by MDR tumor-bearing mice treated with DXS@NPs. Overall, the environmentally responsive dual-targeting nanotheranostics represent a promising approach for overcoming cancer MDR.