Synthesis of Hemiprotonic Phenanthroline-Phenanthroline+ Compounds with both Antitumor and Antimicrobial Activity.

Currently, cancer patients with microbial infection are a severe challenge in clinical treatment. To address the problem, we synthesized hemiprotonic compounds based on the unique structure of hemiprotonic nucleotide base pairs in a DNA i-motif. These compounds were produced from phenanthroline (ph) dimerization with phenanthroline as a proton receptor and ammonium as a donor. The biological activity shows that the compounds have a selective antitumor effect through inducing cell apoptosis. The molecular mechanism could be related to specific inhibition of transcription factor PLAGL2 of tumor cells, assessed by transcriptomic analysis. Moreover, results show that the hemiprotonic ph-ph+ has broad-spectrum antibacterial and antifungal activities, and drug-resistant bacteria, including methicillin-resistant Staphylococcus aureus, are sensitive to the compound. In animal models of liver cancer with fungal infection, the ph-ph+ retards proliferation of hepatoma cells in tumor-bearing mice and remedies pneumonia and encephalitis caused by Cryptococcus neoformans. The study provides a novel therapeutic candidate for cancer patients accompanied by infection.

Photodynamic Nanophotosensitizers: Promising Materials for Tumor Theranostics.

Photodynamic theranostics/therapy (PDT) is a potential strategy for selectively imaging malignant sites and treating cancer via a non-invasive therapeutic method. Photosensitizers, the crucial components of PDT, enable colocalization of photons and light, and photon/light therapy in the therapeutic window of 400-900 nm exhibits photocytotoxicity to tumor cells. Due to their high biostability and photocytotoxicity, nanophotosensitizers (NPSs) are of much interest for malignant tumor theranostics at present. NPS-activated photons transfer energy through the absorption of a photon and convert molecular oxygen to the singlet reactive oxygen species, which leads to apoptosis and necrosis. Moreover, NPSs modified by polymers, including PLGA, PEG-PLA, PDLLA, PVCL-g-PLA, and P(VCL-co-VIM)-g-PLA, exhibit excellent biocompatibility, and a tumor-targeting molecule linked on the nanoparticle surface can precisely deliver NPSs into the tumor region. The development of NPSs will accelerate the progress in tumor theranostics through the photon/light pathway.

Interfacial engineered gadolinium oxide nanoparticles for magnetic resonance imaging guided microenvironment-mediated synergetic chemodynamic/photothermal therapy.

Engineering interfacial structure of biomaterials have drawn much attention due to it can improve the diagnostic accuracy and therapy efficacy of nanomedicine, even introducing new moiety to construct theranostic agents. Nanosized magnetic resonance imaging contrast agent holds great promise for the clinical diagnosis of disease, especially tumor and brain disease. Thus, engineering its interfacial structure can form new theranostic platform to achieve effective disease diagnosis and therapy. In this study, we engineered the interfacial structure of typical MRI contrast agent, Gd2O3, to form a new theranostic agent with improved relaxivity for MRI guided synergetic chemodynamic/photothermal therapy. The synthesized Mn doped gadolinium oxide nanoplate exhibit improved T1 contrast ability due to large amount of efficient paramagnetic metal ions and synergistic enhancement caused by the exposed Mn and Gd cluster. Besides, the introduced Mn element endow this nanomedicine with the Fenton-like ability to generate OH from excess H2O2 in tumor site to achieve chemodynamic therapy (CDT). Furthermore, polydopamine engineered surface allow this nanomedicine with effective photothermal conversion ability to rise local temperature and accelerate the intratumoral Fenton process to achieve synergetic CDT/photothermal therapy (PTT). This work provides new guidance for designing magnetic resonance imaging guided synergetic CDT/PTT to achieve tumor detection and therapy.

Targeted therapy of intracranial glioma model mice with curcumin nanoliposomes.

BACKGROUND: Glioma is the most aggressive and lethal brain tumor in humans, it comprises about 30 per cent of all brain tumors and central nervous system tumors. PURPOSE: The objective of this study was to create novel brain-targeting nanoliposomes to encapsulate curcumin as a promising option for glioma therapy. PATIENTS AND METHODS: Human glioma cells (U251MG) were used to determine cell uptake efficiency and possible internalization mechanism of the curcumin-loaded nanoliposomes modified by a brain-targeting peptide RDP. In addition, intracranial glioma mice model was prepared by transplantation of U251MG cells into the mice striatum, and then the liposomes were intravenously administered into the glioma-bearing mice to evaluate the anti-glioma activity. RESULTS: RDP-modified liposomes (RCL) could enter the brain and glioma region, and were internalized by the glioma cells perhaps through acetylcholine receptor-mediated endocytosis pathway. Furthermore, the RCL prolonged the survival time of the glioma-bearing mice from 23 to 33 days, and the inhibition mechanism of the RCL on glioma cell was partly due to cell cycle arrest at the S phase and induction of cell apoptosis. CONCLUSION: This study would provide a potential approach for targeted delivery of drug-loaded liposomes for glioma treatment.

The synthetic thyroid hormone, levothyroxine, protects cholinergic neurons in the hippocampus of naturally aged mice.

The thyroid hormones, triiodothyronine and thyroxine, play important roles in cognitive function during the mammalian lifespan. However, thyroid hormones have not yet been used as a therapeutic agent for normal age-related cognitive deficits. In this study, CD-1 mice (aged 24 months) were intraperitoneally injected with levothyroxine (L-T4; 1.6 µg/kg per day) for 3 consecutive months. Our findings revealed a significant improvement in hippocampal cytoskeletal rearrangement of actin and an increase in serum hormone levels of L-T4-treated aged mice. Furthermore, the survival rate of these mice was dramatically increased from 60% to 93.3%. The Morris water maze task indicated that L-T4 restored impaired spatial memory in aged mice. Furthermore, level of choline acetyltransferase, acetylcholine, and superoxide dismutase were increased in these mice, thus suggesting that a possible mechanism by which L-T4 reversed cognitive impairment was caused by increased activity of these markers. Overall, supplement of low-dosage L-T4 may be a potential therapeutic strategy for normal age-related cognitive deficits.

Prevention of age-related memory deficit in transgenic mice by human choline acetyltransferase.

Choline acetyltransferase (ChAT, acetylCoA:choline O-acetyltransferase, EC 2.3.1.6) is the biosynthetic enzyme of neurotransmitter acetylcholine. Here we showed for the first time that transgenic mice with human ChAT kept excellent learning and memory ability during aging process. Transgenic mice were prepared through microinjection of human ChAT into mouse fertilized eggs, and PCR reaction was used to screen out the transgenic mice. The results of measurements of ChAT activity and acetylcholine level in mouse brain indicated that human ChAT gene was expressed throughout the life of the transgenic mice. The results of step-through test and water maze test suggested that learning and memory ability was improved in transgenic mice compared to that of their age-matched littermates. The results support our idea that supplement of ChAT might serve as a potential therapeutic strategy for cognitive deficit.